How the Immune System Favors Females in Pulmonary Artery Hypertension? Another Regulatory T Cell Story.

While it is commonly thought that cardiovascular disease is a man’s disease, CVD is the number one killer of women with the same number of deaths per year as cancer, diabetes and respiratory disease combined (according to 2015 statistical data from AHA). In addition, women exhibit different and more silent symptoms of heart attacks. There is a lot of interest in the difference between how males and females respond to CVD. A lot of emphasis is put on hormonal differences, but the immune system also seems to play an important role in this disparity. Females have a more robust immune system and therefore respond faster to infections providing more protection than in males. However, a more responsive immune system also means a more reactive immune system that can result in increased incidence of autoimmune diseases, such as rheumatoid arthritis and lupus.

Part of the difference in the immune system response in females can be attributed to the fact that multiple immune-related genes are expressed on the X chromosome. Since females have two alleles of the X chromosomes and males have only one, it is evident that females express more genes that regulate immune system functions. One of these genes is Foxp3, the key transcription factor for regulatory T cells, an adaptive immune cell which I have discussed before in a previous post. Regulatory T cells play an important protective role in CVD, especially in atherosclerosis and hypertension.

Pulmonary artery hypertension (PAH) is a fatal cardio-pulmonary disorder where the pulmonary arterioles narrow leading to a right ventricular fibrosis, heart failure and death. Regulatory T cells play an important role in this disease as animal models that lack regulatory T cells are more susceptible to PAH. Adding regulatory T cells back prevents the development of PAH showing the protective power of these cells. A recent study published in the journal Circulation Research, shows that in the absence of regulatory T cells, females rats are more prone to PAH than male animals due to a lower levels of PGI2, a pulmonary vasodilator, and the lack of the enzyme COX-2 that regulated PGI2. The researchers conducting the study show that by transferring regulatory T cells into these rats, these immune cells were sufficient to restore the levels of COX-2 and PGI2, as well as other immune inhibitory molecules PDL1 and IL-10. The authors suggest that regulatory T cells have both a direct and indirect effects on the arteries. The direct effects are exerted on the endothelial cells directly via COX-2 and PGI2, and the indirect effect is through the release of inhibitory molecules such as IL-10 and TGF, both of which would result in immune suppression and preventing inflammation. The results from this report suggested that females are more reliant on regulatory T cells for protection against PAH.

These new findings highlight the subtlety of immune regulation between females and males and further proves that in addition to hormonal differences, immune regulation disparities between genders that can alter the outcome of cardiovascular diseases. By understanding more about gender differences in CVD and the immune system, and figuring out ways to manipulate these subtle differences, scientists hope to achieve a more personalized and effective therapies to women versus men to combat CVD.


Dalia Gaddis Headshot

Dalia Gaddis is a postdoctoral fellow at the La Jolla Institute for Allergy and Immunology. She has a Ph.D. in microbiology and immunology. She is currently working on understanding the interactions between the immune system and atherosclerosis development



A Shift in Focus: From a Multi to Single Modality Approach

Since the first A-mode echocardiogram, there have been great revolutional changes and the use of noninvasive cardiac imaging has grown substantially during the past decade. Echocardiography and nuclear modality have been the primary imaging modalities for management in patients with different cardiovascular diseases. The introduction of cardiac magnetic resonance (CMR), computer tomography (CT), and three-dimensional (3D) printing, makes things quite different. Multi-modality imaging plays a role in all cardiovascular diseases that includes ventricular function, coronary artery disease, valvular disease, congenital heart disease, guidance for interventions, and vascular diseases. However, the use of each modality requires knowledge, expertise and forethought about cardiac diagnoses to avoid excess coast, inappropriate testing and to improve outcomes. Unnecessary duplication of investigations must be avoided for cost effective healthcare delivery.

For more than a decade, organizations such as the American College of Radiology and the American College of Cardiology Foundation have published criteria delineating the appropriate use of cardiac imaging. These specialty society guidance documents are designed to provide clinicians with recommendations regarding the use of imaging and are focused on reducing unnecessary and inappropriate testing. In response to rapid and unsustainable growth in the use of cardiac imaging procedures, various professional medical organizations have developed appropriate use criteria (AUC) to guide physicians and payers on effective use of these procedures. The AUC serves as a guide for physicians to incorporate symptoms, risk factors, and clinical history in selecting the patients for whom testing is most appropriate, based on the best available evidence or expert consensus; Furthermore, the AUC can help physicians steer other patients to alternative tests or no testing at all.

The AUC classify the appropriateness of testing across a range of clinical scenarios in 3 categories: “appropriate” (established value), “may be appropriate” (uncertain value), and “rarely appropriate” (no clear value). The AUC are intended to be used as part of a comprehensive disease management plan to maximize the value of care by minimizing unnecessary imaging and resultant downstream invasive procedures. (1). Appropriate use helps to avoid excess costs; enhances the value of imaging in risk stratification and decision making; and reduces radiation risk, particularly in women (2). Moreover, the principle of applying expert consensus criteria to choose the best testing strategy for each patient is widely accepted by payers, physicians, and patient groups.

  • The goal of this statement is not to showcase CMR as the exclusive modality for cardiac diagnosis but to highlight this tool as the corner stone of noninvasive cardiac imaging. By using a static and a gradient magnetic field in combination with a radiofrequency field, CMR imaging has evolved from a less commonly used technique into a tool with the potential to find an important clinical role in the near future for the noninvasive assessment of morphological and functional aspects of the heart. Consequently, CMR belongs to the fastest growing new fields of broad MR application. At the same time, CMR uses some of the strongest and fastest switching electromagnetic gradients available in MR imaging. CMR has become the primary imaging tool in many centers in characterizing disease severity and planning of patient management.
  • Volumes and Function: CMR measures ventricular volumes and mass using a simple acquisition of a 3D stack of contiguous short-axis cines with full biventricular coverage. CMR is significantly more accurate and reproducible than other techniques which makes it the technique of choice for longitudinal study of patients over time and for reducing sample size for drug studies.
  • Great Vessels: Three-dimensional angiography with gadolinium enhancement may show the lesion more clearly in high resolution, but it also shows any associated pathology (collaterals). CMR is fast and accurate for the diagnosis of aortic dissection although local issues relative to availability will determine whether CMR, CT, or echocardiography is used.
  • Valvular Heart Disease: CMR has a significant role in valve disease, but it usually acts as a second-line technique to assist when echocardiography with Doppler has proved problematic because of limited acoustic access, highly eccentric jets, or the need for quantification. The quantification of valve regurgitation is a strength of CMR because of its capability of measuring accurate ventricular stroke volumes from multislice ventricular planimetry and comparing this with the measurement of great vessel flow from velocity mapping.
  • Congenital Heart Disease: CMR is widely used to assess congenital heart disease, and when used in concert with echocardiography, the need for invasive assessment has been significantly reduced. CMR is particularly useful for the safe, accurate, and reproducible quantification of the left-to-right shunting of blood that occurs frequently in congenital heart defects such as atrial or ventricular septal defects, patent ductus arteriosus, aortopulmonary window, and partial or total anomalous pulmonary venous return.
  • Myocardial Ischemia: CMR is a safe and proven modality for detecting ischemic heart disease. Within a single study, CMR is able to assess rest and stress regional contraction, and localize and evaluate regions of myocardial ischemia and viability, of importance given the prognostic impact for the patient. With performance that is comparable to PET/SPECT and at times favorable compared to stress echocardiography, it is now an essential tool for diagnosing ischemia and for determining the likelihood of success following myocardial revascularization.
  • Non ischemic cardiomyopathy: CMR with its higher spatial resolution is considered the gold standard for evaluating ventricular mass, volumes, and ejection fraction. CMR can be used for accurate diagnosis of several conditions, especially cardiomyopathies. CMR is an invaluable tool, not only in differentiating nonischemic from ischemic cardiomyopathy, but also in aiding the accurate diagnosis of the subtype of nonischemic cardiomyopathy. CMR should routinely be integrated in the diagnostic workup of various cardiomyopathies.

CMR is a valuable tool for the evaluation of patients with, or at risk for, heart failure and has a growing impact on diagnosis, clinical management, and decision making. Through its ability to characterize the myocardium by using multiple different imaging parameters, it provides insight into the etiology of the underlying heart failure and its prognosis. CMR continues to develop across a broad range of clinical applications, and much can be expected of this technology in the future.

Fawaz Alenezi Headshot

Dr. Fawaz Abdulaziz M Alenezi is a Clinical Imaging Fellow at the Duke University Health Systems. He conducts medical research on the derivation and validation of novel echocardiographic approaches to myocardial deformation and a new echocardiographic technique which assists patients with heart ventricular function.


Shared Decision Making In Cardiac Care

Illustration of seniors with life insurance

Shared decision making (SDM) is an approach both patients and clinicians can use to improve patient education and discussion in decision making. Decision aids are tools that promote SDM by improving patient-clinician communication about all treatment options and how the risks and benefits fit with their personal values and preferences. Today, we’ll chat about SDM in the context of cardiac care, with examples from atrial fibrillation and heart failure, as well as the entire CAD spectrum.

A Chronological Look at SDM
In 2012, Karen Sepucha reflected on shared decision-making and patient decision aids in an editorial for Circulation: Cardiovascular Quality and Outcomes. Two studies published in the same issue evaluated the impact of decision aids in urgent management of acute coronary syndrome (The Chest Pain Choice Decision Aid) and vascular access choice for coronary angiogram procedures. These studies reflect scenarios that are not traditionally thought to be amenable to SDM, but the results show that SDM in the emergency department and regarding technical treatment decisions, such as femoral versus radial access, had a positive impact on patient knowledge and decisional conflict. Sepucha’s concluding statement still rings true today: “Despite considerable evidence from many studies of decision aids, few of these tools are used routinely in practice.”

There are several challenges to using decision tools in practice. Decision aids should be brief and easily incorporated into the workflow of clinical practice, as well as easily accessible in the public domain. In 2015, CMS implemented a policy around healthcare for atrial fibrillation patients requiring all non-implanting physicians to use evidence-based decision tools and SDM practices. A 2017 article by Megan Coylewright and David Holmes in Circulation caution against this CMS mandate for SDM for patients with atrial fibrillation. The authors cite reasons reminiscent of Sepucha’s conclusions in 2012. Coylewright and Holmes point out that there is limited guidance on navigating SDM for patients with atrial fibrillation at risk for stroke. Specifically, while research consistently shows that “decision aids improve patient outcomes including knowledge, engagement, and satisfaction”, SDM has yet to become an integral part of clinical practice for a variety of reasons, both on the patient side and the clinician side. For example, barriers to use of SDM by physicians include insufficient training in the skillsets necessary to implement SDM, such as “inadequate assessment of patient preferences,” in addition to logistic challenges to implementation, whether at the institutional level, the lack of publicly available decision aids, or the time availability during patient-clinician interactions to thoroughly discuss patient preferences.

Atrial Fibrillation
Atrial fibrillation presents a particularly challenging case for optimizing treatment, due to low prescription, low adherence due to side effects and frequent testing, as well as increased risk of negative reactions due to polypharmacy. Thomson et al. found that atrial fibrillation patients at risk of stroke may deicide to forgo treatment with anticoagulants to avoid the medications’ adverse effects, with the knowledge that their stroke risk later on increased. However, professional guidelines on treatment of atrial fibrillation promote SDM and use of evidence-based decision tools while recognizing that inviting patients to participate in care decisions can be challenging to physicians.

A recent systematic review, “Availability of Patient Decision Aids for Stroke Prevention in Atrial Fibrillation” by O’Neill and colleagues summarize the current state of decision aids for patients with atrial fibrillation at risk for stroke and their treating physicians. The current landscape of pharmacologic therapy for stroke reduction includes multiple DOACs, implantable LAA closure devices, aspirin, and warfarin – each treatment with benefits and trade-offs that must be considered “in the context of individual values and preferences and willingness to adhere to therapy”. Many of the decision aids in the studies reviewed by O’Neill et al. did not display all therapeutic choices, were delivered to patients primarily by nonphysicians, and were not publicly available.

Depression and CAD
SDM and decision tools pair nicely with assessment of depression in heart disease patients. In a recent paper, “Identifying and Managing Depression in Patients with CAD,” Aimee Salzer Pragle and Susan Salashor discuss the epidemiology and risk factors, clinical presentation, assessment tools, and treatment options for depression in patients with heart disease. In a 2011 review, Christopher Celano and Jeff Huffman estimated that 20-40% of patients with CAD may suffer from depression, and despite the availability of screening tools brief enough for clinical practice (such as the Patient Health Questionnaire-9 or -2), depression often goes unrecognized in cardiac care. Depression in patients with CAD is associated with progression of heart disease, poor quality of life and physical functioning, repeat cardiac events, and 2-2.5 fold increased risk of mortality [link]. Risk factors for depression in patients with CAD include “younger age, female sex, a history of depression, social isolation, previous cardiac events, and diabetes” and depression can increase risk of suicide, homicide, and substance abuse (which can exacerbate cardiac symptoms and promote further degeneration).

Innovative Frameworks – A Segue to Implementing SDM?
From the clinician side, disease-specific evaluation frameworks inclusive of all relevant aspects of a patient’s health provide another avenue towards optimizing patient-clinician communication. For example, in a recent paper, Gorodeski et al. present a multi-domain framework for managing heart failure and the associated questionnaires and tools that go with each task.

Gorodeski image
These tools include the Mini Nutritional Assessment Short Form (MNA-SF), the Mini-Cog and PHQ-2 (Patient Health Questionnaire) for mental and emotional state, gait speed, timed Up and Go test, FRAIL questionnaire, and ADL/IADL discussion for assessing physical function, as well as inquiries to social support at home, adaptable and safe environment plans, access to nutrition and transportation, as well as abilities and support in medication management (Table 1, Gorodeski et al).

 Does your department or institution use shared decision making or decision aids in practice?

 What barriers to implementation do you see in incorporating these tools into everyday patient interactions?

SDM and Decision Aids Resources
The Ottawa Hospital Research Institute hosts an up-to-date A to Z inventory of patient decision aids, and includes tools for angina, atrial fibrillation, CABG and other cardiac procedures, blood pressure medications, peripheral artery disease surgery, type 2 diabetes, depression, kidney disease and dialysis, and many others. Many of the tools geared towards cardiac care were in the form of informative articles for patients to read, or interactive tutorial-style pages for patients. None that I found were visual or brief enough to be used in clinical practice. Additionally, purely text-based “decision aids” are not useful for low-literacy populations, and online-only resources are not easily accessible for patients who are less tech-savvy. However, the Heart to Heart tool developed by the University of North Carolina General Internal Medicine department provides a user-friendly interface, even for the less technologically-savvy patients, that guides the user through several slides on how to join the discussion of their own treatment with their doctor. Similarly, the AHA Rise above Heart Failure initiative has two resources heart failure patients and physicians might find particularly useful: a guide to overcoming barriers to shared-decision making and a list of questions to ask the doctor. If you are a physician, reviewing these materials provides you with the guidance of what questions and topics to address during the clinic visit.

Quick links to select decision aids related to heart disease:


Bailey DeBarmore Headshot

Bailey DeBarmore is a cardiovascular epidemiology PhD student at the University of North Carolina at Chapel Hill. Her research focuses on diabetes, stroke, and heart failure. She tweets @BaileyDeBarmore and blogs at baileydebarmore.com. Find her on LinkedIn and Facebook.


Stem Cell Therapy For Heart Failure- Results From First Clinical Trial

Among the various treatment regimens being investigated, cell therapies have achieved the furthest development in human medicine. With the paucity of donor organs and long-term immunosuppressive treatment, replacement of damaged cells within the cardiac tissue with stem or primary cells have offered hope to treat heart failure. The choice of cell type for this application is assured by its accessibility, the risks it may pose and their application in clinical practice. While many other types of cells are under investigation, pluripotent stem cells (PSCs) derived from the embryos namely embryonic stem cells (ES cells) have shown unique and extraordinary capabilities in regenerative medicine. Nonetheless, due to their highly expandable nature and ability to differentiate into various cell types including tumor cells, these cells were never tested in clinical trials until recently.

A recently published study dictates the outcome of clinical trial implementing the use of human ES cell-derived progenitors in severe heart failure. This study represents the first clinical testing of human ES cells in patient suffering from cardiac disease. The trial recruited 6 patients from 2013 to 2016 with diagnosis of severe left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 35%, which is characterized as severe class III ischemic heart failure according to New York Heart Association (NYHA). After taking all safety measures into considerations, the group was granted approval for delivering ES cells in vivo by French regulatory agency after 10 years of encouraging preclinical and translational results.  The first clinical case report of this trial was initially submitted in European heart journal in 2015 which presented the details of their approach and 3 month follow up results from a single patient involved in the clinical trial.

In the presented trial, ES cells were obtained from human I6 line and expanded to desired number of cells required for transplantation in a clinical grade environment. As the heart is derived from the mesoderm, commitment of ES cells towards mesodermal lineage was induced by bone morphogenic protein BMP-2 while reduction of fibroblasts growth was maintained by its inhibitor SU-5402. The purified population of stem cells was sorted by expression of stage specific embryonic antigen (SSEA-1, marker for loss of pluripotentcy) co-expressed with cardiac transcription factor Isl-1. These cells were incorporated into fibrin patch and delivered into pocket created between pericardium and epicardium at the same time of coronary bypass.

Upon 1 year follow up, authors observed no complications related to the surgery. Patient’s cardiac functional status showed remarkable improvement with LVEF increased by 12% and reduction in LV end diastolic and end systolic volumes owing to integration of the grafted cells into the heart tissue. An internal cardioverter defibrillator neither showed any signs of ventricular arrhythmias, nor were there any tumor like formations in the heart detected by computed tomography (CT) and %uFB02uorine-18 deoxyglucose positron emission tomography (PET) scans performed at 6 months (PET scan) and 12 months (CT scan) post operatively. Also, no immunosuppression related adverse events were evident. Additional analysis confirmed that delivery of the ES cells patch not only revascularized the infarcted area but also significantly improved the wall motion of cell/patch treated segment of the heart.

By demonstrating that human ES cells can be differentiated in clinical grade cardiovascular progenitors, the authors have confirmed the scalability and pluripotentiality of these cells which can be now safely delivered in patients with heart disease. Thus, encouraging results from this study has certainly provided an insight for taking cell-based therapies from bench to bedside.


  1. Menasché P, Vanneaux V, Hagège A, Bel A, Cholley B, Parouchev A, Cacciapuoti I, Al-Daccak R, Benhamouda N, Blons H, Agbulut O, Tosca L, Trouvin JH, Fabreguettes JR, Bellamy V, Charron D, Tartour E, Tachdjian G, Desnos M, Larghero J. Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction. J Am Coll Cardiol. 2018;71(4):429-438.
  2. Menasché P, Vanneaux V, Hagège A, Bel A, Cholley B, Cacciapuoti I, Parouchev A, Benhamouda N, Tachdjian G, Tosca L, Trouvin JH, Fabreguettes JR, Bellamy V, Guillemain R, Suberbielle Boissel C, Tartour E, Desnos M, Larghero J. Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report. Eur Heart J. 2015;36(30):2011-7.

Keerat Kaur Headshot
Keerat Kaur is a postdoctoral fellow at Icahn school of Medicine at Mount Sinai in department of cardiology, NY. Her research focuses on reprogramming non-cardiacmyocytes to cardiomyocytes using modified mRNA approach.



Women’s Heart Disease – The Interdisciplinary Road Ahead

Every 80 seconds a woman dies from a heart attack or stroke. Once thought to be predominantly found in men, coronary heart disease remains the leading cause of morbidity and mortality for women in the US and worldwide. There have been significant improvements in cardiovascular mortality in women in the last two decades with narrowing of outcomes between women and men which have been attributed to improved therapy for established cardiovascular disease and to primary and secondary preventive interventions. However, women are less likely to receive evidence-based care and have worse outcomes than men. Gender differences have been recognized, but vast knowledge gaps in gender differences regarding pathophysiology, clinical presentation, diagnosis, and optimal acute and chronic treatment strategies for heart attacks and co-existing or resulting complications such as heart failure remain. The AHA Scientific Statement “Acute Myocardial Infarction in Women” provides a comprehensive review of the current evidence.
At the opening plenary session of the American College of Cardiology ACC.18 meeting in Orlando, Florida, the pioneer of women’s cardiology Dr. Nanette Kass Wenger gave her inspiring Simon Dack keynote lecture on Heart Disease & Women titled “Understanding the Journey-The Past, Present and Future of CVD in Women.”
In “Steps on the journey” Dr. Wenger gave a comprehensive review of the early beginnings and showed how far we have come. Some interesting anecdotes were also shared such as that the first women’s heart disease meeting in Iowa in the 1950s was to help women prevent heart attacks in husbands.
Her impactful vision on how to expand the landscape of women’s cardiovascular health research in the next decade struck a nerve with me and made me re-think some of the concepts we are applying in academic cardiology. Dr. Wenger called for an expansion of women’s cardiovascular health research to include social determinants of health as nearly 80% of heart outcomes depend on social factors. Women’s Heart Health is not solely a medical problem and clinical research cannot happen in a vacuum in the hospital. A variety of factors contribute to women’s cardiovascular health and need to be considered for maintenance of health and cure of disease. Women’s Heart Heath needs to be extended. Factors like beliefs and behaviors, the local community, economic, environmental, ethical, legislative/political, public policy – all these social determinants need to be included in heart disease research in women.
My take away for the future was that we cannot longer compartmentalize and that programs focusing on Women’s Heart Heath need to involve all programs available- not only cardiology. It needs to be an interdisciplinary approach to learn more about physiology, psychology and ecology of health for best outcomes and to tackle Women’s Heart Health.
Dr. Wenger quoted the French Victor Hugo in her inspiring lecture.
“There is nothing as powerful as an idea whose time has come.”
Victor Hugo
Histoire d’un crime, 1977

Tanja Dudenbostel Headshot

Tanja Dudenbostel is an Internist, Hypertension Specialist within Cardiology at the University of Alabama at Birmingham where I divide my time as an Assistant Professor between clinical research and seeing patients in cardiology.



A Vicious Cycle: Heart Disease And The Immune System

When I first started my career as a scientist, I had no idea how much impact the immune system has on cardiovascular disease. I was under this naïve idea that disease progression was dependent on blood cholesterol levels, stress or genetics only, never realizing how much the immune system influenced cardiovascular disease. Now that I have been studying the influence of heart disease on the immune system for a few years, I am still amazed by how intertwined these two systems are.
There is a lot of published research, both in patients as well as in experimental animal models, showing that the immune system plays a role in multiple heart conditions. Atherosclerosis is a prime example. The process of hardening of blood vessels due to cholesterol and lipid deposits is an immune system mediated disease. The inflammation triggered by the immune system is the root cause of the process of plaque formation and blood vessels blockage. Viral myocarditis, which can cause sudden death, occurs as a result of a hyper reactive immune response to viral infections. In congestive heart failure, the immune system contributes to disease by releasing inflammatory molecules that further increase the heart size. The influence of the immune system also extends to other disease that can trigger heart disease such as diabetes and obesity.
If you think the interaction between cardiovascular disease and the immune system stops there, think again. Recently, it has become evident that the cardiovascular and the immune systems live in this vicious cycle of constantly influencing each other to worsen disease outcome. For instance, the increase in lipids accumulated during coronary artery disease or obesity affects how the cells of the immune system consume fuel resources such as glucose and fats, a process known as immunometabolism. Changes in immunometabolism influence how immune cells respond to injury triggered by the increased lipids, further worsening disease. Not only that, but by virtue of overall changes in how immune cells function, heart and metabolic disease can affect how the immune system as a whole responds to other conditions such as infections and cancer.
This field of immunometabolism is still at its infancy. It will be interesting to see how much it will advance in the next few years and how much relationship scientists will find between immunometabolism and heart disease. If therapeutic approaches are found that can break this vicious cycle, patients with heart disease and other metabolic disease will gain tremendously. I would expect that the impact of such therapeutic approaches would extend to other ailments that hit those patients beyond the scope of cardiovascular disease.

Dalia Gaddis Headshot

Dalia Gaddis is a postdoctoral fellow at the La Jolla Institute for Allergy and Immunology. She has a Ph.D. in microbiology and immunology. She is currently working on understanding the interactions between the immune system and atherosclerosis development.