case study 2 martorell's leg ulcer

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Case Report
• Published: 23 April 2001

Martorell’s hypertensive leg ulcer: case report and concise review of the literature

• JW Graves 1 ,
• JC Morris 2 &
• SG Sheps 1  

Journal of Human Hypertension volume  15 ,  pages 279–283 ( 2001 ) Cite this article

38 Citations

Metrics details

Hypertensive leg ulcers (Martorell’s ulcers) are a unique form of lower extremity ischaemic leg ulcer. First described by Martorell, and Hines and Farber in the 1940s, these ulcers are defined by pain disproportionate to the size of the ulcer, specific location on the lower extremity, female-to-male predominance, association with long-standing, often poorly, controlled hypertension, and healing response to specific antihypertensive agents. We present a case of Martorell’s hypertensive ischaemic leg ulcer and a concise review of the 104 previous cases in the world’s English literature. Hypertensive ischaemic leg ulcers will be more commonly recognised with a renewed appreciation of the existence of this clinical entity.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 digital issues and online access to articles

111,21 € per year

only 9,27 € per issue

Buy this article

• Purchase on Springer Link
• Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Raynaud phenomenon and digital ulcers in systemic sclerosis

The association between tobacco smoking and systolic toe pressures in active foot ulceration

Patients with healed diabetic foot ulcer represent a cohort at highest risk for future fatal events

Author information, authors and affiliations.

Divisions of Hypertension, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, 55905, MN, USA

JW Graves & SG Sheps

Divisions of Endocrinology, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, 55905, MN, USA

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to JW Graves .

Rights and permissions

Reprints and permissions

About this article

Cite this article.

Graves, J., Morris, J. & Sheps, S. Martorell’s hypertensive leg ulcer: case report and concise review of the literature. J Hum Hypertens 15 , 279–283 (2001). https://doi.org/10.1038/sj.jhh.1001154

Download citation

Received : 10 January 2000

Revised : 20 June 2000

Accepted : 19 September 2000

Published : 23 April 2001

Issue Date : 01 April 2001

DOI : https://doi.org/10.1038/sj.jhh.1001154

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Martorell’s ulcer
• hypertensive ischaemic ulcer
• lower extremity ulcer

This article is cited by

Two cases of hypertensive martorell’s leg ulcers.

• B Bonfiglio

BMC Geriatrics (2010)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Martorell's hypertensive leg ulcer: Case report and concise review of the literature

• Endocrinology, Diabetes, Metabolism, and Nutrition

Research output : Contribution to journal › Article › peer-review

Hypertensive leg ulcers (Martorell's ulcers) are a unique form of lower extremity ischaemic leg ulcer. First described by Martorell, and Hines and Farber in the 1940s, these ulcers are defined by pain disproportionate to the size of the ulcer, specific location on the lower extremity, female-to-male predominance, association with long-standing, often poorly, controlled hypertension, and healing response to specific antihypertensive agents. We present a case of Martorell's hypertensive ischaemic leg ulcer and a concise review of the 104 previous cases in the world's English literature. Hypertensive ischaemic leg ulcers will be more commonly recognised with a renewed appreciation of the existence of this clinical entity.

• Hypertensive ischaemic ulcer
• Lower extremity ulcer
• Martorell's ulcer

ASJC Scopus subject areas

• Internal Medicine

Access to Document

• 10.1038/sj.jhh.1001154

Other files and links

• Link to publication in Scopus
• Link to the citations in Scopus

Fingerprint

• Leg Ulcer Medicine & Life Sciences 100%
• Ulcer Medicine & Life Sciences 53%
• Lower Extremity Medicine & Life Sciences 31%
• Literature Medicine & Life Sciences 21%
• Antihypertensive Agents Medicine & Life Sciences 18%
• Hypertension Medicine & Life Sciences 12%
• Pain Medicine & Life Sciences 11%

T1 - Martorell's hypertensive leg ulcer

T2 - Case report and concise review of the literature

AU - Graves, J. W.

AU - Morris, J. C.

AU - Sheps, S. G.

N2 - Hypertensive leg ulcers (Martorell's ulcers) are a unique form of lower extremity ischaemic leg ulcer. First described by Martorell, and Hines and Farber in the 1940s, these ulcers are defined by pain disproportionate to the size of the ulcer, specific location on the lower extremity, female-to-male predominance, association with long-standing, often poorly, controlled hypertension, and healing response to specific antihypertensive agents. We present a case of Martorell's hypertensive ischaemic leg ulcer and a concise review of the 104 previous cases in the world's English literature. Hypertensive ischaemic leg ulcers will be more commonly recognised with a renewed appreciation of the existence of this clinical entity.

AB - Hypertensive leg ulcers (Martorell's ulcers) are a unique form of lower extremity ischaemic leg ulcer. First described by Martorell, and Hines and Farber in the 1940s, these ulcers are defined by pain disproportionate to the size of the ulcer, specific location on the lower extremity, female-to-male predominance, association with long-standing, often poorly, controlled hypertension, and healing response to specific antihypertensive agents. We present a case of Martorell's hypertensive ischaemic leg ulcer and a concise review of the 104 previous cases in the world's English literature. Hypertensive ischaemic leg ulcers will be more commonly recognised with a renewed appreciation of the existence of this clinical entity.

KW - Hypertensive ischaemic ulcer

KW - Lower extremity ulcer

KW - Martorell's ulcer

UR - http://www.scopus.com/inward/record.url?scp=0035073895&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035073895&partnerID=8YFLogxK

U2 - 10.1038/sj.jhh.1001154

DO - 10.1038/sj.jhh.1001154

M3 - Article

C2 - 11319677

AN - SCOPUS:0035073895

SN - 0950-9240

JO - Journal of Human Hypertension

JF - Journal of Human Hypertension

DermNet provides Google Translate, a free machine translation service. Note that this may not provide an exact translation in all languages

• Skin checker

Martorell ulcer

Author: Dr Delwyn Dyall-Smith FACD, Dermatologist, Australia, 2011. 

What is Martorell ulcer ?

A Martorell ulcer is a very painful ulcer of the lower leg that develops in association with poorly controlled high blood pressure. It is also called Martorell’s hypertensive leg ulcer, arteriosclerotic ulcer of Martorell and Martorell hypertensive ischaemic leg ulcer (Martorell HYTILU).

Who gets Martorell ulcer and why?

Martorell ulcers occur in patients with high blood pressure that is longstanding and often poorly controlled. There is a further association with diabetes mellitus . Martorell ulcers affect women more commonly than men. Most sufferers are in their 50s and 60s, with a reported age range of 41-86 years.

It is believed the ulcer results from narrowing of small blood vessels located in the skin, leading to increased resistance to blood flow, and a lack of blood supply to the skin resulting in skin death. In addition the blood vessels are unable to open up to allow an increase in blood supply. This is the most peripheral form of arterial vascular disease.

Clinical features of Martorell ulcer

Martorell ulcers most commonly occur on the outer aspect of back of the lower leg often just above the ankle. Over the Achilles tendon is another common site.

A significant proportion of patients report the ulcer began after skin trauma , but more commonly it starts as a painful red blister or patch which turns blue then ulcerates.

Ulcer characteristics may include:

• Extreme pain out of proportion to the size and appearance of the ulcer – it is typically described as ‘strong to excruciating’
• Solitary or symmetrical , affecting the same site on both lower legs
• Red-purple inflamed ulcer edge
• Episodes of sudden enlargement due to another area of skin death
• Irregular shape
• Satellite ulcers
• Deep, exposing underlying tendons
• Failure to respond to usual treatments for leg ulcers.

These ulcers typically occur in the absence of significant arterial or venous disease.

Extensive ulceration is associated with a poor outcome.

How is Martorell ulcer diagnosed?

Martorell ulcer should be considered clinically when a patient with longstanding high blood pressure presents with very painful leg ulcer(s) on the outer aspect of the lower leg or over the Achilles tendon. There is no significant disease affecting arteries or veins. Patients with Martorell ulcer do not suffer from rest pain or intermittent claudication (pain in the calf muscles with walking). In addition they do not suffer from kidney disease, so calciphylaxis is excluded.

A deep narrow elliptical incisional skin biopsy across the edge of the ulcer to include both normal skin and the ulcer, and extending down into the subcutaneous fat shows thickening of the arteriolar walls, often with calcium deposits which may resemble calciphylaxis. There is no inflammation of the blood vessels. A punch biopsy from the ulcer does not extend deep enough to find these characteristic changes and the diagnosis may be missed.

Blood tests such as C-reactive protein and white cell count, may be elevated.

Treatment of Martorell ulcer

Treatment is in two parts:

• Better control of blood pressure using medications that open up blood vessels and do not cause constriction of blood vessels. Therefore non-specific beta-blockers should be stopped and calcium channel blockers, specific beta 1-blockers and ACE inhibitors used if possible. A large case series has shown that even a small reduction in blood pressure can have a major impact on ulcer pain and healing.
• Ulcer care usually includes surgical debridement together with compression therapy , subatmospheric pressure technique (vaccuum-assisted closure) and, for large ulcers, skin grafting . Skin grafting leads to a rapid improvement in pain.

Pain relief is required then reduced as appropriate ulcer treatment improves pain. Paracetamol and other nonsteroidal anti- inflammatory drugs are often sufficient but, for severe pain, narcotic analgesics (opiates) may be needed initially.

Antibiotics may be required for secondary bacterial wound infection .

The role for anti-coagulant treatment (blood thinners) and sympathectomy (procedure in which sympathetic nerve fibres are cut) remain unclear at this time.

Preventative measures to reduce the risk of developing Martorell ulcer may include:

• stopping smoking
• compression stockings
• protection from trauma.

This is an important diagnosis to think of if pyoderma gangrenosum is being considered as the treatments are quite different. Immunosuppression is associated with a poor prognosis in Martorell ulcer.

• Graves JW, Morris JC, Sheps SG. Martorell's hypertensive leg ulcer: case report and concise review of the literature. J Hum Hyperten 2001; 15: 279–83. PubMed
• Hafner J, Nobbe S, Partsch H, Läuchli S, Mayer D, Amann-Vesti B, Speich R, Schmid C, Burg G, French LE. Martorell hypertensive ischemic leg ulcer: a model of ischemic subcutaneous arteriolosclerosis. Arch Dermatol. 2010;146:961–8. PubMed
• Vuerstaek JD, Reeder SW, Henquet CJ, Neumann HA. Arteriolosclerotic ulcer of Martorell. J Eur Acad Dermatol Venereol. 2010;24:867–74. PubMed
• Differential diagnosis of leg ulcers
• Erosions and ulcers
• Arterial ulcer
• Bedsores (pressure ulcers)
• Lipodermatosclerosis
• Compression therapy
• Synthetic wound dressings
• Sclerotherapy
• Bioengineered skin

Other websites

• Martorell's Ulcer Revisited  — Medscape Dermatology

Books about skin diseases

• Books about the skin
• Dermatology Made Easy  - second edition

Related information

Sign up to the newsletter.

© 2024 DermNet.

DermNet does not provide an online consultation service. If you have any concerns with your skin or its treatment, see a dermatologist for advice.

• Article Information

Study flowchart and etiologic distribution of 330 screened and treated patients. ABPI indicates ankle-brachial pressure index; HYTILU, hypertensive ischemic leg ulcer; PAD, peripheral arterial disease; and US, ultrasonography.

Decision model for the management of Martorell hypertensive ischemic leg ulcer.

Clinical features of Martorell hypertensive ischemic leg ulcer (HYTILU) located at the laterodorsal lower leg include skin infarction with central necrosis and progressive inflammatory border. Excruciating pain is typical. The clinical appearance of Martorell HYTILU is often confused with pyoderma gangrenosum or with vasculitis.

In approximately 15% of patients, the Achilles tendon can be the next most common location of hypertensive ischemic leg ulcer (HYTILU). When skin necrosis is the only manifestation of Martorell HYTILU, the skin necrosis may be misinterpreted as necrotizing friction blister from footwear.

A skin biopsy specimen from the wound edge of a hypertensive ischemic leg ulcer. The asterisk indicates a subcutaneous arteriole with extensive smooth muscle hyperplasia at the price of a narrowed lumen (increased wall to lumen ratio) (hematoxylin-eosin, original magnification ×4).

A large 5.0 × 0.8-cm spindle-shaped biopsy specimen from healthy-looking skin and skin leading into the wound. Many physicians do not dare to perform such a large biopsy but rather take a punch biopsy from the necrotic wound ground. The figure shows an overview of a cross section of the necrotic border of a Martorell hypertensive ischemic leg ulcer (HYTILU) (A) (hematoxylin-eosin, original magnification ×10). Ironically, when taking a punch biopsy from the wound ground of a Martorell HYTILU, one will find a dense neutrophil infiltrate in a necrotic dermis (B) (hematoxylin-eosin, original magnification ×40). In other words, a superficial wound biopsy can imitate the diagnosis of pyoderma gangrenosum at a histologic level and confirm the erroneous suspicion of pyoderma gangrenosum. A clinician, unaware of the existence of Martorell HYTILU, could perform a superficial wound biopsy and receive a histologic confirmation of pyoderma gangrenosum. If the clinician were to perform a long, narrow, and deep biopsy down to fascia, he or she would find the highly characteristic stenotic arterioles in the subcutis (C) (hematoxylin-eosin, original magnification ×40).

• Clinical Approach to Atypical Wounds With a New Model for Understanding Hypertensive Ulcers Archives of Dermatology Editorial September 1, 2010 Michael L. Shelling, MD; Daniel G. Federman, MD; Robert S. Kirsner, MD, PhD

See More About

Select your interests.

Customize your JAMA Network experience by selecting one or more topics from the list below.

• Academic Medicine
• Acid Base, Electrolytes, Fluids
• Allergy and Clinical Immunology
• American Indian or Alaska Natives
• Anesthesiology
• Anticoagulation
• Art and Images in Psychiatry
• Artificial Intelligence
• Assisted Reproduction
• Bleeding and Transfusion
• Caring for the Critically Ill Patient
• Challenges in Clinical Electrocardiography
• Climate and Health
• Climate Change
• Clinical Challenge
• Clinical Decision Support
• Clinical Implications of Basic Neuroscience
• Clinical Pharmacy and Pharmacology
• Complementary and Alternative Medicine
• Consensus Statements
• Coronavirus (COVID-19)
• Critical Care Medicine
• Cultural Competency
• Dental Medicine
• Dermatology
• Diabetes and Endocrinology
• Diagnostic Test Interpretation
• Drug Development
• Electronic Health Records
• Emergency Medicine
• End of Life, Hospice, Palliative Care
• Environmental Health
• Equity, Diversity, and Inclusion
• Facial Plastic Surgery
• Gastroenterology and Hepatology
• Genetics and Genomics
• Genomics and Precision Health
• Global Health
• Guide to Statistics and Methods
• Hair Disorders
• Health Care Delivery Models
• Health Care Economics, Insurance, Payment
• Health Care Quality
• Health Care Reform
• Health Care Safety
• Health Care Workforce
• Health Disparities
• Health Inequities
• Health Policy
• Health Systems Science
• History of Medicine
• Hypertension
• Images in Neurology
• Implementation Science
• Infectious Diseases
• Innovations in Health Care Delivery
• JAMA Infographic
• Law and Medicine
• Leading Change
• Less is More
• LGBTQIA Medicine
• Lifestyle Behaviors
• Medical Coding
• Medical Devices and Equipment
• Medical Education
• Medical Education and Training
• Medical Journals and Publishing
• Mobile Health and Telemedicine
• Narrative Medicine
• Neuroscience and Psychiatry
• Notable Notes
• Nutrition, Obesity, Exercise
• Obstetrics and Gynecology
• Occupational Health
• Ophthalmology
• Orthopedics
• Otolaryngology
• Pain Medicine
• Palliative Care
• Pathology and Laboratory Medicine
• Patient Care
• Patient Information
• Performance Improvement
• Performance Measures
• Perioperative Care and Consultation
• Pharmacoeconomics
• Pharmacoepidemiology
• Pharmacogenetics
• Pharmacy and Clinical Pharmacology
• Physical Medicine and Rehabilitation
• Physical Therapy
• Physician Leadership
• Population Health
• Primary Care
• Professional Well-being
• Professionalism
• Psychiatry and Behavioral Health
• Public Health
• Pulmonary Medicine
• Regulatory Agencies
• Reproductive Health
• Research, Methods, Statistics
• Resuscitation
• Rheumatology
• Risk Management
• Scientific Discovery and the Future of Medicine
• Shared Decision Making and Communication
• Sleep Medicine
• Sports Medicine
• Stem Cell Transplantation
• Substance Use and Addiction Medicine
• Surgical Innovation
• Surgical Pearls
• Teachable Moment
• Technology and Finance
• The Art of JAMA
• The Arts and Medicine
• The Rational Clinical Examination
• Tobacco and e-Cigarettes
• Translational Medicine
• Trauma and Injury
• Treatment Adherence
• Ultrasonography
• Users' Guide to the Medical Literature
• Vaccination
• Venous Thromboembolism
• Veterans Health
• Women's Health
• Workflow and Process
• Wound Care, Infection, Healing

Others Also Liked

• Download PDF
• X Facebook More LinkedIn

Hafner J , Nobbe S , Partsch H, et al. Martorell Hypertensive Ischemic Leg Ulcer : A Model of Ischemic Subcutaneous Arteriolosclerosis . Arch Dermatol. 2010;146(9):961–968. doi:10.1001/archdermatol.2010.224

Manage citations:

© 2024

• Permissions

Martorell Hypertensive Ischemic Leg Ulcer : A Model of Ischemic Subcutaneous Arteriolosclerosis

Author Affiliations: Departments of Dermatology (Drs Hafner, Nobbe, Läuchli, Burg, and French), Cardiovascular Surgery (Dr Mayer), and Internal Medicine (Drs Amann-Vesti, Speich, and Schmid), University Hospital of Zurich, Zurich, Switzerland; and Department of Dermatology, Wilhelminen Hospital, Vienna, Austria (Dr Partsch [retired]).

• Editorial Clinical Approach to Atypical Wounds With a New Model for Understanding Hypertensive Ulcers Michael L. Shelling, MD; Daniel G. Federman, MD; Robert S. Kirsner, MD, PhD Archives of Dermatology

Objectives   To better define the diagnosis and treatment of Martorell hypertensive ischemic leg ulcer (HYTILU) and to compare Martorell HYTILU with calciphylaxis (calcific uremic arteriolopathy) and nonuremic forms of calciphylaxis.

Design   Retrospective study from 1999 through 2007.

Setting   Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland.

Participants   Of 330 patients with leg ulcers, 31 had a clinical diagnosis of Martorell HYTILU confirmed by dermatopathologic examination.

Main Outcome Measures   Clinical features, suspected diagnosis at initial presentation, cardiovascular risk factors, findings from vascular examination and histologic analysis, specific medical and surgical management, and outcome.

Results   Of the 31 patients, all presented with 1 or multiple painful necrotic skin ulcers on the laterodorsal part of the leg, with bilateral involvement in 16 of 31 cases (52%), and 16 were referred with suspected pyoderma gangrenosum. All patients had arterial hypertension, and 18 (58%) had diabetes. All patients had subcutaneous stenotic arteriolosclerosis on histologic analysis, with medial calcification in 22 of 31 of cases (71%). Martorell HYTILU, calciphylaxis, and nonuremic forms of calciphylaxis shared identical histologic features. Of the 31 patients, 29 (94%) were successfully treated with surgical debridement and split-thickness skin grafting. Three patients (9%) died of sepsis, 2 of whom were undergoing immunosuppressive treatment for wrongly diagnosed pyoderma gangrenosum.

Conclusions   Ischemic subcutaneous arteriolosclerosis is the hallmark of Martorell HYTILU, calciphylaxis, and the nonuremic forms of calciphylaxis. All patients are hypertensive and approximately 60% are diabetic. Martorell HYTILU can easily be confused with pyoderma gangrenosum, which can be detrimental, since the 2 diseases require a completely different treatment strategy.

Martorell hypertensive ischemic leg ulcer (HYTILU) was originally described by Fernandes Martorell in 1945 in Barcelona, Spain. 1 Martorell described 4 obese, hypertensive female patients with painful leg ulcers on the lateral aspect of their legs. One year later, Hines and Farber and coworkers 2 , 3 reported an association of such leg ulcers with the histologic presence of hypertrophic stenotic subcutaneous arterioles and coined the term hypertensive-ischemic ulcer . In 1966, Schnier et al 4 reported a series of 40 patients with HYTILU, pointing out the very characteristic location of the principal lesion on the laterodorsal lower leg. In 1995, Lazareth and Priollet 5 described the benefit of skin grafting for the treatment of l'angiodermite nécrotique , the term used by the French to describe HYTILU, which was confirmed by Henderson et al 6 in a survey on 16 patients. The literature on HYTILU is otherwise scarce, 7 and to our knowledge, studies analyzing the clinical and dermatopathologic characteristics and possible therapies on a significant number of patients do not exist.

At our department, Martorell HYTILU has become one of the leading causes of chronic leg ulceration in the past 10 years. Martorell HYTILU shares striking clinical and histopathological similarities with calciphylaxis (calcific uremic arteriolopathy) 8 - 11 and eutrophication in morbid obesity. 12 The latter has recently been referred to as “calciphylaxis with normal renal and parathyroid function” 13 or “calciphylaxis from nonuremic causes.” 14 This study of a large series of patients with Martorell HYTILU defines common pathophysiologic hallmarks of 4 entities that are linked to ischemic subcutaneous arteriolosclerosis ( Table 1 ) and outlines treatment protocols.

Confusing Martorell HYTILU with pyoderma gangrenosum (PG) can be detrimental to the patient. Necrosectomy (debridement of necrotic tissue), with skin grafting and antibiotic therapy as required, is probably the key to timely and effective treatment of Martorell HYTILU, but an erroneous diagnosis of PG virtually excludes surgical measures from the therapeutic decision. 15

As noted by Weenig et al, 16 one of the risks of misdiagnosing an inflammatory type of skin ulcer as PG is that the systemic immunosuppression used to treat PG exposes the patients to the risk of sepsis. 16 Therefore, this study also aims to clarify the description of Martorell HYTILU and PG to avoid misdiagnosis and therapeutic decisions.

Medical records of 330 patients with leg ulcers who visited our outpatient or inpatient department between 1999 and 2007 were screened for the diagnosis of Martorell HYTILU ( Figure 1 ). We identified 31 patients with both clinically and histologically proven HYTILU, whose files, clinical photodocumentation, and skin biopsy specimens were re-examined. During the same period, 2 patients with calciphylaxis (calcific uremic arteriolopathy) and 1 patient with eutrophication in morbid obesity (calciphylaxis with normal renal and parathyroid function) were treated in the department, and their records were also re-evaluated in the present study. The study was submitted to and approved by the local ethics committee.

Clinical characteristics that were studied included age, sex, wound location, documentation of pain, diagnosis at the time of referral (specifically PG), medication at the time of referral (specifically antihypertensive or antidiabetic drugs and immunosuppression for supposed PG), and cardiovascular risk factors.

Skin biopsy specimens derived from the wound border were re-examined with a focus on the presence of subcutaneous stenotic arteriolosclerosis with or without medial calcification.

Vascular assessment comprised a thorough clinical examination, measurement of the ankle-brachial pressure index (ABPI), segmental oscillography in case of medial calcinosis, and, in the presence of pathologic findings, imaging via fine-needle angiography.

To identify patients with end-stage renal disease (ESRD) or kidney transplant recipients and hence patients with potential calciphylaxis (calcific uremic arteriolopathy) or with a primary hyperparathyroidism, the records of all 31 included patients were checked for renal function and parathyroid hormone and calcium phosphate product levels. The latter two were prospectively determined in the 16 patients who were included in the study between 2005 and 2007.

Our standardized treatment protocol for the management of Martorell HYTILU is summarized in Figure 2 . Basically, the diagnosis is based on the typical history and clinical presentation and confirmed by obtaining a large wedge-shaped biopsy specimen (approximately 5.0 × 0.8 cm, reaching the fascia) starting from healthy skin at the wound border and extending into the necrotic area. Immunosuppression for presumptive PG was stopped and antibiotic treatment initiated as required by the general or local condition. In addition, necrosectomy using adequate—usually tumescent—local anesthesia was undertaken, local negative pressure treatment was started if the wound bed still contained subvital tissue, and split-thickness skin grafting (0.2-mm-thick, meshed graft) was then performed as soon as possible.

Of the 31 patients included, 19 (61%) were female, and the mean age of patients was 72 years (range, 61-91 years). The main clinical observation at presentation was skin necrosis with a polycyclic violaceous-black border localized on the laterodorsal part of the leg ( Figure 3 ), with a surface area ranging from 2 to 242 cm 2 . Skin necrosis involved the entire subcutis down to the fascia. Sixteen patients (52%) had bilateral lower leg necrosis, and the Achilles tendon was the principal wound location in 4 of the 31 of patients (13%) ( Figure 4 and Table 2 ). Pain was typically strong to excruciating. Seven patients (23%) reported a minor trauma to be the initial trigger, whereas the remaining persons reported a spontaneous onset presenting as a violaceous macule or nodule.

All patients had arterial hypertension and were receiving antihypertensive treatment. It was not possible to collect valid data on the history and duration of hypertension because the majority of patients could not recall the year in which hypertension was diagnosed. However, several patients recalled taking antihypertensive medications for more than 20 years. Of the 31 included patients, 18 (58%) had documented type 2 diabetes mellitus ( Table 2 ) and 5 (16%) had a history of cigarette smoking. Of the 25 patients in which lipid levels were recorded, 5 (20%) had elevated serum lipid levels, all of whom were being treated with a statin.

Of the 31 patients, 16 (52%) had a referral letter stating PG as the suspected diagnosis. Of these 16 patients, 9 (56%) were unresponsive to high-dose systemic immunosuppressive drugs, of whom 8 received treatment with high-dose oral steroids associated with steroid-sparing agents (cyclosporine [n = 3], mycophenolate mofetil [n = 3], and intravenous cyclophosphamide pulses [n = 2]) and 1 received cyclosporine monotherapy.

In another 6 patients (19%), necrotizing cutaneous leukocytoclastic vasculitis was mentioned as the likely diagnosis. Three of these patients were treated with oral steroids, resulting in a total of 12 patients (12 of 31 [39%]) taking immunosuppressive treatment at the time of admission.

Re-examination of the histologic specimens revealed stenotic arteriolosclerosis of the subcutaneous arterioles with an inverse wall to lumen ratio ( Figure 5 ). In 22 of 31 patients (71%), medial calcinosis of the subcutaneous arterioles was found to be an additional characteristic feature ( Figure 6 B). Of these 22 patients, 14 (61%) with medial calcinosis of the subcutaneous arterioles were diabetic, compared with 18 of all 31 patients (58%).

Fourteen patients (45%) underwent pathologic arterial screening examinations, with medial calcinosis found in 7 (50%). Peripheral arterial disease (>50% stenosis) was confirmed in all 14 patients, and all had lesions that were amenable to percutaneous transluminal angioplasty ( Table 2 ).

Mönckeberg medial calcinosis with incompressible ankle arteries was documented in 11 of 31 cases (35%). Of these 11 patients, 4 (36%) with incompressible ankle arteries had normal oscillography and, therefore, no further investigations, whereas the remaining 7 (64%) underwent angiography.

None of the 31 patients with Martorell HYTILU had end-stage chronic renal failure, and none were kidney transplant recipients. Creatinine levels and glomerular filtration rates were normal in 25 of 31 patients (84%) and slightly or moderately impaired (creatinine level, 1.38-1.60 mg/dL [reference range, 0.79-1.19 mg/dL] [to convert to micromoles per liter, multiply by 88.4], and glomerular filtration rate, 34-52 mL/min [reference range, >60 mL/min]) in the remaining 5 (16%).

Among 16 of 31 included patients (52%), parathyroid hormone level was slightly raised (72.1-100.8 pg/mL; reference range, 15-65 pg/mL [to convert to nanograms per liter, multiply by 1.0]) in 6 (38%), of whom 4 had normal renal function and 2 had slightly impaired renal function. In all 16 patients, calcium phosphate product level was normal.

In only 2 of the 31 patients (6%), wounds were healed with conservative treatment. The remaining patients had refractory wounds, or even progressive skin necrosis. All of these patients underwent repeated bedside debridement with a disposable ring curette and local anesthesia with EMLA (eutectic mixture of lidocaine and prilocaine) cream, or they underwent sharp necrosectomy in the operating room, usually with tumescent local anesthesia and some required spinal or general anesthesia. Vacuum-assisted negative pressure local wound care was used in 18 patients (58%). Twenty-six patients (85%) received autologous split-thickness skin grafts, of whom 14 (54%) were grafted once; 7 (27%), twice; and 4 (15%), 3 times; and 1 required 6 successive skin grafting procedures.

By the end of the study, 28 patients (91%) survived and finished the treatment protocol with completely healed wounds. Three patients (9%), all of whom had extensive skin necrosis and 2 of whom had received immunosuppressive therapy for supposed PG, died of sepsis during the active phase of disease.

All patients reported strong or even excruciating pain at study entry (8-10 on a visual analog scale ranging from 0 to 10). The multistaged medical treatment of pain consisted sequentially of nonsteroidal anti-inflammatory drugs (particularly paracetamol and metamizol), oral or transcutaneous morphine derivatives, tricyclic antidepressive agents, and pregabalin. Patients who did not respond adequately to this regimen within 5 days of onset were referred to the pain control unit of the department of anesthesiology. Skin grafting was by far the single most effective treatment for pain.

On the basis of our case series and review of the medical literature, 1 - 14 we suggest grouping the 4 medical conditions with ischemic subcutaneous arteriolosclerosis as a common pathophysiologic feature as follows: (1) Martorell HYTILU 1 - 7 ; (2 and 3) calciphylaxis (calcific uremic arteriolopathy) 8 - 11 in its distal and more serious proximal pattern; and (4) nonuremic calciphylaxis with normal renal and parathyroid function (eutrophication in morbid obesity) 12 - 14 ( Table 1 ). This characteristic arteriolar pathologic feature represents the most peripheral type of atherosclerosis and seems to be associated with 2 major cardiovascular risk factors often present in patients with Martorell HYTILU, namely long-standing arterial hypertension (in 100% of cases) and diabetes (frequent).

Martorell HYTILU represents the distal pattern of nonuremic calciphylaxis. 1 - 7 Clinically, it is defined by a rapidly progressive, extremely painful eschar on the laterodorsal side of the leg or on the Achilles tendon. Hypertension and histologically proven subcutaneous arteriolosclerosis (showing medial calcinosis in 70% of specimens) are mandatory to make the diagnosis. The mortality in our series was 9%, and immunosuppression may contribute to increase the risk of potentially fatal septicemia.

Eutrophication 12 represents the proximal pattern of nonuremic calciphylaxis. 13 , 14 Clinically, it is defined by extensive, rapidly progressive and extremely painful eschar formation on the trunk and proximal extremities, particularly on the proximal and inner portion of the thighs, on the abdomen, and on the breasts. 12 - 14 Both macroscopically and microscopically, eutrophication cannot be distinguished from calciphylaxis of the proximal pattern. 9 Case reports of eutrophication describe severe comorbid disease, cancer, and liver cirrhosis. 13 , 14 However, we hypothesize that hypertension and diabetes, which both are regularly found in the context of metabolic syndrome and morbid obesity, may be the driving forces behind calciphylaxis of nonuremic origin. Eutrophication in morbid obesity has been reported to have a mortality of approximately 40% to 60%, 12 - 14 which is comparable to the proximal pattern of calciphylaxis. 8 , 9

In calciphylaxis, an elevated calcium phosphate product level due to secondary hyperparathyroidism has been proposed to be involved in the pathogenesis. 8 - 11 There is good clinical evidence that an elevated calcium phosphate product level increases the risk for cardiovascular events. 17 - 20 By analogy, it would appear probable that it also enhances subcutaneous arteriolosclerosis, but this is not easy to prove. Not all ESRD patients with calciphylaxis exhibit secondary hyperparathyroidism, and parathyroidectomy does not result in clinical improvement in all cases. 9

The matrix protein GLA (serum protein α2–Heremans-Schmid glycoprotein/fetuin A) is an effective vascular and tissue protector against calcification. 21 - 24 Future studies on the aforementioned 4 arteriolosclerosis entities will hopefully investigate the role of this protein in disease pathogenesis. Matrix GLA requires vitamin K–dependent γ-carboxylation to become active, which would support the impression of several authors that the condition of patients with calciphylaxis may deteriorate when they are placed on warfarin therapy. 11

Martorell HYTILU is certainly more common than diagnosed and reported in the literature (3 case series in the literature from 1966-1995). 4 - 6 In our series, 50% of patients with Martorell HYTILU were admitted under the referral diagnosis of PG and another 20% under the diagnosis of necrotizing vasculitis. In the literature, there are a considerable number of cases that indeed could represent Martorell HYTILU instead of “leg ulcers in calcinosis cutis” 25 or, more commonly, PG. 26 - 29 Moreover, case series reporting the successful surgical management of PG by skin grafts should probably be revisited taking into consideration Martorell HYTILU. 26 - 29

Confusing Martorell HYTILU with entities such as PG or vasculitis can be deleterious, 16 since management of the latter 2 diseases is completely different ( Table 3 ). Martorell HYTILU requires anti-infectious treatment and wound surgery, and immunosuppression may expose these patients to an increased risk of septicemia. Martorell HYTILU is an extremely painful eschar that usually occurs on the laterodorsal side of the leg in hypertensive patients aged 60 to 75 years, whereas PG presents as more superficial pustular skin breakdown with a less precise location and 50% of patients have one of the characteristically associated diseases such as inflammatory bowel disease. Histologic proof of subcutaneous arteriolosclerosis ( Figure 5 and Figure 6 A and B) is warranted before making the diagnosis of Martorell HYTILU. Since the results from superficial wound biopsies (“punch” biopsies) can be totally misleading, special attention should be paid to the quality of the biopsy specimen (long, narrow, and deep elliptical biopsy specimen from healthy- looking skin to necrotic skin) ( Figure 6 ).

The wound border in Martorell HYTILU is strikingly inflammatory, so that the existing confusion with PG is to some extent understandable. As with PG, serological parameters of Martorell HYTILU, such as C-reactive protein level and leukocyte counts, can also be markedly elevated during the active phase of disease progression. Martorell HYTILU is initially an atherosclerotic vascular process, and the observed inflammatory response is secondary to the tissue breakdown resulting from local ischemia. The exact cause and pathomechanism of the inflammatory bursts that can be observed during disease progression in Martorell HYTILU are unknown and should be further investigated in future studies.

Duncan and Faris 30 compared the skin perfusion of patients with Martorell HYTILU to that of patients with peripheral arterial disease and normal controls, using a scintigraphic method measuring the elimination of intradermally injected technetium Tc 99m under standardized external compression. Patients with Martorell HYTILU had reduced skin perfusion pressure comparable to that in peripheral arterial disease, which was caused by the locally increased vascular resistance instead of a reduced arterial inflow.

Primary (“essential”) arterial hypertension is mainly the result of increased peripheral vascular resistance, which is essentially regulated via the tonus of arterioles. 31 Long-standing arteriolar vasoconstriction can lead to a fixed increase in vessel wall thickness and an inverse wall to lumen ratio (“athletic” arterioles as described by Hines and Farber and colleagues 2 , 3 ) ( Figure 5 ). The specificity of this finding for the diagnosis of Martorell HYTILU has not been defined. This could be done by a comparative study on cadaveric skin of the laterodorsal leg of a control group of patients.

Some authors believe that arteriole thrombosis is a decisive criterion for making a diagnosis of ischemic arteriolosclerosis, particularly in calciphylaxis 7 , 8 We cannot confirm this hypothesis, since approximately half of the arterioles examined in our specimens were patent. Arteriole thrombosis can occur either primarily or subsequent to tissue breakdown, and the two cannot be distinguished by histopathologic analysis. However, this question could be addressed in future studies using serial sections of the wound border of larger necrosectomy specimens.

The characteristic location of Martorell HYTILU on the laterodorsal side of the leg or the Achilles tendon 4 is not explained to date, but it is most probably related to the anatomy of calf arteries, arterial perforators, and the distribution of subcutaneous arterioles in the leg. Corrosion preparations of amputated limbs of patients with known subcutaneous arteriolosclerosis or postmortem investigations could be helpful in addressing these open questions.

Recent reports promise progress in both conservative and surgical treatment of uremic and nonuremic forms of ischemic arteriolosclerosis. The introduction of the calcimimetic cinecalcet 32 and of the polymeric (and calcium-free) intestinal phosphate binder sevelamer 33 seem to have a beneficial effect on the incidence of macrovascular events in patients with relevant medium-size artery (such as coronary artery) calcification. Cinecalcet has at least been used twice successfully to treat patients with calciphylaxis 11 ; however, these promising reports need to be validated in larger series of patients or, ideally, controlled studies. Of even more interest is the intravenous use of sodium thiosulfate for classic calciphylaxis 34 as well as nonuremic forms of calciphylaxis. 35 The beneficial effect of sodium thiosulfate is ascribed to its potential to dissolve already precipitated calcium salts in the vessels and tissues. 34 , 35 Empirically, it has been administered 3 times per week intravenously, eg, before dialysis in patients with ESRD. It causes extensive metabolic acidosis and therefore requires specialized monitoring and equipment.

Adequate therapeutic control of hypertension does not appear to be sufficient for the treatment of Martorell HYTILU. All our patients with newly diagnosed Martorell HYTILU were receiving adequate antihypertensive treatment on admission. It seems that the active process of Martorell HYTILU cannot be stopped or reversed with intensified medical antihypertensive treatment alone. Future epidemiologic studies may answer the question as to how well optimal antihypertensive control over many years may prevent the occurrence of Martorell HYTILU.

The incidence of Martorell HYTILU may be on the rise owing to better recognition, an actual increase in incidence, or both. We hypothesize that improved antihypertensive treatment helps to extend a patient's life expectancy and decreases the rate of death due to major cardiovascular complications early in life, specifically myocardial infarction and stroke, which may have contributed to the apparent increase in frequency of Martorell HYTILU. Martorell HYTILU may thus be understood as late “minor” vascular complication of long-standing arterial hypertension in a population that benefits from improved antihypertensive treatment.

Ischemic arteriolosclerosis appears to be a unifying clinicopathological concept for 4 clinical entities that share a common pathophysiologic mechanism, namely (1) distal calciphylaxis (uremic); (2) distal Martorell HYTILU (nonuremic); (3) proximal calciphylaxis (uremic); and (4) eutrophication in morbid obesity or proximal nonuremic calciphylaxis. We suggest that ischemic subcutaneous arteriolosclerosis may be caused by 2 well-established classic cardiovascular risk factors: long-standing arterial hypertension and diabetes. For disease management, it is of utmost importance that these diseases are not confused with PG or necrotizing vasculitis because their treatment is completely different (namely surgical), and exposing patients with tissue necrosis due to ischemic arteriolosclerosis to systemic immunosuppression may raise the risk of septicemia.

Future studies should address the role of the calcification protective matrix protein GLA, as well as the cytokine pattern during the inflammatory phase of progressive tissue breakdown that characterizes the aforementioned diseases causing ischemic arteriolosclerosis and skin lesions. Furthermore, morphological questions regarding the vascular pathologic mechanisms (eg, the role of calcification, intimal hyperplasia, and thrombosis) and the peculiar location of the skin necroses in Martorell HYTILU should be further studied. Therapeutic studies may help define the value of the nonsurgical approach using sodium thiosulfate compared with the surgical approach using early escharectomy and mesh grafting.

Correspondence: Jürg Hafner, MD, Department of Dermatology, University Hospital of Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland ( [email protected] ).

Accepted for Publication: February 6, 2010.

Author Contributions: All of the authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design : Hafner. Acquisition of data : Hafner, Nobbe, Läuchli, Mayer, and Speich. Analysis and interpretation of data : Hafner, Nobbe, Partsch, Läuchli, Mayer, Amann-Vesti, Speich, Schmid, Burg, and French. Drafting of the manuscript : Hafner, Nobbe, Partsch, and French. Critical revision of the manuscript for important intellectual content : Hafner, Nobbe, Partsch, Läuchli, Mayer, Amann-Vesti, Speich, Schmid, Burg, and French. Statistical analysis : Nobbe. Administrative, technical, and material support : Hafner, Nobbe, Partsch, Läuchli, and Mayer. Study supervision : Hafner, Partsch, Schmid, and French.

Financial Disclosure: None reported.

• Register for email alerts with links to free full-text articles
• Access PDFs of free articles
• Manage your interests
• Save searches and receive search alerts

Investigative Report

Julia Deinsberger 1,2 , Jonas Brugger 3 , Philipp Tschandl 2 , Barbara Meier-Schiesser 4 , Florian Anzengruber 4 , Simon Bossart 5 , Stanislava Tzaneva 2 , Peter Petzelbauer 1,2 , Kornelia Böhler 2 , Helmut Beltraminelli 5 , Jürg Hafner 4 and Benedikt Weber 1,2,4,5

1 Skin and Endothelium Research Division (SERD), Department of Dermatology, 2 Department of Dermatology, 3 Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Vienna, Austria, 4 Department of Dermatology, University Hospital of Zurich, Zurich, and 5 Department of Dermatology, Inselspital Bern University Hospital, University of Bern, Bern, Switzerland

Clinical differential diagnosis of arteriolosclerotic ulcers of Martorell is challenging due to the lack of clearly affirmative instrument-based diagnostic criteria. The aim of this study was to develop vascular histomorphological diagnostic criteria differentiating Martorell ulcers from other types of leg ulcers. The histomorphology of patients diagnosed with arteriolosclerotic ulcers of Martorell ( n  = 67) was compared with that of patients with venous leg ulcers, necrotizing leukocytoclastic vasculitis, pyoderma gangrenosum, and non-ulcerative controls ( n  = 15 each). In a multivariable logistic regression model, the rates of arteriolar calcification (odds ratio (OR) 42.71, 95% confidence interval (CI) 7.43–443.96, p  < 0.001) and subendothelial hyalinosis (OR 29.28, 95% CI 4.88–278.21, p  <0.001) were significantly higher in arteriolosclerotic ulcers of Martorell. Arteriolar cellularity was significantly lower in Martorell ulcers than in controls (OR 0.003, 95 CI < 0.001–0.97, p  = 0.05). However, the wall-to-lumen ratio was similar in all ulcers (OR 0.975, 95% CI 0.598–2.04, p  =0.929). Based on the Youden index, a wall cellularity of < 0.24 cells/100 μm 2 was determined as the optimum cut-off point (sensitivity 0.955, specificity 0.944). Thus, arteriolar calcification, subendothelial hyalinosis, and arteriolar cellularity revealed high discriminatory power for arteriolosclerotic ulcers of Martorell.

Key words: arteriolosclerosis; Martorell; leg ulcer; histomorphology; hyalinosis.

Accepted Apr 14, 2021; Epub ahead of print Apr 15, 2021

Acta Derm Venereol 2021; 101: adv00449.

doi: 10.2340/00015555-3804

Corr : Benedikt Weber, MD PhD, Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, AT-1090 Vienna, Austria. E-mail: [email protected]

The arteriolosclerotic ulcer of Martorell is characterized by necrotic leg ulcers and is associated with long-standing arterial hypertension. Differential diagnosis, however, is challenging due to a lack of clearly affirmative instrument-based diagnostic criteria. This study provides quantitative histomorphological information on arteriolar wall changes in patients with arteriolosclerotic ulcer of Martorell in comparison with ulcerative and/or non-ulcerative controls. This information may facilitate the histological diagnosis, differentiating Martorell ulcers from other types of leg ulcers, and may also contribute to a better understanding of the aetiopathogenesis of the disease.

T he differential diagnosis of leg ulcers covers a wide range of diagnoses, often posing a difficult diagnostic challenge. Approximately 75% of all ulcers occur due to vascular aetiologies (1). While most leg ulcers are caused by chronic venous insufficiency (2), arterial disease represents the second leading cause (3). Besides peripheral arterial occlusive disease, stenotic diseases of the cutaneous arterioles are also significant. Originally described by Fernando Martorell in 1945 (4, 5), the arteriolosclerotic ulcer of Martorell (ASUM) is defined by several characteristics. These include location of the ulcer on the lower leg, absence of relevant macrovascular diseases, disproportionate pain, and longstanding arterial hypertension (4, 5). It is characterized by skin infarctions, presenting with deep necrotic ulcers and purple-reddish edges (6). Although the exact prevalence of ASUM remains to be elucidated, recent reports estimate that it accounts for up to 5% of all leg ulcers (7). Treatment with sharp necrosectomy, followed by vacuum-assisted negative pressure and split-thickness skin grafting, has achieved the most successful results, leading to remission in up to 90% of patients (7). However, the clinical differential diagnosis is challenging, given the lack of clearly affirmative instrument-based diagnostic criteria. Nevertheless, the differential diagnosis of ASUM harbours the risk of underdiagnosis or misdiagnosis. This is particularly disconcerting considering the reports of frequent misdiagnosis with necrotizing leukocytoclastic vasculitis or pyoderma gangrenosum (PG), potentially resulting in fatal complications due to immunosuppressive treatment (1, 7–10). Previously published diagnostic criteria (4, 5, 11), such as arterial hypertension or tissue necrosis, are not specific to ASUM. Thus, the criteria can only be used to stratify risk populations. In addition, considering that the patient population of ASUM consists primarily of multimorbid elderly patients, mixed ulcer aetiologies are frequent (7, 12–14). Uncovering a potential arteriolosclerotic component in these cases, based simply on clinical criteria, seems impossible. Therefore, histological assessment of peri-ulcerative skin biopsies has gained increasing interest over the years. Although several authors have advocated for a bioptic assessment in suspected cases (7, 13, 15), others question its value (16, 17). Since the first report on histopathology in ASUM by Faber & Hines (18), several different “typical” histological findings in patients with ASUM have been reported. Accordingly, histological investigation of peri-ulcerative biopsy specimens evolved into an ancillary element of its diagnosis (6, 13, 19) ( Table SI ). However, the specificity of these findings has been questioned, and remains a subject of ongoing controversial scientific discussions. Currently, there are no generally accepted and validated histological criteria for ASUM (6, 8, 16, 20, 21). In addition, no comparative study of the histomorphology of ASUM vs other types of leg ulcers has been conducted.

Therefore, this study aimed at a systematic multimodal microstructural analysis of deep skin biopsies of a large series of patients diagnosed with ASUM in 3 independent European academic dermatological wound centres. To determine the specificity of the results, the histopathological and microstructural vascular findings of patients diagnosed with ASUM were systematically compared with patients with venous leg ulcers, necrotizing leukocytoclastic vasculitis, and pyoderma gangrenosum, representing the most important clinical differential diagnoses of ASUM. In addition, findings were compared with samples from non-ulcerative skin of non-hypertensive and hypertensive controls. These results may serve as a basis for the development of histological “minimal diagnostic criteria”, compatible with the diagnosis of ASUM in suspected cases.

This study was conducted in compliance with Good Clinical Practice and the Declaration of Helsinki (22) and in accordance with the Austrian and Swiss laws. The study protocols and patient enrolment were formally approved by the local ethics committees at the Medical University of Vienna (number 2017-1171), the Canton of Zurich (number 2017-00290), and the Canton of Bern (number 2017-01216).

Case selection

This study included patients diagnosed with ASUM between 1998 and 2019 at the University Hospital of Vienna in Austria, the University Hospital of Zurich in Switzerland, and the University Hospital of Bern in Switzerland. The “ASUM” diagnosis was based on clinical and histological presentations (for details, see Appendix S1 ). The ASUM study group was compared with the following control groups: venous leg ulcers (Venous), necrotizing leukocytoclastic vasculitis (Vasculitis), pyoderma gangrenosum (PG), non-ulcerative skin of non-hypertensive controls (Control N), and non-ulcerative skin of hypertensive controls (Control H). Skin biopsies from ulcers were performed for diagnostic reasons, according to previous recommendations on biopsies in patients with ASUM (1, 7, 13). Biopsies extended from the edge of the ulceration, including: ( i ) the healthy adjacent skin, ( ii ) the wound margin, and ( iii ) the ulcer ground itself. Biopsies were performed in an elliptical shape with a length:width ratio of > 3:1 and extended into the deep subcutaneous tissue (in most cases down to the fascia of the muscle). All non-ulcerative healthy control samples were recruited from patients receiving re-excisions after previous tumour excisions on the lower leg (without signs of the initially described neoplastic tissue).

Histological analysis

All histological specimens were initially stained with haematoxylin and eosin (H&E). Based on previous publications on the vascular histological criteria of ASUM (see Table SI ), the following criteria were selected for in-depth assessment of arterioles at the dermal-subcutaneous junction: ( i ) quantification of the wall-to-lumen ratio according to a method adapted from a previously published protocol (23); ( ii ) quantification of subendothelial “hyalinosis”, defined as the accumulation of an amorphous, eosinophilic substance, supposedly consisting of plasma proteins, collagen, lipids and basement membrane material, in the media of arteriolar vessels, including the calculation of a cellularity index (nuclei per 100 μm 2 vessel wall surface); ( iii ) evaluation of the presence of arteriolar calcification; and ( iv ) scoring of periarteriolitis. All non-artificial intelligence histological assessments were independently performed by 2 operators (for details, see Appendix S1 ).

Convolutional neural network analysis

To evaluate the vascular histomorphological distinguishability between ASUM and the control groups, an operator-independent analysis was performed using convolutional neural networks (CNN). The learned task of the CNN was to predict the diagnosis of a case based on a series of manually acquired histological image crops, showing vessels and their immediate surroundings at the dermal-subcutis junction. Target classes were binarized to “ASUM” and “Not ASUM”. Twenty percent of the cases were split for final test evaluations. To obtain predictions for a case rather than single images, the predicted probability of “ASUM” was averaged over all images of a single case. The resulting value was measured for cases included in the validation set, and an optimal cut-off value with the highest sensitivity and specificity was set. Given that ASUM is a rare type of leg ulcer, more emphasis was placed on sensitivity; and it was provided twice the weight on this measurement. The test set included 523 images with a mean of 8 images (standard deviation ±  6.5) per lesion (for details, see Appendix S1 ).

Discriminatory power and biostatistical analysis

For statistical comparison, Fisher’s exact tests were performed for binary variables and Wilcoxon–Mann–Whitney tests for continuous variables. p  ≤ 0.05 were considered statically significant. p  ≤ 0.01 were considered highly significant. The significance levels were adjusted using a Bonferroni post-hoc correction (24), if applicable. Continuous variables are depicted as medians (interquartile ranges; IQR), if not indicated otherwise. A logistic regression model was defined, using the diagnosis of ASUM vs controls as the target variable and wall-to-lumen ratio, calcification, hyalinosis, and cellularity index as explanatory variables. A second model with only calcification and cellularity index as explanatory variables was defined. Receiver operating characteristic (ROC) curves were generated to test the goodness of both models. Optimal cut-off values for cellularity dependent on the presence of calcification for ASUM vs controls were obtained by calculating the Youden index in the model that included only calcification and cellularity as the explanatory variables. All statistical analyses were performed using IBM SPSS Statistics 24 (IBM Inc., Armonk, NY, USA) or R-Version 3.6.1 (25) (for details, see Appendix S1 ).

Case selection and patient characteristics

A total of 67 patients with ASUM passed the eligibility criteria. In addition, 15 patients per control group (Venous, Vasculitis, PG, Control N, Control H) were selected for the study. Altogether, 156 samples from 142 patients were analysed, resulting in an assessment of 921 arterioles.

All 67 (100%) patients with ASUM had been diagnosed with arterial hypertension, 33 (49%) had diabetes mellitus type II (DM II), 12 (18%) had renal insufficiency, 12 (18%) had peripheral arterial occlusive disease (PAOD stage I), and 16 (24%) had chronic venous disease (CVD, Clinical-Etiological-Anatomical-Pathophysiological stage < C4). All patient characteristics are summarized in Table SII .

Arteriolar hyalinosis

Arteriolar subendothelial hyalinosis is characterized by the deposition of glassy, amorphous fibrosclerotic material in arteriolar walls. Based on conventional H&E histology, 62 (93%) patients with ASUM showed hyalinized arteriolar vessels. This was significantly more than that in all control groups (all p  < 0.001), in which hyalinization could only be detected sporadically. The median share of hyalinized vessels in ASUM samples was 50% (28.57–70.00), which was also significantly higher than that in all other groups (0%, 0.00–0.00, p  < 0.001) ( Fig. 1 a).

Fig. 1. Assessment of hyalinosis and arteriolar wall-to-lumen ratio. (a) Elastica staining of a dermo-hypodermal arteriole that shows subendothelial hyalinization ( asterisk indicates hyalinized area) ( left ). Number of patients with hyalinized vessels (in %) ( middle ) and number of hyalinized vessels per patient (in %) ( right ). (b) Method for the calculation of the cellularity index (cells/100 μm 2 ) ( left ) and comparison of study groups ( right ), (c) Quantification of arteriolar wall/lumen ratio (AWLR) showing the formula used ( left ), examples (middle; N.d.: not definable) and AWLR of the study groups ( right ). Boxplots are plotted with median, interquartile range (IQR) and 5 th –95 th percentiles. Outliers are indicated as dots. ns indicates not significant, *significant ( p  < 0.05) and **highly significant ( p  < 0.01) results, comparing the arteriolosclerotic ulcer of Martorell (ASUM) group with the respective control group. Venous: venous leg ulcers; Vasculitis: necrotizing leukocytoclastic vasculitis;

Cellularity index

To quantify the fibrosclerotic subendothelial changes (“hyalinosis”) resulting in acellular concentric matrix structures in the arteriolar wall, the cellularity index was determined. The cellularity index is defined as the number of nuclei per 100 μm 2 of arteriolar wall surface (Fig. 1b). The cellularity index of arterioles in patients with ASUM (0.13, 0.06–0.27) was significantly lower than that in all control groups (Venous: 0.53, 0.28–0.69, p  < 0.001; Vasculitis: 0.44, 0.31–0.63, p  < 0.001; PG: 0.52, 0.47–0.63, p  < 0.001; Control N:0.47, 0.40–0.62, p  < 0.001; Control H: 0.50, 0.40–0.57, p  < 0.001).

Wall-to-lumen ratio

To quantify and compare the luminal obstruction, the ratio between the thickness of the arteriolar wall and the lumen was determined according to a standardized protocol (23). The median arteriolar wall-to-lumen ratio (AWLR) in the ASUM samples was 1.74 (1.33–2.18). AWLRs in the control groups were 0.96 (0.72–1.39), 1.01 (0.86–1.33), 1.1 (0.82–1.75), 1.1 (0.78–1.43), and 1.23 (0.84–1.62) for Venous ulcers, Vasculitis, PG, Control N, and Control H, respectively (all p  < 0.05, Fig. 1c). However, despite the statistical significance, a more detailed analysis revealed that the quartiles of patients with ASUM and control groups showed a substantial overlap, indicating a low discriminatory power.

Calcification

Arteriolar calcification was present in 51 (76%) patients with ASUM. In all control groups, arteriolar calcification could only be seen sporadically compared with that in the ASUM group (all p  < 0.001, Fig. 2 a).

Fig. 2. Assessment of calcification and periarteriolitis. (a) von Kossa-stained arteriolosclerotic ulcer of Martorell (ASUM) sample showing an arteriolar vessel with calcification ( left ) and number of patients with calcified vessels (in %) ( right ), (b) Periarteriolitis grading scale from 0 (no periarteriolitis) to 4 (severe periarteriolitis) (c) Number of vessels with periarteriolitis per patient (in %, left ) and mean periarteriolitis grade of vessels per patient ( right ). Column bar graphs are displayed with mean and standard deviation. ns: not significant, *significant ( p  < 0.05) and **highly significant ( p  < 0.01) results comparing the ASUM group with the respective control group. Magnification: a) von Kossa staining: 400x. b) Periarteriolitis Grading: 0, 1, 2: 250x; 3, 4: 400x. Venous: venous leg ulcers; Vasculitis: necrotizing leukocytoclastic vasculitis; PG: pyoderma gangrenosum; Control N: non-ulcerative skin of non-hypertensive controls; Control H: non-ulcerative skin of hypertensive controls.

Periarteriolitis

Periarteriolitis is characterized by immune cell infiltrates next to the arteriolar wall. In 61 (91%) patients with ASUM, periarteriolitis was detected in at least one vessel, as well as in 10 (67%), 13 (87%), 15 (100%), 7 (47%) and 6 (40%) patients of the Venous, Vasculitis, PG, Control N, and Control H groups, respectively. The mean percentage of affected vessels was 73% ( ±  31.3), 44% ( ±  41.3), 82% ( ±  35.9), 98.7% ( ±  5.2), 22.1% ( ±  28.3) and 18.9% ( ±  31.4) in the ASUM, Venous, Vasculitis, PG, Control N, and Control H groups, respectively (Fig. 2c). To quantify the severity, periarteriolitis was graded from 0 (no periarteriolitis) to 4 (severe periarteriolitis). The median severity scores were 1.45 (0.79–1.85), 0.56 (0.00–2.67), 1.00 (1.00–2.00), 3.00 (2.20–4.00), 0.00 (0.00–0.50) and 0.00 (0.00–0.25) for the ASUM, Venous, Vasculitis, PG, Control N, and Control H groups, respectively. In both assessments, only the differences in the ASUM group compared with those in the PG, Control N, and Control H groups were statistically significant ( p  < 0.001, Fig. 2c).

Convolutional neural network (CNN) analysis was performed to evaluate the histomorphological distinguishability between the ASUM and control groups. Automated predictions of 523 test images showed a mean sensitivity of 0.882 (95% CI 0.834–0.931), specificity of 0.7 (95% CI 0.446–0.954), and an area under the ROC curve (AUC) of 0.889 (95% CI 0.824–0.995). Fig. 3 a shows the application of Grad-CAM (26) to image crops, where image regions with the 200 highest and lowest activation values for ASUM were extracted to interpret probably useful distinctive features, as perceived by the CNN. Manual qualitative post-hoc analysis of the resulting image regions with the highest activation for ASUM showed hypocellular (81%), lamellar convex (19%), and strongly eosinophilic (3.5%) features, corresponding to hyalinosis and basophilic regions indicating calcification (13.5%).

Fig. 3. Convolutional neural network (CNN) analysis and logistic regression model. (a) Analysis of a convolutional neural network trained to distinguish arteriolosclerotic ulcer of Martorell (ASUM) from controls, based on vessel-centred image crops. Grad-CAM (26) analysis for ASUM-prediction on an example image ( upper left ) shows the highest activation within the vessel wall ( upper middle and right ). Extraction of the 200 image areas of the highest and lowest ASUM-activation of all training and test images ( lower left and middle ) indicate more eosinophilic colour and hypocellularity as objective distinctive features. Manual review of highly ASUM-activated areas of the test images is shown on the right , (b) Receiver operating characteristic (ROC) curve of the logistic regression model with the diagnosis ASUM vs controls as the target variable and wall/lumen ratio, calcification, hyalinosis and cellularity as the explanatory variables ( red ) and with cellularity and calcification as explanatory variables ( blue ). (c) Evaluation of ASUM and controls using 2 criteria, cellularity index (Cel) < 0.24 and presence of calcification (Cal). Purple box indicates patients, who fulfil at least 1 criterion. The blue box indicates patients, who fulfil none of the criteria. AUC: Area under the curve.

A logistic regression model was defined using the diagnosis of ASUM vs controls as target variable and wall-to-lumen ratio , calcification, hyalinosis and cellularity index as explanatory variables. A second model with only calcification and cellularity index as explanatory variables was calculated. Odds ratios (OR) for calcification, hyalinosis, and cellularity were significantly different from 1. Calcified vessels were more likely found in patients with ASUM (OR 42.7, 95% CI 7.4–444.0, p  < 0.001). Similarly, patients with ASUM were more likely to have vessels with hyalinosis (OR 29.3, 95% CI 4.9–278.2, p  < 0.001). Patients with ASUM showed lower cellularity (OR 0.003, 95% CI < 0.001–0.97, p  = 0.05). The AWLR did not significantly differ (OR 0.98, 95% CI 0.60–2.04, p  = 0.929). The AUC values of 0.983 (all parameters included) and 0.971 (only cellularity and calcification) suggest a good diagnostic ability of both models (Fig. 3b).

The optimal cut-off values for cellularity based on the Youden index were 0.24 (if no calcification was observed) and 0.64 (if calcification was observed). Classifying individuals with lower cellularity than the above-mentioned thresholds will result in a sensitivity of 0.955 and a specificity of 0.944 for the diagnosis of ASUM. When “cellularity < 0.24” and “presence of calcification” were applied as criteria, 97% of patients with ASUM and only 5.3% of the controls fulfilled at least one of the criteria (Fig. 3c and Fig. S1 ).

The presence of hyalinosis and calcification in patients with ASUM did not differ significantly depending on the comorbidities, including DM II, chronic kidney disease, PAOD, and CVI. However, calcification of arterioles was significantly more frequent in patients taking vitamin K antagonists (92% vs 67%; p  = 0.036; Fig. 4 ).

Fig. 4. Presence of hyalinization and calcification in arteriolosclerotic ulcer of Martorell (ASUM), dependent on comorbidities. Presence of hyalinization and calcification in samples of patients with ASUM is dependent on the following comorbidities: arterial hypertension, diabetes mellitus type II (Diabetes), peripheral arterial occlusive disease (PAOD), chronic venous disease (CVD), and intake of vitamin K inhibitors. ns: not significant, *significant ( p  <0.05) and **highly significant ( p  <0.01) results.

ASUM represents an important differential diagnosis of leg ulcers of vascular origin. However, its diagnosis is challenging, given the lack of clearly affirmative instrument-based diagnostic criteria. Consequently, ASUM poses a major risk of underdiagnosis or misdiagnosis, which is particularly disconcerting considering reports of misdiagnosis with other types of leg ulcers, potentially resulting in fatal complications due to immunosuppressive treatment (1, 7–10). Although several different histological findings in patients with ASUM have been reported, there are no generally accepted, validated histological criteria for ASUM available to date (6, 8, 16, 20, 21). The presence of “stenosing arteriolosclerosis”, composed of hyalinosis, muscular hypertrophy, and calcification, has been considered the histological hallmark of ASUM by several authors (6, 13, 18, 19). Hyalinosis, which is characterized by the accumulation of an amorphous eosinophilic substance, supposedly consisting of plasma proteins, collagen, lipids, and basement membrane material, in the media of arteriolar vessels, is mostly accompanied by the loss of smooth muscle cells involving hardening and loss of elasticity of the arteriolar wall (27–29). Although it has been reported by several authors (7, 13, 20, 30, 31), the term “hyalinosis” represents a rather unspecific term. The exact molecular composition of these hyaline subendothelial deposits in ASUM has not been elucidated thus far. However, given the reports on similar histological changes in some non-ulcerative hypertensive patients (23), the specificity of these findings has been questioned (8, 16).

The aim of the present study was to perform a systematic multimodal microstructural comparative analysis of skin biopsies of a large series of patients diagnosed with ASUM and different ulcerative and non-ulcerative control groups. To achieve a maximum number of typical ASUM cases, the patient material from 3 independent European wound care centres was combined. Stringent eligibility criteria were initially applied to exclude ulcers that may also harbour another, particularly macrovascular, aetiological component. To investigate their specificity, the histological signs of arteriolosclerosis and -stenosis found in ASUM were compared with the most important clinical differential diagnoses of ASUM, namely venous leg ulcers, necrotizing leukocytoclastic vasculitis, pyoderma gangraenosum, and non-ulcerative non-hypertensive as well as hypertensive controls. A multivariable regression model with ASUM as the target variable and wall-to-lumen ratio, calcification, hyalinosis, and cellularity as explanatory variables showed that calcified vessels occurred significantly more often in patients with ASUM in addition to vessels with hyalinosis. While the AWLR did not significantly differ, the cellularity indices were significantly higher in all control groups. Therefore, arteriolar calcification, subendothelial hyalinosis, and decreased cellularity (with a cellularity index of < 0.24 cells/100 μm 2 representing the optimum cut-off value based on the Youden index) revealed high discriminatory power for ASUM compared with that for ulcerative and non-ulcerative controls.

These observations were supported by an operator-independent CNN analysis, as the image regions with highest activation for ASUM showed hypocellular, lamellar convex, and eosinophilic regions corresponding to hyalinosis, and strongly basophilic regions corresponding to calcification.

The presence of hyalinosis and calcification did not differ based on comorbidities, including DM II, chronic kidney disease, PAOD, and CVI. However, calcification of arterioles was significantly more frequent in patients taking vitamin K antagonists. This is consistent with the hypothesis that vitamin K deficiency promotes vascular calcification by decreasing the activation of matrix Gla-protein, which is synthesized by vascular smooth muscle and endothelial cells and acts as a strong inhibitor of vascular calcification by keeping the extracellular matrix free of calcium deposits (32–34).

Study limitations

This study has several limitations. One major limitation is the retrospective study design. The patient data was collected from 3 different study centres and finally combined to achieve the maximum number of cases. In addition, differences in diagnostic work-up and histological sample processing cannot be fully excluded. Due to the rather limited incidence of the disease, patients with ASUM were collected over a long study period of 21 years, which brings about a heterogeneous study population, particularly regarding therapeutic measures of ASUM as well as of secondary factors, such as the use of anticoagulants or the use of different standard antihypertensive drugs, which has changed over the years. These differences in pharmaceutical interventions might have also had an impact on the disease course and histological findings, such as the presence of arteriolar calcification. Several patients had to be excluded a priori , due to the presence of a relevant concomitant macrovascular disease. However, this selection process also represents a potential bias with regard to the extrapolation of the findings to a non-selected patient population in daily clinical routine.

This study provides quantitative histomorphological information on arteriolar wall changes in patients with ASUM in comparison with that in ulcerative and/or non-ulcerative controls. Overall, both manual and operator-independent computational histomorphological analysis suggest arteriolar calcification and hyalinosis (quantified by decreased wall cellularity, particularly < 0.24 cells/100 μm 2 ) as the main discriminatory parameters in the microstructural differential diagnosis of ASUM from other leg ulcer entities. This may facilitate the histological diagnosis in unclear cases in the future. However, this may also contribute to a better understanding of the aetiopathogenesis of the disease, involving a loss of cellularity in the subendothelial arteriolar wall. Future studies will have to further unravel the exact molecular composition of this acellular fibrosclerosis. This would allow for: ( i ) a more detailed understanding of the underlying pathophysiological mechanisms, ( ii ) a potential molecular differentiation from the vascular acellular fibrosclerosis observed in other types of diseases, such as diabetic ulcers (10), and ( iii ) the development of future therapeutic strategies targeting these vascular deposits in affected patients.

The authors thank Mark S. Wienand from the Department of Dermatology at Inselspital Bern, Klaudia Schossleitner, Silvio Holzner, and Sophie Bromberger from the Department of Dermatology at the Medical University of Vienna for their scientific advice and input. We thank the NVIDIA Corporation for donation of the Titan Xp GPU used for CNN analyses in this research. We thank the team of the Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Medical University of Vienna, Vienna, Austria for their assistance and help with the biostatistical data analysis.

Funding . The authors thank the following funding institutions for their support: Austrian Science Fund (FWF; P-30615), Medical Scientific Fund of the Mayor of the City of Vienna (MA-GMWF-501912-2019), Vienna Science and Technology Fund (WWTF; LS18-080), and institutional funding of the Medical University of Vienna, Austria.

The authors have no conflicts of interest to declare.

Europe PMC requires Javascript to function effectively.

Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page.

Search life-sciences literature (44,130,713 articles, preprints and more)

• Full text links
• Citations & impact
• Similar Articles

Martorell's hypertensive leg ulcer: case report and concise review of the literature.

Author information, affiliations.

• Graves JW 1

Journal of Human Hypertension , 01 Apr 2001 , 15(4): 279-283 https://doi.org/10.1038/sj.jhh.1001154   PMID: 11319677 

Abstract 

Full text links .

Read article at publisher's site: https://doi.org/10.1038/sj.jhh.1001154

Citations & impact 

Impact metrics, citations of article over time, article citations, differentiating arteriolosclerotic ulcers of martorell from other types of leg ulcers based on vascular histomorphology..

Deinsberger J , Brugger J , Tschandl P , Meier-Schiesser B , Anzengruber F , Bossart S , Tzaneva S , Petzelbauer P , Böhler K , Beltraminelli H , Hafner J , Weber B

Acta Derm Venereol , 101(5):adv00449, 04 May 2021

Cited by: 0 articles | PMID: 33856037 | PMCID: PMC9367051

Martorell's Ulcer Successfully Treated by Wireless Microcurrent Stimulation Technology.

Wirsing PG , Konstantakaki M , Poulas KA

Adv Skin Wound Care , 32(2):81-84, 01 Feb 2019

Cited by: 1 article | PMID: 30653186

[Retrospective study of hypertensive leg ulcers at Reims University Hospital: Epidemiological, clinical, disease progression data, effects of vitamin K antagonists].

Nicol P , Bernard P , Nguyen P , Durlach A , Perceau G

Ann Dermatol Venereol , 144(1):37-44, 19 Oct 2016

Cited by: 1 article | PMID: 27771120

Painful Leg Ulceration in a Poorly Controlled Hypertensive Patient: A Case Report of Martorell Ulcer.

Malhi HK , Didan A , Ponosh S , Kumarasinghe SP

Case Rep Dermatol , 9(1):95-102, 01 Jan 2017

Cited by: 3 articles | PMID: 28512404 | PMCID: PMC5422727

Clinical conditions responsible for hyperviscosity and skin ulcers complications.

Caimi G , Canino B , Lo Presti R , Urso C , Hopps E

Clin Hemorheol Microcirc , 67(1):25-34, 01 Jan 2017

Cited by: 2 articles | PMID: 28550239

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Hypertensive ischemic leg ulcer (Martorell's ulcer): a specific disease entity?

Int Angiol , 11(2):132-136, 01 Apr 1992

Cited by: 9 articles | PMID: 1402217

[Martorell's ulcer].

Abate S , Marranzini A , Ferulano GP

Minerva Cardioangiol , 27(4):233-239, 01 Apr 1979

Cited by: 1 article | PMID: 471247

[The Martorell ischemic hypertensive leg ulcer].

Trabattoni P , Gerloni A

Minerva Med , 68(1):37-40, 01 Jan 1977

Cited by: 0 articles | PMID: 834383

Arteriolosclerotic ulcer of Martorell.

Vuerstaek JD , Reeder SW , Henquet CJ , Neumann HA

J Eur Acad Dermatol Venereol , 24(8):867-874, 22 Jan 2010

Cited by: 18 articles | PMID: 20113382

Use of a spinal cord stimulator for treatment of Martorell hypertensive ulcer.

De Andrés J , Villanueva VL , Mazzinari G , Fabregat G , Asensio JM , Monsalve V

Reg Anesth Pain Med , 36(1):83-86, 01 Jan 2011

Cited by: 4 articles | PMID: 21455092

Europe PMC is part of the ELIXIR infrastructure

Introduction

Case report, statement of ethics, disclosure statement, martorell's ulcer: diagnostic and therapeutic challenge.

• Split-Screen
• Article contents
• Figures & tables
• Supplementary Data
• Peer Review
• Open the PDF for in another window
• Get Permissions
• Cite Icon Cite
• Search Site

Ana Paula Frade Lima Pinto , Nelson Araújo Silva Jr. , Carolina Teixeira Osorio , Lina Maria Rivera , Sueli Carneiro , Marcia Ramos-e-Silva , Blanca Elena Rios Gomes Bica; Martorell's Ulcer: Diagnostic and Therapeutic Challenge. Case Rep Dermatol 1 August 2015; 7 (2): 199–206. https://doi.org/10.1159/000430884

Download citation file:

• Ris (Zotero)
• Reference Manager

Martorell's ulcer is an uncommon ischemic and extremely painful lesion located in the distal portion of the lower limb, resulting from severe systemic and poorly controlled hypertension. It is common in women between 50 and 70 years of age. The diagnosis is clinical and mostly belated, following exclusion of other causes. The response to treatment takes time and is unsatisfactory. A combination of several drugs associated with surgery may be required for wound healing. The authors present a case of Martorell's hypertensive ulcer, with emphasis on the diagnostic and therapeutic difficulties.

The most common causes of ulcers in the lower limbs are arterial insufficiency and venous stasis [ 1 ]. Martorell's hypertensive ulcer is an ischemic lesion of the tissue caused by obstruction of the small arterioles of the medial artery.

Haxthausen [ 2 ], in 1940, for the first time reported the association of ischemic ulcers as a consequence of arterial hypertension complications, and Martorell, five years later, published four cases correlating systemic arterial hypertension, arteriolar lesion and ulcer formation [ 3,4 ]. These findings were supported by Hines and Farber from the Mayo Clinic [ 5 ]. The clinical criteria described by Martorell for the diagnosis of hypertensive ulcer were: location on the inner side of the distal third of the lower limbs; diastolic arterial hypertension in the lower limbs; ‘hyperpulsatility' of the arteries of the lower limbs, absence of arterial calcifications; absence of chronic venous insufficiency; symmetrical lesions or residual hyperpigmentation of previous ulceration in the inner side of the inferior limb; increased pain in the horizontal position, with greater prevalence in women [ 3,4,6 ].

It is believed that the pathogenesis of hypertensive ulcer is related to local factors of the microvasculature and not to involvement of large vessels, as observed in the most common peripheral vascular diseases. Trauma can be a triggering factor, although half of the ulcers arise spontaneously [ 7 ]. From the pathophysiological point of view, the dermal arterioles with uncontrolled systemic arterial hypertension present arteriosclerotic changes, such as hyperplasia of the core elements of the middle layer cells in the vessels with thickening of the elastic lamina. Such a process, called hyalinosis [ 7,8,9 ], leads to an increase in the dermal arterioles lumen diameter [ 6,10 ]. Luminal stenosis produces increased local vascular resistance and reduced skin perfusion pressure [ 11 ].

Hypertensive ulcers are more common in women between 50 and 70 years of age, often symmetrical and located in the distal inner side of the lower limbs. Pain in greater intensity than in ulcers of other etiologies, referred to as being disproportionate to the size of the lesion, is the most relevant symptom. Inefficiency of ordinary analgesics is common [ 1,12 ]. Classically, the ulcer has variable depth, necrotic base and violaceous edges. The presence of satellite lesions and irregular edges are also features that suggest additional cutaneous ischemia. The diagnosis is usually belated and requires the exclusion of other causes. The healing process is slow and the response to treatment is poor [ 13 ].

Proposed treatments are antihypertensive therapy, especially with drugs that reduce vasoconstriction, such as calcium channel blockers and inhibitors of angiotensin-converting enzyme. Pacifico et al. [ 14 ] in 2011 suggested the use of prostaglandin E (PGE 1 ).

A black woman, a 40-year-old housewife born in Rio de Janeiro, was referred for ulcers on the toes for 2 months. She reported intense pain in the lesions with a progressive increase in size. At the primary care clinic, she was treated with benzathine, penicillin and ciprofloxacin in addition to local care, however without presenting significant improvement. She had systemic arterial hypertension upon irregular monitoring, without adequate blood pressure control. She was taking digoxin 0.25 mg/day, carvedilol 3.125 mg/day, captopril 100 mg/day, furosemide 80 mg/day, spironolactone 50 mg/day and simvastatin 20 mg/day. Both parents had suffered from hypertension and had died from encephalic strokes.

At the initial physical examination, the patient did not present fever, but was hypertensive (blood pressure 240/120 mm Hg), with mild edema of the lower limbs. There were two irregular edge ulcers and necrotic bases in the lower limbs located in the 3rd and 4th right and left toes (fig. 1 , fig. 2 , fig. 3 ). She did not show any signs of inflammation or wound secretion in the region. Peripheral arterial pulses of the posterior tibial and posterior tibial arteries were palpable bilaterally. Radiography of the feet excluded osteomyelitis. Eye fundus examination showed Keith-Wagener-Baker hypertensive retinopathy grade III (arteriolar narrowing, with silver wire arteries, increased vascular tortuosity with A/V pathological groups). Transthoracic echocardiography demonstrated parietal concentric hypertrophy of the left ventricle with diastolic dysfunction grade I and left atrial enlargement. Doppler study of the carotid and vertebral arteries only revealed mild bilateral intimal thickening without atheromatous plaques. In echo color Doppler of the lower limbs, arterial thickening and irregularities were detected without parietal diffuse atherosclerosis and with normal bilateral flow.

Ulcer with irregular borders and dry necrosis at the base of the 4th left toe.

Ulcer involving all of the 3rd right toe with dry necrosis.

Detail of the extension of the lesion.

Histopathological examination of the biopsy of the ulcer in the left leg showed a nonspecific chronic inflammation process with ulceration, consistent with the diagnosis of Martorell's ulcer. The clinical picture and laboratory tests showed that the ulcers had a hypertensive etiology. The patient was admitted for a proper treatment for systemic arterial hypertension and surgical debridement of the ulcer (fig. 4 ). The local dressings were made ​​with petrolatum and the ulcer progressed with healing.

After surgical debridement.

Martorell's hypertensive ulcer is an unusual injury and, although cases have been seen in men, it is more common in women. It is frequently symmetrical and located in the distal third and anterolateral surfaces of the lower limbs [ 15 ].

The most common histopathological findings are thickening of the elastic lamina, proliferation of the intimal layer and hyperplasia of the middle layer with hyalinization resulting in luminal narrowing [ 16 ]. Studies have shown that the presence of intimal hyperplasia is the primary event for ulcer formation. The shear stress, caused by persistently high blood pressure levels, stimulates endothelial remodeling with thickening of the wall vessel, luminal narrowing and consequent obstruction of the blood flow. It was also admitted that there is a loss of the offsetting vasodilation physiological reflex of the distal arterioles in the obstructed region, further compromising the tissue perfusion. When the perfusion reaches critical levels, cutaneous ischemia occurs, with epidermal necrosis and ulcer formation [ 11 ].

Total ulcer healing requires the combination of various therapies. Reduction of blood pressure levels is critical to the success of the treatment and not only prevents increased vascular damage, but improves blood supply through local vasodilation. Nonselective beta-blockers are contraindicated for reducing cardiac output, worsening the skin perfusion pressure. The drugs of choice are calcium channel blockers and angiotensin-converting enzyme inhibitors, and all patients must be anticoagulated with heparin or coumarin [ 17 ].

Surgical treatments involve the debridement of devitalized tissue with second intention closure or skin grafting and lumbar sympathectomy. Surgical closure of lesions >4 cm 2 is recommended [ 18 ]. Lumbar sympathectomy aims at promoting vasodilation, improving perfusion of the affected limb and controlling pain. The result is variable, from complete recovery to little impact on healing [ 19 ].

Mild to moderate pain can be managed by the use of ordinary painkillers such as non-steroidal anti-inflammatories, and in severe cases opioids are the drugs of choice. The use of spinal cord stimulation therapy, with good results in reduction of pain and healing of ulcers, has been mentioned and consists of the use of small electrodes that stimulate certain points of the spinal cord, influencing the transmission of the pain signals to the brain [ 20 ].

The type of therapy called hyperbaric oxygen therapy consists in the supply of pure oxygen in a pressurized environment above atmospheric pressure. Its action mechanism is not entirely understood, but it can be used as an adjunct in the treatment of chronic wounds, although the level of evidence in patients with Martorell's ulcer is low [ 21 ].

Behavioral measures, such as avoiding trauma, stopping to smoke and wearing compressive stockings (25 and 30 mm Hg) must be encouraged [ 22 ].

In the case presented, the patient featured four out of the seven criteria set up by Martorell. Complementary tests allowed the exclusion of other etiologies. The lower limbs Doppler excluded chronic venous insufficiency and coagulopathy, while the histopathological examination did not show any signs of cutaneous vasculitis. The observation of lesions secondary to hypertension in other target organs also contributed to the diagnostic conclusion. The patient underwent daily dressing while hospitalized. After the optimization of oral antihypertensive medication doses, obtaining acceptable pressure levels allowed the lesion to heal.

Hypertensive ulcer should always be considered in the differential diagnosis of painful lesions of the lower limbs.

Our patient gave her written authorization for the publication of her case and the authors followed all ethical guidelines.

The authors declare no conflict of interest.

Email alerts

Citing articles via, suggested reading.

• Online ISSN 1662-6567

INFORMATION

• Contact & Support
• Information & Downloads
• Rights & Permissions
• Terms & Conditions
• Catalogue & Pricing
• Policies & Information
• People & Organization
• Stay Up-to-Date
• Regional Offices
• Community Voice

SERVICES FOR

• Researchers
• Healthcare Professionals
• Patients & Supporters
• Health Sciences Industry
• Medical Societies
• Agents & Booksellers

Karger International

• S. Karger AG
• P.O Box, CH-4009 Basel (Switzerland)
• Allschwilerstrasse 10, CH-4055 Basel
• Tel: +41 61 306 11 11
• Fax: +41 61 306 12 34
• Contact: Front Office
• Experience Blog
• Privacy Policy
• Terms of Use

This Feature Is Available To Subscribers Only

Sign In or Create an Account

• Open access
• Published: 11 June 2012

Pulmonary hypertension in patients with Martorell hypertensive leg ulcer: a case control study

• Leonardo Glutz von Blotzheim 1 ,
• Felix C Tanner 2 ,
• Georg Noll 2 ,
• Matthias Brock 1 ,
• Manuel Fischler 1 ,
• Jürg Hafner 3 ,
• Rudolf Speich 1 ,
• Silvia Ulrich 1 &
• Lars C Huber 1  

Respiratory Research volume  13 , Article number:  45 ( 2012 ) Cite this article

1 Citations

Metrics details

Martorell hypertensive ischemic leg ulcer (Martorell ulcer) is characterized by distinct alterations in the arteriolar wall of subcutaneous vessels, leading to progressive narrowing of the vascular lumen and increase of vascular resistance. These changes are similar to the alterations observed in pulmonary arterioles in patients with chronic pulmonary hypertension (PH). This study was aimed to assess an association between the two disorders.

In this case–control study, 14 patients with Martorell ulcer were clinically assessed for the presence of pulmonary hypertension using transthoracic Doppler echocardiography. Data from patients were compared to 28 matched hypertensive controls.

Systolic pulmonary arterial pressure (sPAP) in patients with Martorell ulcer was significantly higher than in the control group (33.8 ± 16.9 vs 25.3 ± 6.5 mmHg, p = 0.023); the prevalence of pulmonary hypertension was 31% (5/14) in patients and 7% (2/28) in controls (p = 0.031). No differences were seen in left heart size and function between patients and controls.

This study provides first evidence that subcutaneous arteriolosclerosis, the hallmark of Martorell ulcer, is associated with PH. These findings suggest that patients with Martorell leg ulcer might be at significant risk to develop elevated pulmonary arterial pressure. Patients with leg ulcers who present with dyspnea should be evaluated by echocardiography for the presence of pulmonary hypertension.

Martorell hypertensive ischemic leg ulcer (HYTILU, Martorell ulcer) and pulmonary hypertension (PH) are distinct clinical entities that share common pathogenic features. Of particular interest are similar morphologic changes of arterioles that cause elevated vascular resistance. These similarities suggest a possible association between the two disorders.

In 1945, Fernandes Martorell described 4 cases of patients with ischemic leg ulcers [ 1 ] that occurred in the absence of peripheral arterial or venous disease; histological analysis of these ulcers revealed hypertensive changes of subcutaneous arterioles (i.e. hypertrophy and stenosis), which resulted in the descriptive term “hypertensive ischemic leg ulcer” [ 2 , 3 ]. Martorell ulcer is an entity defined by ischemic subcutaneous arteriolosclerosis of the leg in hypertensive subjects. Martorell ulcer is a rare cause for leg ulcers and is found in approximately 5% of cases. Diagnosis is based on clinical presentation, patient history and deep skin biopsy. Histology reveals hypertrophy of the smooth muscle cell layer of the vessel’s media resulting in an increased thickness of the arteriolar wall to the cost of a narrow lumen (Figure 1 a/b). Systemic arterial hypertension is present in all cases, type 2 diabetes is observed in approximately 60% [ 4 – 6 ].

a) Overview of necrotic skin area at the border of a Martorell hypertensive ischemic leg ulcer, containing a group of two sclerotic arterioles; 1 b ) Higher magnification of Figure 1 a ; Group of two sclerotic arterioles, one with a thickened wall to the cost of a narrow lumen and one showing medial calcification.

Histopathology of pulmonary vasculature in patients with P(A)H are comparable to those of Martorell ulcer. PAH is a pre-capillary disorder of the small pulmonary arteries and arterioles, characterized by extensive vasoconstriction, in situ thrombosis and vascular remodelling. Cellular changes defining the vascular remodelling include intimal fibrosis, medial and adventitial hyperplasia and a pro-proliferative, apoptosis-resistant phenotype of vascular cells. These alterations progressively narrow the arteriolar lumen and, thus, increase the pulmonary vascular resistance (PVR) leading to an increase of the right ventricular afterload and, ultimately, cardiac failure [ 7 – 10 ]. Of interest, these histopathological changes are not restricted to PAH but can be observed in several other forms of PH [ 11 ].

On the other hand, Martorell ulcers have been found to develop secondary to limited skin perfusion pressures resulting from an increase of vascular resistance in small cutaneous vessels. It has also been suggested that this increase of vascular resistance affects the vessel relaxation that usually follows distal to an arterial narrowing, which might further decrease tissue perfusion [ 12 ].

The striking histopathological and pathophysiologic similarities between Martorell ulcer and PAH as well as chronic PH due to other conditions prompted this case–control study. The aim was to analyse a potential association between Martorell ulcer and the development of PH.

From May 1999 to April 2011, 46 patients with Martorell ulcer were diagnosed at the Department of Dermatology, University Hospital of Zurich [ 4 ]. After reviewing the cases, a total of 15 patients were identified for further diagnostic workup according to the study design (Figure 2 ). Patient history was checked for i) the presence of chronic obstructive or restrictive pulmonary disease, ii) chronic thromboembolic pulmonary hypertension and iii) concomitant diagnosis of systemic disorders that have been associated with the development of pulmonary hypertension due to unclear multifactorial mechanisms (e.g. sarcoidosis, neurofibromatosis, tumoral obstruction, etc.) [ 13 ]. Patients characteristics are shown in Table 1 . For each case, 2 controls were matched to gender, age at time of echocardiography (± 2 years), presence of hypertension, current smoking and presence or absence of diabetes mellitus. Data were retrieved from the electronical data pool of the hospital and included in-patients from all hospital departments. Echocardiographic workup was performed at the Department of Cardiology, University Hospital of Zurich, Switzerland (12 of 14 patients) as well as in 2 other hospitals (2 of 14 patients).

Study design.

Study design

The study was conducted at a tertiary care hospital (University Hospital of Zurich, Switzerland) and was approved by the ethics committee of the medical faculty of the University of Zurich. The study was designed as case–control study to investigate a potential correlation between the presence of Martorell ulcer and pulmonary hypertension (PH).

• Echocardiography

All patients underwent a complete transthoracic echocardiographic study. Pulmonary arterial pressure (systolic pulmonary arterial pressure, sPAP) was estimated in a non-invasive manner by measuring the maximal velocity of the tricuspid regurgitation jet and calculating the maximal instantaneous systolic pressure difference between the right ventricle and the right atrium [ 14 ]. Pulmonary hypertension was defined according to the Dana Point criteria as sPAP >36 mmHg, i.e. a tricuspid jet velocity of >2.8 m/s corresponding to an RV/RA gradient of >31 mmHg and adding a right atrial pressure estimate of 5 mmHg [ 15 ]. Diastolic dysfunction was estimated by measurement of left atrial diameter [reference < 4.0 cm] and right atrial diameter (as assessed by short [< 4.1 cm] and long axis [< 5.0 cm]) as well as analysis of the E/A-ratio, defined as flow velocity of passive filling of the left ventricle divided by flow velocity of active filling due to atrial contraction [> 1].

All data are shown as mean ± standard deviation (confidence interval of 95%). Data were checked for normality by using the Kolmogorov-Smirnov test. Statistical comparison between patients and controls were assessed with the use of the student’s t-test. A p-value <0.05 was considered to be statistically significant. Spearman’s test was used for correlation analysis.

Characteristics of patients and controls

46 patients with Martorell ulcer were retrieved from a retrospective data base. Twentytwo files concerned subjects who were already deceased, leaving a total of 24 eligible patients. One patient was excluded because of retrospectively revised diagnosis of peripheral arterial disease instead of Martorell ulcer. Eight patients refused to participate at the study. Fifteen patients were further evaluated for the presence of PH by echocardiography. One patient was excluded after analysis because systolic RV/RA gradient could not be measured due to absence of tricuspid regurgitation.

Patient data from 14 patients with Martorell ulcer were compared to data of the control group; details of patients’ characteristics are provided in Table 2 . Briefly, 6 of 14 patients (42%) were male, the mean age was 77 years (range 70–89 years). Hypertension was present in all patients with Martorell ulcer (100%), type 2 diabetes mellitus was found in 5 of 14 patients (37%). 2 patients (14%) were still active smokers whereas 3 (22%) had stopped smoking (former smokers), 9 (64%) had never smoked. Creatinine levels and estimated glomerular filtration rate (GFR) as calculated according to MDRD (modified diet in renal disease formula [ 16 ]) were normal in 6 of 14 patients (42%) and in 12 of 28 controls (43%) [reference range 70 – 110 μmol/l]. Renal function was moderately reduced in 6 of 14 patients (CKD stage 3 in 42% patients) and in 14 of 28 controls (50%). 2 of 14 patients (16%) and 2 of 28 controls (7%) showed severe (CKD stage 4) reduction in renal function. Creatinine levels at time of echocardiography (109 ± 51 vs. 104 ± 42 μmol/l) and GFR according to MDRD (64 ± 37 vs. 59 ± 19 ml/min) did not reveal significant differences between patients and controls. Oral anticoagulation was established in 8 of 14 patients (50%) and in 8 of 28 controls (28%). Levels of antinuclear antibodies (ANA) were negative in 6 of 14 patients; elevations above 1:160, which is used as cut-off at the University Hospital Zurich, were observed in 2 patients (14%) without clinical signs of a systemic autoimmune disease. Since Martorell ulcer was diagnosed by tissue biopsy, no evidence for coumarin-induced skin necrosis or autoimmune disorders associated with the development of ulcerating lesions has been found.

Body mass index (BMI, defined as body weight in kilograms divided per height in square meters) of patients with Martorell ulcer was significantly higher than in the control group (29.5 ±7.0 vs 25.8 ± 4.0 kg/m 2 ).

The RV/RA gradient is significantly elevated in patients with martorell ulcer

As shown in Figure 3 a, the RV/RA gradient systolic pulmonary arterial pressure (sPAP) in patients with Martorell ulcer (33.8 ± 16.9 mmHg) was significantly higher than the pressure measured in the control group (25.3 ± 6.5 mmHg, p = 0.023). The absolute difference between the means of the gradients of cases and controls was 8.5 mmHg. This difference was independent of left heart function, since all 14 patients showed a normal left ventricular ejection fraction (LVEF ≥ 50%, 62% ± 3). On the other hand, in 4 of 28 controls the LVEF was found to be impaired (58% ± 12); the difference observed between left ventricular function of patients and controls however was not significant. Dilatation of the left atrium (end-systolic-diameter (ESD) > 4 cm) is considered to be an important surrogate marker of diastolic dysfunction, which, in turn, might lead to pulmonary hypertension. Left atrial ESD exceeding 4.0 cm was found in 10 of 14 patients (71%) and in 16 of 28 controls (57%). The difference in left atrial ESD between patients (4.47 cm ± 1.05) and controls (4.35 cm ± 0.80) is illustrated in Figure 3 b and was not statistically significant. Measurement of right atrial diameter assessed by long and short axis did not differ between patients and controls. Similarly, no significant differences were found in the E/A-ratio between the patient group and the control group.

Differences between patients and controls. a ) The RV/RA gradient is significantly higher in patients as compared to matched controls (p = 0.023); b ) the end systolic diameter (ESD) of the left atrium is not significantly different between patients and controls; c ) the BMI is higher in patients than in controls (p = 0.036); d ) prevalence of PH in patients and controls with elevated BMI (cut-off 25 kg/m 2 ). Data in a - c are plotted as median including upper and lower whisker.

The prevalence of pulmonary hypertension in patients with martorell ulcer is significantly higher than in controls

When pulmonary hypertension was defined as sPAP >36 mmHg or as RV/RA gradient of >31 mmHg, respectively [ 15 ], the prevalence of pulmonary hypertension in patients with Martorell ulcer was 5 out of the 14 cases (36%). This figure was significantly higher than in the control group, in which only 2 out of 28 cases (7%) had an elevated RV/RA gradient (p = 0.031).

The BMI in patients with martorell ulcer was higher than in controls

Of interest, the absolute difference of the BMI between patients and controls was 3.7 kg/m 2 ; this difference did reach statistical significance (Figure 3 c, p = 0.036). Figure 3 d shows the prevalence of pulmonary hypertension in patients and controls with or without elevated BMI. 30% of patients with a BMI > 25 were found to have pulmonary hypertension as compared to 6.25% of obese controls. On the other hand, 50% of Martorell patients with a BMI < 25 were detected to have an elevated sPAP as compared to 8.3% of non-obese controls. For severity of pulmonary hypertension, no association between BMI and sPAP was found in patients or in the collective population of investigated patients and controls (data not shown).

In the present study, we investigated the prevalence of PH in subjects with Martorell ulcer and found that the sPAP as assessed by echocardiography is significantly elevated in patients as compared to matched hypertensive controls.

Martorell ulcer is caused by hypertensive changes in subcutaneous skin arterioles leading to reduced tissue perfusion; Martorell ulcer is, though underdiagnosed, an uncommon cause for leg ulcers [ 4 ]. PAH is another orphan disease defined by increased pulmonary arterial pressure due to remodelling of small pulmonary arteries. The list of associated conditions and risk factors predisposing for the development of PAH however has been growing constantly [ 13 ]. Moreover, when all conditions are considered that result in elevation of pulmonary pressure, PH is of emerging clinical relevance.

Histopathological changes observed in the peripheral arterial vessels within a Martorell ulcer include stenotic arteriosclerosis with calcification and hypertrophy of the vessels media, resulting in an increase of the wall to lumen ratio [Figure 1 . Of interest, similar changes are seen in the remodeling of arteries described in the pulmonary vasculature of patients with several forms of chronic PH including hypertrophy and hyperplasia of smooth muscle fibers in the media of muscular arteries resulting in an increase of the cross sectional area [ 11 , 17 ].

In this case–control study, we found that patients with Martorell ulcer have significantly higher levels of sPAP compared to a matched control group. This difference has been assessed in a non-invasive manner by the use of transthoracic echocardiography. This method has been challenged by a recent study and was found to be inaccurate for diagnosing PH [ 18 ]; however, Doppler echocardiography is a validated and largely utilized modality to assess right ventricular function and is the currently established approach to screen patients for elevated pressure within the pulmonary circulation [ 19 ]. Of course, the method is limited for several reasons and does not permit direct conclusions on the type of PH. Right heart catheterization to confirm the diagnosis and evaluate the severity of PH was not considered as feasible approach within this distinct study population; study design and ethical proposal thus were based on echocardiographic assessment. Patients and controls did not show significant differences when compared for left ventricular function, volume of left and right atrium, E/A ratio or the presence of significant valvular heart disease.

However, the difference in BMI between patients and controls reached statistical significance. Together with the presence of other risk factors for a metabolic syndrome, such as age, systemic arterial hypertension and diabetes mellitus, these data suggest that diastolic heart failure is of major importance in the development of an elevated pulmonary arterial pressure – in both patients with Martorell leg ulcer and hypertensive controls. Of interest, however, more Martorell patients with a normal BMI developed pulmonary hypertension than obese patients. Whether the significantly increased prevalence of pulmonary hypertension in patients with Martorell leg ulcer might additionally be caused by other, pre-capillary factors remains, mainly due to the lack of invasive hemodynamic data and the absence of histopathological evidence for remodelling of pulmonary arterioles, hypothetically.

The main finding of this study, i.e. that the prevalence of an elevated pulmonary arterial pressure in patients with Martorell leg ulcer was significantly higher than in the control group, suggest that patients with Martorell ulcer appear to have an increased risk to develop PH, most probably due to diastolic heart failure, which can be prominent in patients with Martorell leg ulcer due to longstanding arterial hypertension. Other studies will have to investigate whether the presence of Martorell leg ulcer might additionally predispose for pre-capillary PH as it was shown similarly for hyperthyroidism [ 20 ], concomitant HIV infection [ 21 ] or smoking [ 22 ].

Our data further imply that hypertensive patients with leg ulcers who present with signs of right heart failure including dyspnea, peripheral edema, hypoxemia and reduced exercise capacity should undergo prompt echocardiographic evaluation to exclude or confirm the presence of an elevated sPAP. Since adequate treatment of hypertension does not prevent Martorell ulcer [ 4 ], it seems unlikely that the development of PH can be avoided by the control of systemic blood pressure. On the other hand, it remains unclear whether the specific therapy with vasodilatating agents (e. g. phosphodiesterase-5 inhibitors or endothelin receptor antagonists) might improve tissue perfusion and, thus, would enhance the wound healing of Martorell ulcer. However, patients with Martorell ulcer and concomitant PH could benefit from early diagnosis and onset of an adequate therapy.

Our study is limited, as mentioned above, by the fact that pulmonary arterial pressures were assessed non-invasively by echocardiography and not by right heart catheterization; moreover, the study lacks supporting biomarker data, and, finally, the case number is low, which is due to the fact that Martorell ulcer is a rare disease. Since this study was designed as observational and not as interventional study, the low case numbers should not severely affect our conclusions.

Taken together, this is to our knowledge the first report showing a potential association between the development of PH and Martorell ulcer. Patients with Martorell ulcer might be at significant risk to develop PH. Our data emphasize that hypertensive patients with leg ulcers should promptly be screened for the presence of an elevated pulmonary arterial pressure when presenting with dyspnea, hypoxemia or reduced exercise capacity.

Abbreviations

Body-Mass-Index (kg/m2)

Chronic kidney disease

End systolic diameter (cm)

Glomerular filtration rate (ml/min)

Left ventricular ejection fraction (%)

Modified diet in renal disease formula

Not applicable

Pulmonary arterial hypertension

• Pulmonary hypertension

Right atrial diameter

Right ventricular – right atrial pressure gradient (mmHg)

Systolic pulmonary arterial pressure (mmHg).

Martorell F: Las ulceras supramaleolares por arteriolitis de las grandes hipertensas. Actas (Reun Cientif Cuerpo Facul) Inst Policlinico Barcelona. 1945, 1 (1): 6-9.

Google Scholar  

Hines EA, Farber EM: Ulcer of the leg due to arteriosclerosis and ischemia, occurring in the presence of hypertensive disease (hypertensive-ischemic ulcers); a preliminary report. Proc Staff Meet Mayo Clin. 1946, 21: 337-346.

PubMed   Google Scholar  

Farber EM, Hines EA, Montgomery H, Craig W: The arterioles of the skin in essential hypertension. J Invest Dermatol. 1947, 9 (6): 285-298.

Article   PubMed   CAS   Google Scholar  

Hafner J, Nobbe S, Partsch H, Läuchli S, Mayer D, Amann-Vesti B, Speich R, Schmid C, Burg G, French LE: Martorell hypertensive ischemic leg ulcer; A model of ischemic subcutaneous arteriolosclerosis. Arch Dermatol. 2010, 146 (9): 961-968. 10.1001/archdermatol.2010.224.

Shutler SD, Baragwanath P, Harding KG: Martorell’s ulcer. Postgrad Med J. 1995, 71 (842): 717-719. 10.1136/pgmj.71.842.717.

Article   PubMed   CAS   PubMed Central   Google Scholar  

Henderson CA, Highet AS, Lane SA, Hall R: Arterial hypertension causing leg ulcers. Clin Exp Dermatol. 1995, 20: 107-114. 10.1111/j.1365-2230.1995.tb02666.x.

Gaine SP, Rubin LJ: Primary pulmonary hypertension. Lancet. 1998, 352: 719-725. 10.1016/S0140-6736(98)02111-4.

Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G: Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006, 173: 1023-1030. 10.1164/rccm.200510-1668OC.

Article   PubMed   Google Scholar  

Ghofrani HA, Barst RJ, Benza RL, Champion HC, Fagan KA, Grimminger F, Humbert M, Simonneau G, Stewart DJ, Ventura C, Rubin LJ: Future perspectives for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009, 54 (Suppl): S108-S117.

Hassoun PM, Mouthon L, Barberà JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX, Humbert M: Inflammation, growth factors, and pulmonary vascular remodelling. J Am Coll Cardiol. 2009, 54 (Suppl): S10-S19.

Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, Reid LM, Tuder RM: Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004, 43 (Suppl): S25-S32.

Article   Google Scholar  

Duncan HJ, Faris IB: Martorell's hypertensive ischemic leg ulcers are secondary to an increase in the local vascular resistance. J Vasc Surg. 1985, 2 (4): 581-584.

Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R: Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009, 54 (Suppl): S43-S54.

Zipes DP, Libby P, Bonow RO, Braunwald E: Braunwald´s Heart Disease, A Textbook of Cardiovascular Medicine. 2001, PA: Elsevier Saunders, 173-

Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A: Diagnosis and assessment of pulmonary hypertension. J Am Coll Cardiol. 2009, 54 (Suppl): S55-

Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F: Chronic Kidney Disease Epidemiology Collaboration, Expressing the modification of diet in renal disease study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem. 2007, 53 (4): 766-772. 10.1373/clinchem.2006.077180.

Galiè N, Hoeper MM, Humbert M: Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009, 30 (20): 2499-

Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S: Inaccuracy of Doppler echocardiographic estimates of pulmonary artery pressures in patients with pulmonary hypertension: implications for clinical practice. Chest. 2011, 139 (5): 988-993. 10.1378/chest.10-1269.

Lau EM, Manes A, Celermajer ES, Galiè N: Early detection of pulmonary vascular disease in pulmonary arterial hypertension: time to move forward. Eur Heart J. 2011, 32 (20): 2489-2498. 10.1093/eurheartj/ehr160. May 26

Thurnheer R, Jenni R, Russi EW, Greminger P, Speich R: Hyperthyroidism and pulmonary hypertension. J Intern Med. 1997, 242 (2): 185-188. 10.1046/j.1365-2796.1997.00191.x.

Speich R, Jenni R, Opravil M, Pfab M, Russi EW: Primary pulmonary hypertension in HIV infection. Chest. 1991, 100 (5): 1268-1271. 10.1378/chest.100.5.1268.

Schiess R, Senn O, Fischler M, Huber LC, Vatandaslar S, Speich R, Ulrich S: Tobacco smoke: a risk factor for pulmonary hypertension? A case control study. Chest. 2010, 138 (5): 1086-1092. 10.1378/chest.09-2962.

Download references

Acknowledgements

The authors thank Ulla Treder, Simone Stickel, Vreni Widmer, Jana Kunst, Isabel Schmied and Ulrike Held for their assistance.

Author information

Authors and affiliations.

Pulmonary Hypertension Working Group, Clinic and Policlinic of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland

Leonardo Glutz von Blotzheim, Matthias Brock, Manuel Fischler, Rudolf Speich, Silvia Ulrich & Lars C Huber

Department of Cardiology, University Hospital of Zurich, Zurich, Switzerland

Felix C Tanner & Georg Noll

Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland

Jürg Hafner

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Leonardo Glutz von Blotzheim .

Additional information

Competing interests.

The authors declare that they have no competing interests.

Authors’ contributions

LGvB, MF, RS, SU and LCH contributed to the design of the study and data collection, performed statistical analysis and interpreted data, FCT performed transthoracic Doppler echocardiography, JH contributed to data collection. GN and MB reviewed drafts of the manuscript. All authors read and approved the final manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2, authors’ original file for figure 3, rights and permissions.

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article.

Glutz von Blotzheim, L., Tanner, F.C., Noll, G. et al. Pulmonary hypertension in patients with Martorell hypertensive leg ulcer: a case control study. Respir Res 13 , 45 (2012). https://doi.org/10.1186/1465-9921-13-45

Download citation

Received : 01 February 2012

Accepted : 30 May 2012

Published : 11 June 2012

DOI : https://doi.org/10.1186/1465-9921-13-45

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Martorell ulcer

Respiratory Research

ISSN: 1465-993X

• General enquiries: [email protected]

Martorell's Ulcer Successfully Treated by Wireless Microcurrent Stimulation Technology

Affiliation.

• 1 Peter G. Wirsing, MD, is Head of the Wound Center, Ostalb-Klinikum Aalen, Germany. Maria Konstantakaki is a researcher and Konstantinos A. Poulas, PhD, is Associate Professor in the Department of Pharmacy, University of Patras, Greece. The authors have disclosed no financial relationships related to this article. Submitted March 31, 2018; accepted in revised form June 22, 2018.
• PMID: 30653186
• DOI: 10.1097/01.ASW.0000550590.31545.67

Martorell's ulcers are hard-to-heal leg ulcers typically accompanied by a significant elevation of blood pressure and severe pain. This case study examines the use of an innovative technology, wireless microcurrent stimulation, for the healing of a Martorell's ulcer. Using wireless microcurrent stimulation, study authors managed to reduce the size of a large Martorell's ulcer by 90% within 8 weeks. In this article, the case of a 65-year-old woman is discussed in detail, and this new, contactless method is compared with traditional ulcer healing methods.

Publication types

• Case Reports
• Leg Ulcer / pathology
• Leg Ulcer / therapy*
• Middle Aged
• Transcutaneous Electric Nerve Stimulation / methods*
• Treatment Outcome
• Wireless Technology*
• Wound Healing

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• v.13(1); 2012

Pulmonary hypertension in patients with Martorell hypertensive leg ulcer: a case control study

Leonardo glutz von blotzheim.

1 Pulmonary Hypertension Working Group, Clinic and Policlinic of Internal Medicine, University Hospital of Zurich, Zurich, Switzerland

Felix C Tanner

2 Department of Cardiology, University Hospital of Zurich, Zurich, Switzerland

Matthias Brock

Manuel fischler, jürg hafner.

3 Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland

Rudolf Speich

Silvia ulrich, lars c huber.

Martorell hypertensive ischemic leg ulcer (Martorell ulcer) is characterized by distinct alterations in the arteriolar wall of subcutaneous vessels, leading to progressive narrowing of the vascular lumen and increase of vascular resistance. These changes are similar to the alterations observed in pulmonary arterioles in patients with chronic pulmonary hypertension (PH). This study was aimed to assess an association between the two disorders.

In this case–control study, 14 patients with Martorell ulcer were clinically assessed for the presence of pulmonary hypertension using transthoracic Doppler echocardiography. Data from patients were compared to 28 matched hypertensive controls.

Systolic pulmonary arterial pressure (sPAP) in patients with Martorell ulcer was significantly higher than in the control group (33.8 ± 16.9 vs 25.3 ± 6.5 mmHg, p = 0.023); the prevalence of pulmonary hypertension was 31% (5/14) in patients and 7% (2/28) in controls (p = 0.031). No differences were seen in left heart size and function between patients and controls.

This study provides first evidence that subcutaneous arteriolosclerosis, the hallmark of Martorell ulcer, is associated with PH. These findings suggest that patients with Martorell leg ulcer might be at significant risk to develop elevated pulmonary arterial pressure. Patients with leg ulcers who present with dyspnea should be evaluated by echocardiography for the presence of pulmonary hypertension.

Martorell hypertensive ischemic leg ulcer (HYTILU, Martorell ulcer) and pulmonary hypertension (PH) are distinct clinical entities that share common pathogenic features. Of particular interest are similar morphologic changes of arterioles that cause elevated vascular resistance. These similarities suggest a possible association between the two disorders.

In 1945, Fernandes Martorell described 4 cases of patients with ischemic leg ulcers [ 1 ] that occurred in the absence of peripheral arterial or venous disease; histological analysis of these ulcers revealed hypertensive changes of subcutaneous arterioles (i.e. hypertrophy and stenosis), which resulted in the descriptive term “hypertensive ischemic leg ulcer” [ 2 , 3 ]. Martorell ulcer is an entity defined by ischemic subcutaneous arteriolosclerosis of the leg in hypertensive subjects. Martorell ulcer is a rare cause for leg ulcers and is found in approximately 5% of cases. Diagnosis is based on clinical presentation, patient history and deep skin biopsy. Histology reveals hypertrophy of the smooth muscle cell layer of the vessel’s media resulting in an increased thickness of the arteriolar wall to the cost of a narrow lumen (Figure ​ (Figure1a/b). 1 a/b). Systemic arterial hypertension is present in all cases, type 2 diabetes is observed in approximately 60% [ 4 - 6 ].

a) Overview of necrotic skin area at the border of a Martorell hypertensive ischemic leg ulcer, containing a group of two sclerotic arterioles; 1 b ) Higher magnification of Figure ​ Figure1 1 a ; Group of two sclerotic arterioles, one with a thickened wall to the cost of a narrow lumen and one showing medial calcification.

Histopathology of pulmonary vasculature in patients with P(A)H are comparable to those of Martorell ulcer. PAH is a pre-capillary disorder of the small pulmonary arteries and arterioles, characterized by extensive vasoconstriction, in situ thrombosis and vascular remodelling. Cellular changes defining the vascular remodelling include intimal fibrosis, medial and adventitial hyperplasia and a pro-proliferative, apoptosis-resistant phenotype of vascular cells. These alterations progressively narrow the arteriolar lumen and, thus, increase the pulmonary vascular resistance (PVR) leading to an increase of the right ventricular afterload and, ultimately, cardiac failure [ 7 - 10 ]. Of interest, these histopathological changes are not restricted to PAH but can be observed in several other forms of PH [ 11 ].

On the other hand, Martorell ulcers have been found to develop secondary to limited skin perfusion pressures resulting from an increase of vascular resistance in small cutaneous vessels. It has also been suggested that this increase of vascular resistance affects the vessel relaxation that usually follows distal to an arterial narrowing, which might further decrease tissue perfusion [ 12 ].

The striking histopathological and pathophysiologic similarities between Martorell ulcer and PAH as well as chronic PH due to other conditions prompted this case–control study. The aim was to analyse a potential association between Martorell ulcer and the development of PH.

From May 1999 to April 2011, 46 patients with Martorell ulcer were diagnosed at the Department of Dermatology, University Hospital of Zurich [ 4 ]. After reviewing the cases, a total of 15 patients were identified for further diagnostic workup according to the study design (Figure ​ (Figure2). 2 ). Patient history was checked for i) the presence of chronic obstructive or restrictive pulmonary disease, ii) chronic thromboembolic pulmonary hypertension and iii) concomitant diagnosis of systemic disorders that have been associated with the development of pulmonary hypertension due to unclear multifactorial mechanisms (e.g. sarcoidosis, neurofibromatosis, tumoral obstruction, etc.) [ 13 ]. Patients characteristics are shown in Table ​ Table1. 1 . For each case, 2 controls were matched to gender, age at time of echocardiography (± 2 years), presence of hypertension, current smoking and presence or absence of diabetes mellitus. Data were retrieved from the electronical data pool of the hospital and included in-patients from all hospital departments. Echocardiographic workup was performed at the Department of Cardiology, University Hospital of Zurich, Switzerland (12 of 14 patients) as well as in 2 other hospitals (2 of 14 patients).

Study design.

Characteristics of patients and controls

Study design.

The study was conducted at a tertiary care hospital (University Hospital of Zurich, Switzerland) and was approved by the ethics committee of the medical faculty of the University of Zurich. The study was designed as case–control study to investigate a potential correlation between the presence of Martorell ulcer and pulmonary hypertension (PH).

Echocardiography

All patients underwent a complete transthoracic echocardiographic study. Pulmonary arterial pressure (systolic pulmonary arterial pressure, sPAP) was estimated in a non-invasive manner by measuring the maximal velocity of the tricuspid regurgitation jet and calculating the maximal instantaneous systolic pressure difference between the right ventricle and the right atrium [ 14 ]. Pulmonary hypertension was defined according to the Dana Point criteria as sPAP >36 mmHg, i.e. a tricuspid jet velocity of >2.8 m/s corresponding to an RV/RA gradient of >31 mmHg and adding a right atrial pressure estimate of 5 mmHg [ 15 ]. Diastolic dysfunction was estimated by measurement of left atrial diameter [reference < 4.0 cm] and right atrial diameter (as assessed by short [< 4.1 cm] and long axis [< 5.0 cm]) as well as analysis of the E/A-ratio, defined as flow velocity of passive filling of the left ventricle divided by flow velocity of active filling due to atrial contraction [> 1].

All data are shown as mean ± standard deviation (confidence interval of 95%). Data were checked for normality by using the Kolmogorov-Smirnov test. Statistical comparison between patients and controls were assessed with the use of the student’s t-test. A p-value <0.05 was considered to be statistically significant. Spearman’s test was used for correlation analysis.

46 patients with Martorell ulcer were retrieved from a retrospective data base. Twentytwo files concerned subjects who were already deceased, leaving a total of 24 eligible patients. One patient was excluded because of retrospectively revised diagnosis of peripheral arterial disease instead of Martorell ulcer. Eight patients refused to participate at the study. Fifteen patients were further evaluated for the presence of PH by echocardiography. One patient was excluded after analysis because systolic RV/RA gradient could not be measured due to absence of tricuspid regurgitation.

Patient data from 14 patients with Martorell ulcer were compared to data of the control group; details of patients’ characteristics are provided in Table ​ Table2. 2 . Briefly, 6 of 14 patients (42%) were male, the mean age was 77 years (range 70–89 years). Hypertension was present in all patients with Martorell ulcer (100%), type 2 diabetes mellitus was found in 5 of 14 patients (37%). 2 patients (14%) were still active smokers whereas 3 (22%) had stopped smoking (former smokers), 9 (64%) had never smoked. Creatinine levels and estimated glomerular filtration rate (GFR) as calculated according to MDRD (modified diet in renal disease formula [ 16 ]) were normal in 6 of 14 patients (42%) and in 12 of 28 controls (43%) [reference range 70 – 110 μmol/l]. Renal function was moderately reduced in 6 of 14 patients (CKD stage 3 in 42% patients) and in 14 of 28 controls (50%). 2 of 14 patients (16%) and 2 of 28 controls (7%) showed severe (CKD stage 4) reduction in renal function. Creatinine levels at time of echocardiography (109 ± 51 vs. 104 ± 42 μmol/l) and GFR according to MDRD (64 ± 37 vs. 59 ± 19 ml/min) did not reveal significant differences between patients and controls. Oral anticoagulation was established in 8 of 14 patients (50%) and in 8 of 28 controls (28%). Levels of antinuclear antibodies (ANA) were negative in 6 of 14 patients; elevations above 1:160, which is used as cut-off at the University Hospital Zurich, were observed in 2 patients (14%) without clinical signs of a systemic autoimmune disease. Since Martorell ulcer was diagnosed by tissue biopsy, no evidence for coumarin-induced skin necrosis or autoimmune disorders associated with the development of ulcerating lesions has been found.

Comparison between patients and controls

* E / A ratio could not be assessed due to atrial fibrillation in 5 of 14 patients and in 8 of 28 controls.

† Mitral insufficiency in 1 of 14 patients and 3 of 28 controls; severe aortic stenosis in 2/14 and 2/28, respectively.

Body mass index (BMI, defined as body weight in kilograms divided per height in square meters) of patients with Martorell ulcer was significantly higher than in the control group (29.5 ±7.0 vs 25.8 ± 4.0 kg/m 2 ).

The RV/RA gradient is significantly elevated in patients with martorell ulcer

As shown in Figure ​ Figure3a, 3 a, the RV/RA gradient systolic pulmonary arterial pressure (sPAP) in patients with Martorell ulcer (33.8 ± 16.9 mmHg) was significantly higher than the pressure measured in the control group (25.3 ± 6.5 mmHg, p = 0.023). The absolute difference between the means of the gradients of cases and controls was 8.5 mmHg. This difference was independent of left heart function, since all 14 patients showed a normal left ventricular ejection fraction (LVEF ≥ 50%, 62% ± 3). On the other hand, in 4 of 28 controls the LVEF was found to be impaired (58% ± 12); the difference observed between left ventricular function of patients and controls however was not significant. Dilatation of the left atrium (end-systolic-diameter (ESD) > 4 cm) is considered to be an important surrogate marker of diastolic dysfunction, which, in turn, might lead to pulmonary hypertension. Left atrial ESD exceeding 4.0 cm was found in 10 of 14 patients (71%) and in 16 of 28 controls (57%). The difference in left atrial ESD between patients (4.47 cm ± 1.05) and controls (4.35 cm ± 0.80) is illustrated in Figure ​ Figure3b 3 b and was not statistically significant. Measurement of right atrial diameter assessed by long and short axis did not differ between patients and controls. Similarly, no significant differences were found in the E/A-ratio between the patient group and the control group.

Differences between patients and controls. a ) The RV/RA gradient is significantly higher in patients as compared to matched controls (p = 0.023); b ) the end systolic diameter (ESD) of the left atrium is not significantly different between patients and controls; c ) the BMI is higher in patients than in controls (p = 0.036); d ) prevalence of PH in patients and controls with elevated BMI (cut-off 25 kg/m 2 ). Data in a - c are plotted as median including upper and lower whisker.

The prevalence of pulmonary hypertension in patients with martorell ulcer is significantly higher than in controls

When pulmonary hypertension was defined as sPAP >36 mmHg or as RV/RA gradient of >31 mmHg, respectively [ 15 ], the prevalence of pulmonary hypertension in patients with Martorell ulcer was 5 out of the 14 cases (36%). This figure was significantly higher than in the control group, in which only 2 out of 28 cases (7%) had an elevated RV/RA gradient (p = 0.031).

The BMI in patients with martorell ulcer was higher than in controls

Of interest, the absolute difference of the BMI between patients and controls was 3.7 kg/m 2 ; this difference did reach statistical significance (Figure ​ (Figure3c, 3 c, p = 0.036). Figure ​ Figure3d 3 d shows the prevalence of pulmonary hypertension in patients and controls with or without elevated BMI. 30% of patients with a BMI > 25 were found to have pulmonary hypertension as compared to 6.25% of obese controls. On the other hand, 50% of Martorell patients with a BMI < 25 were detected to have an elevated sPAP as compared to 8.3% of non-obese controls. For severity of pulmonary hypertension, no association between BMI and sPAP was found in patients or in the collective population of investigated patients and controls (data not shown).

In the present study, we investigated the prevalence of PH in subjects with Martorell ulcer and found that the sPAP as assessed by echocardiography is significantly elevated in patients as compared to matched hypertensive controls.

Martorell ulcer is caused by hypertensive changes in subcutaneous skin arterioles leading to reduced tissue perfusion; Martorell ulcer is, though underdiagnosed, an uncommon cause for leg ulcers [ 4 ]. PAH is another orphan disease defined by increased pulmonary arterial pressure due to remodelling of small pulmonary arteries. The list of associated conditions and risk factors predisposing for the development of PAH however has been growing constantly [ 13 ]. Moreover, when all conditions are considered that result in elevation of pulmonary pressure, PH is of emerging clinical relevance.

Histopathological changes observed in the peripheral arterial vessels within a Martorell ulcer include stenotic arteriosclerosis with calcification and hypertrophy of the vessels media, resulting in an increase of the wall to lumen ratio [Figure ​ [Figure1. 1 . Of interest, similar changes are seen in the remodeling of arteries described in the pulmonary vasculature of patients with several forms of chronic PH including hypertrophy and hyperplasia of smooth muscle fibers in the media of muscular arteries resulting in an increase of the cross sectional area [ 11 , 17 ].

In this case–control study, we found that patients with Martorell ulcer have significantly higher levels of sPAP compared to a matched control group. This difference has been assessed in a non-invasive manner by the use of transthoracic echocardiography. This method has been challenged by a recent study and was found to be inaccurate for diagnosing PH [ 18 ]; however, Doppler echocardiography is a validated and largely utilized modality to assess right ventricular function and is the currently established approach to screen patients for elevated pressure within the pulmonary circulation [ 19 ]. Of course, the method is limited for several reasons and does not permit direct conclusions on the type of PH. Right heart catheterization to confirm the diagnosis and evaluate the severity of PH was not considered as feasible approach within this distinct study population; study design and ethical proposal thus were based on echocardiographic assessment. Patients and controls did not show significant differences when compared for left ventricular function, volume of left and right atrium, E/A ratio or the presence of significant valvular heart disease.

However, the difference in BMI between patients and controls reached statistical significance. Together with the presence of other risk factors for a metabolic syndrome, such as age, systemic arterial hypertension and diabetes mellitus, these data suggest that diastolic heart failure is of major importance in the development of an elevated pulmonary arterial pressure – in both patients with Martorell leg ulcer and hypertensive controls. Of interest, however, more Martorell patients with a normal BMI developed pulmonary hypertension than obese patients. Whether the significantly increased prevalence of pulmonary hypertension in patients with Martorell leg ulcer might additionally be caused by other, pre-capillary factors remains, mainly due to the lack of invasive hemodynamic data and the absence of histopathological evidence for remodelling of pulmonary arterioles, hypothetically.

The main finding of this study, i.e. that the prevalence of an elevated pulmonary arterial pressure in patients with Martorell leg ulcer was significantly higher than in the control group, suggest that patients with Martorell ulcer appear to have an increased risk to develop PH, most probably due to diastolic heart failure, which can be prominent in patients with Martorell leg ulcer due to longstanding arterial hypertension. Other studies will have to investigate whether the presence of Martorell leg ulcer might additionally predispose for pre-capillary PH as it was shown similarly for hyperthyroidism [ 20 ], concomitant HIV infection [ 21 ] or smoking [ 22 ].

Our data further imply that hypertensive patients with leg ulcers who present with signs of right heart failure including dyspnea, peripheral edema, hypoxemia and reduced exercise capacity should undergo prompt echocardiographic evaluation to exclude or confirm the presence of an elevated sPAP. Since adequate treatment of hypertension does not prevent Martorell ulcer [ 4 ], it seems unlikely that the development of PH can be avoided by the control of systemic blood pressure. On the other hand, it remains unclear whether the specific therapy with vasodilatating agents (e. g. phosphodiesterase-5 inhibitors or endothelin receptor antagonists) might improve tissue perfusion and, thus, would enhance the wound healing of Martorell ulcer. However, patients with Martorell ulcer and concomitant PH could benefit from early diagnosis and onset of an adequate therapy.

Our study is limited, as mentioned above, by the fact that pulmonary arterial pressures were assessed non-invasively by echocardiography and not by right heart catheterization; moreover, the study lacks supporting biomarker data, and, finally, the case number is low, which is due to the fact that Martorell ulcer is a rare disease. Since this study was designed as observational and not as interventional study, the low case numbers should not severely affect our conclusions.

Taken together, this is to our knowledge the first report showing a potential association between the development of PH and Martorell ulcer. Patients with Martorell ulcer might be at significant risk to develop PH. Our data emphasize that hypertensive patients with leg ulcers should promptly be screened for the presence of an elevated pulmonary arterial pressure when presenting with dyspnea, hypoxemia or reduced exercise capacity.

Abbreviations

BMI, Body-Mass-Index (kg/m2); CKD, Chronic kidney disease; ESD, End systolic diameter (cm); GFR, Glomerular filtration rate (ml/min); LVEF, Left ventricular ejection fraction (%); MDRD, Modified diet in renal disease formula; n/a, Not applicable; PAH, Pulmonary arterial hypertension; PH, Pulmonary hypertension; RAD, Right atrial diameter; RV/RA, Right ventricular – right atrial pressure gradient (mmHg); sPAP, Systolic pulmonary arterial pressure (mmHg).

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

LGvB, MF, RS, SU and LCH contributed to the design of the study and data collection, performed statistical analysis and interpreted data, FCT performed transthoracic Doppler echocardiography, JH contributed to data collection. GN and MB reviewed drafts of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors thank Ulla Treder, Simone Stickel, Vreni Widmer, Jana Kunst, Isabel Schmied and Ulrike Held for their assistance.

• Martorell F. Las ulceras supramaleolares por arteriolitis de las grandes hipertensas. Actas (Reun Cientif Cuerpo Facul) Inst Policlinico Barcelona. 1945; 1 (1):6–9. [ Google Scholar ]
• Hines EA, Farber EM. Ulcer of the leg due to arteriosclerosis and ischemia, occurring in the presence of hypertensive disease (hypertensive-ischemic ulcers); a preliminary report. Proc Staff Meet Mayo Clin. 1946; 21 :337–346. [ PubMed ] [ Google Scholar ]
• Farber EM, Hines EA, Montgomery H, Craig W. The arterioles of the skin in essential hypertension. J Invest Dermatol. 1947; 9 (6):285–298. [ PubMed ] [ Google Scholar ]
• Hafner J, Nobbe S, Partsch H, Läuchli S, Mayer D, Amann-Vesti B, Speich R, Schmid C, Burg G, French LE. Martorell hypertensive ischemic leg ulcer; A model of ischemic subcutaneous arteriolosclerosis. Arch Dermatol. 2010; 146 (9):961–968. doi: 10.1001/archdermatol.2010.224. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Shutler SD, Baragwanath P, Harding KG. Martorell’s ulcer. Postgrad Med J. 1995; 71 (842):717–719. doi: 10.1136/pgmj.71.842.717. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Henderson CA, Highet AS, Lane SA, Hall R. Arterial hypertension causing leg ulcers. Clin Exp Dermatol. 1995; 20 :107–114. doi: 10.1111/j.1365-2230.1995.tb02666.x. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet. 1998; 352 :719–725. doi: 10.1016/S0140-6736(98)02111-4. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006; 173 :1023–1030. doi: 10.1164/rccm.200510-1668OC. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Ghofrani HA, Barst RJ, Benza RL, Champion HC, Fagan KA, Grimminger F, Humbert M, Simonneau G, Stewart DJ, Ventura C, Rubin LJ. Future perspectives for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54 (Suppl):S108–S117. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Hassoun PM, Mouthon L, Barberà JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX, Humbert M. Inflammation, growth factors, and pulmonary vascular remodelling. J Am Coll Cardiol. 2009; 54 (Suppl):S10–S19. [ PubMed ] [ Google Scholar ]
• Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, Reid LM, Tuder RM. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004; 43 (Suppl):S25–S32. [ PubMed ] [ Google Scholar ]
• Duncan HJ, Faris IB. Martorell's hypertensive ischemic leg ulcers are secondary to an increase in the local vascular resistance. J Vasc Surg. 1985; 2 (4):581–584. [ PubMed ] [ Google Scholar ]
• Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009; 54 (Suppl):S43–S54. [ PubMed ] [ Google Scholar ]
• Zipes DP, Libby P, Bonow RO, Braunwald E. Braunwald´s Heart Disease, A Textbook of Cardiovascular Medicine. PA: Elsevier Saunders; 2001. p. 173. [ Google Scholar ]
• Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. Diagnosis and assessment of pulmonary hypertension. J Am Coll Cardiol. 2009; 54 (Suppl):S55. [ PubMed ] [ Google Scholar ]
• Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, Van Lente F. Chronic Kidney Disease Epidemiology Collaboration, Expressing the modification of diet in renal disease study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem. 2007; 53 (4):766–772. doi: 10.1373/clinchem.2006.077180. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Galiè N, Hoeper MM, Humbert M. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT) Eur Heart J. 2009; 30 (20):2499. [ PubMed ] [ Google Scholar ]
• Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S. Inaccuracy of Doppler echocardiographic estimates of pulmonary artery pressures in patients with pulmonary hypertension: implications for clinical practice. Chest. 2011; 139 (5):988–993. doi: 10.1378/chest.10-1269. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Lau EM, Manes A, Celermajer ES, Galiè N. Early detection of pulmonary vascular disease in pulmonary arterial hypertension: time to move forward. Eur Heart J. 2011; 32 (20):2489–2498. doi: 10.1093/eurheartj/ehr160. May 26. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Thurnheer R, Jenni R, Russi EW, Greminger P, Speich R. Hyperthyroidism and pulmonary hypertension. J Intern Med. 1997; 242 (2):185–188. doi: 10.1046/j.1365-2796.1997.00191.x. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest. 1991; 100 (5):1268–1271. doi: 10.1378/chest.100.5.1268. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Schiess R, Senn O, Fischler M, Huber LC, Vatandaslar S, Speich R, Ulrich S. Tobacco smoke: a risk factor for pulmonary hypertension? A case control study. Chest. 2010; 138 (5):1086–1092. doi: 10.1378/chest.09-2962. [ PubMed ] [ CrossRef ] [ Google Scholar ]