Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator-activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Association of activin A and postpartum blood pressure in peripartum cardiomyopathy.

BACKGROUND: Activin A has been implicated in the pathogenesis of patients with chronic hypertension and heart failure as well as patients with hypertensive disorders of pregnancy (HDP). Whether activin A correlates with blood pressure in patients with peripartum cardiomyopathy (PPCM) and HDP history has not previously been explored. METHODS AND RESULTS: 82 women with PPCM w/ and w/out HDP or hypertension history were selected for analysis from the Investigations in Pregnancy Associated Cardiomyopathy (IPAC) study. Serum biomarkers and blood pressure were assessed at the time of enrollment (median postpartum day 24). Levels of both sFlt-1 (SBP: r 0.47, p = 0.008; DBP: r 0.57, p < 0.001) and activin A (SBP: r 0.59, p < 0.001;DBP: r 0.68, p < 0.001) were noted to significantly correlate with blood pressure in patients with a history of HDP who went on to develop PPCM, but not in patients with chronic hypertension or no hypertensive history. The strongest correlation was between activin A levels and postpartum diastolic blood pressure for the subset with preeclampsia (DBP: r0.82, p < 0.001). This remained significant in multivariable linear regression analysis (DBP: ß = 0.011, p = 0.015). CONCLUSION: In patients with PPCM, activin A and sFlt-1 levels had direct correlations with both systolic (SBP) and diastolic blood pressures (DBP), but only in participants with history of HDP. This correlation was more evident for activin A and strongest with a history of preeclampsia. Our findings suggest that activin A may play an important role in blood pressure modulation in women with HDP who subsequently develop PPCM.

Cardiovascular Fellowship Training in Cardio-Obstetrics: JACC Review Topic of the Week.

The United States has the highest maternal mortality in the developed world with cardiovascular disease as the leading cause of pregnancy-related deaths. In response to this, the emerging subspecialty of cardio-obstetrics has been growing over the past decade. Cardiologists with training and expertise in caring for patients with cardiovascular disease in pregnancy are essential to provide effective, comprehensive, multidisciplinary, and high-quality care for this vulnerable population. This document provides a blueprint on incorporation of cardio-obstetrics training into cardiovascular disease fellowship programs to improve knowledge, skill, and expertise among cardiologists caring for these patients, with the goal of improving maternal and fetal outcomes.

Serum Proteomic Analysis of Peripartum Cardiomyopathy Reveals Distinctive Dysregulation of Inflammatory and Cholesterol Metabolism Pathways.

BACKGROUND: The pathophysiology of peripartum cardiomyopathy (PPCM) and its distinctive biological features remain incompletely understood. High-throughput serum proteomic profiling, a powerful tool to gain insights into the pathophysiology of diseases at a systems biology level, has never been used to investigate PPCM relative to nonischemic cardiomyopathy. OBJECTIVES: The aim of this study was to characterize the pathophysiology of PPCM through serum proteomic analysis. METHODS: Aptamer-based proteomic analysis (SomaScan 7K) was performed on serum samples from women with PPCM (n = 67), women with nonischemic nonperipartum cardiomyopathy (NPCM) (n = 31), and age-matched healthy peripartum and nonperipartum women (n = 10 each). Serum samples were obtained from the IPAC (Investigation of Pregnancy-Associated Cardiomyopathy) and IMAC2 (Intervention in Myocarditis and Acute Cardiomyopathy) studies. RESULTS: Principal component analysis revealed unique clustering of each patient group (P for difference <0.001). Biological pathway analyses of differentially measured proteins in PPCM relative to NPCM, before and after normalization to pertinent healthy controls, highlighted specific dysregulation of inflammatory pathways in PPCM, including the upregulation of the cholesterol metabolism-related anti-inflammatory pathway liver-X receptor/retinoid-X receptor (LXR/RXR) (P < 0.01, Z-score 1.9-2.1). Cardiac recovery by 12 months in PPCM was associated with the downregulation of pro-inflammatory pathways and the upregulation of LXR/RXR, and an additional RXR-dependent pathway involved in the regulation of inflammation and metabolism, peroxisome proliferator-activated receptor α/RXRα signaling. CONCLUSIONS: Serum proteomic profiling of PPCM relative to NPCM and healthy controls indicated that PPCM is a distinct disease entity characterized by the unique dysregulation of inflammation-related pathways and cholesterol metabolism-related anti-inflammatory pathways. These findings provide insight into the pathophysiology of PPCM and point to novel potential therapeutic targets.

Professional Preferences and Perceptions of Cardiology Among Internal Medicine Residents: Temporal Trends Over the Past Decade.

Importance: Internal medicine residents' professional development preferences were discordant with their perceptions of cardiology in a survey circulated a decade ago; no contemporary data exist. This information is important for effective recruitment and retention of a highly talented and diverse future cardiology workforce. Objective: To identify residents' professional development preferences and cardiology perceptions, in relation to specialty choice, and compare the findings with those from a decade prior. Design, Setting, and Participants: The original survey from the 2010 study was updated and sent to US internal medicine programs. Respondents (ie, internal medicine residents) rated 38 professional development preferences and 20 cardiology perceptions. Data were collected in 2020 and compared with survey results from the prior 2010 study. Multivariable models were created for specialty choice using scaled independent variables dichotomized using the top 2 options; categorical variables were recoded into binary variables for analysis. Main Outcomes and Measures: Multivariable models were used to determine the association of demographic characterisitcs and survey responses with prospective career choice. Responses were examined by total group, by gender, by self-reported consideration of entering cardiology as a profession, and by comparison with a decade prior both as a group and by gender. Results: A total of 840 residents (mean [SD] age, 29.24 [2.82] years; 49.8% male; 55.4% White) completed the survey. The survey incorporated a 5-point Likert scale of 1 (not important) to 5 (extremely important) for some of the questions, with additional questions on demographic characteristics. The most important professional development preferences by descending Likert score were as follows: positive role models (4.56), stimulating career (3.81), and family friendly (3.78). The cardiology perception statements with the highest agreement were as follows: interferes with family life during training (3.93) and having met positive role models or having positive views of cardiovascular disease as a topic (3.85). Multivariable analysis yielded a 22-element model predicting cardiology as career choice. Compared with the 2010 survey, the findings of this survey indicated increased importance of work-life balance components for both male and female residents, with a greater change in male residents. Contemporary residents were more likely than their predecessors to agree with negative perceptions of cardiology. Conclusions and Relevance: This survey study found that both male and female residents place a high value on support for optimal work-life balance; these preferences have intensified over the past decade and factor into career choice. Negative perceptions of cardiology persist and, in some aspects, are worsening. Improving the culture of cardiology may make this specialty a more attractive career choice for all.

Peripartum cardiomyopathy: Characteristics and outcomes among women seen at a referral hospital in Lusaka, Zambia.

Background: Peripartum cardiomyopathy (PPCM) disproportionately affects women of African descent, however knowledge about this disease in African countries is limited. Objectives: To describe the phenotype of women with PPCM seen at a referral hospital in Zambia and examine outcomes at 6 months. Methods: A prospective observational study describing characteristics and 6-month outcomes was performed at the University Teaching Hospital Echocardiography Lab in Lusaka, Zambia. Results: We enrolled 45 participants with PPCM and 38 were seen at 6-month follow up; 3 (7 %) died and 4 (9 %) were lost to follow up. Mean age was 32.9 years (SD:7.0); mean BMI was 25.3 kg/m2 (SD:4.1), mean parity was 3.4 (SD:2.2) children and twin pregnancies occurred in 4 (9 %). Median time from symptom onset to diagnosis was 60 days (IQR: 1-280). 20 (44 %) reported gestational hypertension and 10 (22 %) reported preeclampsia. Baseline median left ventricular ejection fraction (LVEF) was 36 % (IQR: 11-45), median left ventricular end-diastolic volume (LVEDV) was 150 mL (IQR: 58-229) and 79 % described New York Heart Association (NYHA) functional class IV symptoms. Median LVEF after 6 months was 49 % (IQR: 23-68; p < 0.001) and median LVEDV was 121 mL (IQR: 66-200; p < 0.001). At 6-month follow up 45 % had LVEF ≥ 50 %, 42 % had LVEDV ≤ 106 mL and 1 (3 %) had NYHA functional class IV symptoms. Conclusions: Hypertension was prevalent in this cohort. Overall mortality rate was low and clinically significant improvements in cardiac parameters were seen in over 40%. Further research is needed to identify and mitigate gaps in diagnosis and management.

Burnout and Well-Being Among Cardiology Fellowship Program Directors.

OBJECTIVES: The third annual Cardiovascular Diseases (CV) Fellowship Program Directors (PDs) Survey sought to understand burnout and well-being among CV fellowship PDs. BACKGROUND: Physician burnout is a common phenomenon. Data on burnout among cardiologists, specifically CV PDs, remain limited. METHODS: The survey contained 8 questions examining satisfaction, stress, and burnout among CV fellowship PDs. Burnout was defined based on the self-reported presence of ≥1 symptom of burnout, constant feelings of burnout, or complete burnout. RESULTS: Survey response rate was 57%. Most respondents were men (78%) and 54% represented university-based programs. Eighty percent reported satisfaction with their current job as PD, and 96% identified interactions with fellows as a driver of their satisfaction. Forty-five percent reported feeling a great deal of stress from their job. Stress was higher among women PDs, early-career PDs, and PDs of larger and university-based programs. Twenty-one percent reported some symptoms of burnout, and only 36% reported enjoyment without stress or burnout. Rates of enjoyment without stress or burnout were higher among men and late-career PDs, PDs of smaller programs, and PDs of community-based programs. Seventeen percent of PDs reported a high likelihood of resigning in the next year, of which the most common reason was the tasks of PDs were becoming overwhelming. CONCLUSIONS: Most CV fellowship PDs are satisfied with their position, but stress and burnout remain common. Women PDs, early-career PDs, and PDs of larger, university-based programs demonstrate more adverse markers of well-being. Opportunities exist to support CV fellowship PDs in their critical role.

Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor truncating variants in TTN (TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM. METHODS: Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including TTN, and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated. RESULTS: Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected P [P*]=1.2×10-46). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8, P*=7.0×10-8), DSP (odds ratio=14.9, P*=1.0×10-8), and BAG3 (odds ratio=53.1, P*=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%, P=2.5×10-4), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery. CONCLUSIONS: This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.

Program Directors Survey on Diversity in Cardiovascular Training Programs.

BACKGROUND: Women and minorities are under-represented in cardiovascular disease (CVD) specialties. It remains unknown how characteristics of the CVD learning environment affect diversity and how program directors (PDs) approach these critical issues. OBJECTIVES: The second annual Cardiovascular PD Survey aimed to investigate characteristics of the CVD learning environment that may affect diversity and strategies PDs use to approach these issues. METHODS: The survey contained 20 questions examining U.S.-based CVD PD perceptions of diversity in CVD and related characteristics of the CVD fellowship learning environment. RESULTS: In total, 58% of PDs completed the survey. Responding programs demonstrated geographic diversity. The majority were university-based or -affiliated. A total of 86% of PDs felt diversity in CVD as a field needs to increase, and 70% agreed that training programs could play a significant role in this. In total, 89% of PDs have attempted to increase diversity in fellowship recruitment. The specific strategies used were associated with PD sex and the presence of under-represented minority trainees in the program. PDs identified lack of qualified candidates and overall culture of cardiology as the 2 most significant barriers to augmenting diversity. A majority of programs have support systems in place for minority fellows or specific gender groups, including procedures to report issues of harassment or an unsafe learning environment. PDs identified shared best practices for recruitment and implicit bias training, among others, as important resources in their efforts to support diversity in CVD training. CONCLUSIONS: Diversity is important to CVD PDs. They are striving to increase it in their programs through recruitment and strategies directed toward the fellowship learning environment. The CVD community has opportunities to standardize strategies and provide national resources to support PDs in these critical efforts.

Perceptions on Diversity in Cardiology: A Survey of Cardiology Fellowship Training Program Directors.

Background The lack of diversity in the cardiovascular physician workforce is thought to be an important driver of racial and sex disparities in cardiac care. Cardiology fellowship program directors play a critical role in shaping the cardiology workforce. Methods and Results To assess program directors' perceptions about diversity and barriers to enhancing diversity, the authors conducted a survey of 513 fellowship program directors or associate directors from 193 unique adult cardiology fellowship training programs. The response rate was 21% of all individuals (110/513) representing 57% of US general adult cardiology training programs (110/193). While 69% of respondents endorsed the belief that diversity is a driver of excellence in health care, only 26% could quote 1 to 2 references to support this statement. Sixty-three percent of respondents agreed that "our program is diverse already so diversity does not need to be increased." Only 6% of respondents listed diversity as a top 3 priority when creating the cardiovascular fellowship rank list. Conclusions These findings suggest that while program directors generally believe that diversity enhances quality, they are less familiar with the literature that supports that contention and they may not share a unified definition of "diversity." This may result in diversity enhancement having a low priority. The authors propose several strategies to engage fellowship training program directors in efforts to diversify cardiology fellowship training programs.