Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials
SMAD5 Is A Potential Novel Gene In Patients With Familial PAH
Among patients with familial pulmonary arterial hypertension (PAH), SMAD5 appears to be a novel gene that warrants consideration for genetic testing, according to findings from a study conducted in Germany and published in Clinical Science (London).
Individuals with the rare disorder PAH experience elevated pulmonary vascular resistance and right ventricular hypertrophy, which eventually lead to right heart failure. Of note, genetic mutations in 18 or fewer recognized PAH genes have been shown to be associated with abnormal proliferation and apoptosis of endothelial cells, pulmonary vascular smooth muscle cells, and fibroblasts. This, in turn, causes thickening of the pulmonary arterial walls.
Approximately 85% of patients with familial PAH and 15% of those with idiopathic PAH present with a disease-associated mutation. The main causative gene in PAH is recognized as being the bone morphogenetic protein receptor type 2 (BMRP2), which is part of the super family known as transforming growth factor beta (TGF-β). Since the discovery of the BMRP2 gene, additional genes both within and outside the BMRP2 pathway have been detected as causative agents of PAH.
BMRP2 signaling is facilitated after the binding of bone morphogenetic proteins to BMRP2 and a type 1 receptor via small mothers against decapentaplegic (SMAD) homologous proteins. Notably, SMAD1, SMAD5, and SMAD8 each form a complex with the "common" SMAD protein, which is known as SMAD4.
Read more about PAH history
Eighteen PAH genes were routinely sequenced via next generation sequencing, using a patented PAH gene panel at the largest German referral center for the genetic testing of patients with PAH.
By using this technique, the researchers of the current study previously identified mutations among 23% of 325 consecutive patients with PAH. In the same analysis, however, families with heritable PAH and those with other potential genetically established types of PAH, such as PAH associated with congenital heart disease, without a genetic cause in any of the currently recognized PAH genes were identified.
Among these individuals, the researchers sequenced up to 41 additional candidate genes, including SMAD5, which had not been previously identified as a disease-causing gene in PAH. Among a cohort of the remaining 251 patients with PAH and no known disease-causing variant in any of the 18 known PAH genes, the investigators were able to detect 2 rare and novel missense variants in SMAD5. "The variant c.1175T>C p.(Leu392Pro) was identified in a heritable PAH family and the variant c.277T>A p.(Trp93Arg) in a patient with [PAH associated with congenital heart disease]."
The researchers sought to clinically characterize the variant carriers and to functionally evaluate the role played by the 2 novel SMAD5 variants in cell proliferation, viability, and apoptosis in vitro.
The first SMAD5 missense variant—c.1175T>C p.(Leu392Pro)—was identified in a Ukrainian family with heritable PAH. In this family, there was a patient with heritable PAH who had a healthy son. The mother died of suspected PAH at 42 years of age.
The second variant in SMAD5—c.277T>A p.(Trp93Arg)—was identified in a female patient with PAH associated with congenital heart disease. In this case, the variant was associated with a surgically repaired ventricle septal defect in the patient's father, who died at 33 years of age of an unrecorded cause.
"Taking into account familial aggregation, clinical findings and functional evidence[,] both variants could be classified as likely pathogenic," the authors noted. "This is the first description of SMAD5 as a potential novel PAH gene for genetic diagnostic testing," they concluded.
This article originally appeared on Rare Disease Advisor
Cardiac Aging Lab
Division of Kinesiology and Health
The Bruns lab is interested in the molecular mechanisms underlying heart disease and heart failure. Our research focuses on the impact of age on the failing heart, sex differences in heart failure development and treatment, exercise as medicine for heart failure, and the identification of new therapies for the treatment of cardiac disease.
dbruns1@uwyo.Edu Interested in being a student in the Cardiac Aging Lab? Please contact Dr.Bruns - we're always seeking motivated students! Collaborators Emily Schmitt, PhD. UW K&H. Circadian rhythm in the heartEvan Johnson, PhD. UW K&H Circadian rhythm and the aging kidneyKathleen Woulfe, PhD. UC-Denver Cardiology. Heart failure across the life courseCurrent Projects
The right heart: You're only as strong as your weakest link
The heart is a 4-chambered organ with two sides- the left heart which pumps to the periphery and the right heart which pumps through the lungs. Cardiac function is limited by the performance of its weakest ventricle, meaning that even in contexts of healthy left ventricular (LV) function, the heart can only perform as well as its weakest link. In the setting of many human diseases such as heart failure and pulmonary hypertension, this means that right ventricular (RV) function predicts survival. Our group is interested in understanding how the right heart fails and identifying therapeutic targets for the RV- a disease in which very few therapeutic options exist.
The aging right heart
Aging imparts known changes to the left heart- including hypertrophy, fibrosis, inflammation, and overall reduced cardiac function. How these changes impact the right heart remains unknown. Our group uses two models of right heart failure- high altitude induced pulmonary hypertension and a surgical model of disease (pulmonary artery banding; PAB)- to understand how the old heart remodels in a distinct manner from the young heart and how this may inform therapeutic approaches for older patients with heart failure. Specifically, we are currently testing an AMPK activator as novel therapy for the aging right heart.
Skeletal muscle dysfunction in heart failure
Heart failure is a systemic disease, with peripheral effects including skeletal muscle dysfunction. In human patients, muscle dysfunction manifests as exercise intolerance. We're interested in the molecular mechanisms underlying this skeletal muscle dysfunction, and the identification pf therapies to improve muscle function in young and old patients with heart failure.
Exercise as Medicine for Heart Failure
Regular endurance exercise is the best protection against development of cardiovascular disease. However, the precise molecular mechanisms for how exercise is so potently cardioprotective are not fully understood. Our group aims to understand how exercise improves cardiac function in the healthy, aging, and failing right hearts, as well as how commonly prescribed medications may interfere with exercise adaptations.
Heart Failure Across the Life-Course
Heart failure impacts patients of all ages- from pediatrics to geriatrics. The risk factors, disease development, and treatment outcomes differ by patient age and sex, suggesting that important differences exist that might impact therapeutic strategies. We aim to understand how age and sex impact disease development, and use these differences to develop personalized medicine for heart failure patients of all ages.
Heart Failure, Pulmonary Hypertension And Cardiology ICU Fellowship Program
In our comprehensive one-year Heart Failure Fellowship program, you will gain robust comprehensive inpatient and outpatient training in the specialty of heart failure.
Our one-year fellowship is offered to PGY-4 level candidates for training focused on heart failure management, pulmonary HTN, with cardiology ICU exposure. Fellows develop the ability to recognize and manage heart failure and understand disease progression. This is a non-standard training (NST) program that is not ACGME accredited.
Our program provides superior cardiology training in a collaborative environment. We have specialty clinics across our medical campus, which is anchored by our 1,200 bed inpatient center UAB Hospital—the eighth largest public hospital in the nation. The hospital is in close proximity to the Birmingham VA Medical Center, UAB Hospital Highlands campus, The Kirklin Clinic, and Children's Hospital of Alabama where fellows also train.
Clinical RotationsOur program offers comprehensive, multidisciplinary training within a collaborative environment. We focus on developing our heart failure fellows by expanding their expertise in areas of advanced heart failure, transplant cardiology, mechanical circulatory support, and pulmonary vascular disease through a combination of inpatient and outpatient care. At the Kirklin Clinic, fellows will engage in specialized clinics for CHF, PH, VAD, transplant, and biopsy suites.
At the Birmingham VA Medical Center, fellows manage a panel of patients longitudinally throughout their training. They also participate in Block model rotations, covering general cardiology, arrhythmia, heart failure, pulmonary hypertension, and elective time including adult congenital heart disease over the three-year program.
Our inpatient services are anchored in our heart transplant ICU, where leading-edge clinical programs for heart transplant, VAD, and PH are managed. Our teams work closely with cardiovascular surgery and interventional/structural cardiologist to address cardiogenic shock using temporary MCS techniques like ECMO, Impella, and TandemHeart. Furthermore, we provide exposure to unique clinical programs such as Cardio-Obstetrics, Cardio-Oncology, and Amyloid/infiltrative cardiomyopathies. Our heart failure fellows aid in supporting our team in managing complex valvular diseases.
Research OpportunitiesOur Heart Failure, Pulmonary Hypertension and Cardiology ICU program works closely with the UAB Comprehensive Cardiovascular Center to foster multi-disciplinary and multi-investigator collaborations and programmatic development in cardiovascular research. We strive to enrich our fellows training experience by exposing them to cutting-edge research in basic, clinical, population, and translational cardiovascular research.
It's not just what you learn. It's also about the people you learn with. Our cardiology fellowship program leaders are dedicated to developing the potential of every talented trainee.Meet our people
Frequently Asked QuestionsAll applications are reviewed by our UAB Cardiology Review Team. All submissions require the following documents:
Current Curriculum Vitae
Professional Photo
Personal Statement
Three (3) total Letters of Recommendation
Certificate/verification from previous residency training
Must be eligible for Alabama Medical License and Alabama Controlled Substance Certificate (all step scores completed at the time of application)
Must be eligible for Federal DEA registration
USMLE or COMLEX Scores
Our program provides benefits and insurance plans available to all fellows at UAB. You can find the list of salaries and benefits for fellows based on PGY level here.
There is no minimum USMLE score requirement. We take the score into account as part of the overall review of an application.
Applications Open and Close — Applications open Decemeber 1 and close December 31.
Applications Reviewed — December
Interview Invitations Released — Mid December
Interviews Begin — December
Fellowship begins — July 1
It would be my pleasure to speak with you about the amazing training opportunties we provide at UAB. Please contact me if you have any questions about our Heart Failure, Pulmonary Hypertension and Cardiology ICU Fellowship program. Andrew Lenneman, M.D., Program Director
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I'd be delighted to talk with you about the many exciting possibilities that await you at UAB and Birmingham. Contact me for more details about our fellowship.
Joanna Joly, M.D., Associate Program Director
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