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BACKGROUND: Black women with peripartum cardiomyopathy (PPCM) have a higher prevalence of hypertensive disorders of pregnancy (HDP) and worse clinical outcomes compared with non-Black women. We examined the impact of HDP on myocardial recovery in Black women with PPCM. METHODS: A total of 100 women were enrolled into the Investigation in Pregnancy Associated Cardiomyopathy (IPAC) study. Left ventricular ejection fraction (LVEF) was assessed by echocardiography at entry, 6, and 12-months post-partum (PP). Women were followed for 12 months postpartum and outcomes including persistent cardiomyopathy (LVEF ≤35%), left ventricular assist device, (LVAD), cardiac transplantation, or death were examined in subsets based on race and the presence of HDP. RESULTS: Black women with HDP were more likely to present earlier compared to Black women without HDP (days PP HDP: 34 ± 21 vs 54 ± 27 days, P = .03). There was no difference in LVEF at study entry for Black women based on HDP, but better recovery with HDP at 6 (HDP: 52 ± 11% vs no HDP: 40 ± 14%, P = .03) and 12-months (HDP:53 ± 10% vs no HDP:40 ± 16%, P = .02). At 12-months, Black women overall had a lower LVEF than non-Black women (P < .001), driven by less recovery in Black women without HDP compared to non-Black women (P < .001). In contrast, Black women with HDP had a similar LVEF at 12 months compared to non-Black women (P = .56). CONCLUSIONS: In women with PPCM, poorer outcomes evident in Black women were driven by women without a history of HDP. In Black women, a history of HDP was associated with earlier presentation and recovery which was comparable to non-Black women.
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Negro ou Afro-Americano , Cardiomiopatias , Hipertensão Induzida pela Gravidez , Período Periparto , Complicações Cardiovasculares na Gravidez , Volume Sistólico , Humanos , Feminino , Gravidez , Adulto , Cardiomiopatias/fisiopatologia , Cardiomiopatias/etnologia , Cardiomiopatias/epidemiologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Complicações Cardiovasculares na Gravidez/etnologia , Complicações Cardiovasculares na Gravidez/epidemiologia , Hipertensão Induzida pela Gravidez/fisiopatologia , Hipertensão Induzida pela Gravidez/etnologia , Hipertensão Induzida pela Gravidez/epidemiologia , Volume Sistólico/fisiologia , Negro ou Afro-Americano/estatística & dados numéricos , Ecocardiografia , Função Ventricular Esquerda/fisiologia , Transplante de Coração/estatística & dados numéricos , Coração Auxiliar/estatística & dados numéricosRESUMO
AIMS: Acute myocarditis, although a rare disease, can be associated with sudden cardiac death or the need for transplantation in both children and young adults. To date, there is no definitive evidence to support the routine use of immunosuppressive therapy or treatment targeting inflammation in patients with myocarditis. Animal models of cardiovascular (CV), as well as neurological diseases, have demonstrated that cannabidiol has significant anti-inflammatory properties and may represent a promising therapy in acute myocarditis. This efficacy has been shown in a murine model of autoimmune myocarditis as well as in in vitro and in vivo models of heart failure (HF). METHODS AND RESULTS: We present the rationale and design of the ARCHER Trial, an international multicentre, double-blind, randomized, placebo-controlled, phase II study examining the safety and efficacy of a pharmaceutically produced cannabidiol formulation, in patients with mild to moderate acute myocarditis. Eligible patients are those with acute myocarditis, randomized within 10 days of the diagnostic cardiac MRI (CMR), which has met defined diagnostic criteria for myocarditis. Oral treatment (cannabidiol or placebo) is titrated from 2.5 mg/kg of body weight up to 10 mg/kg of body weight b.i.d. (or highest tolerated dose) and taken for 12 weeks in addition to standard of care therapy for HF. The primary endpoints are defined as changes in global longitudinal strain (GLS) and extra cellular volume (ECV), measured by CMR at 12 weeks. Assuming 80% power, a 5% alpha risk and 25% missing CMR follow-up data at Week 12, 100 patients are required to demonstrate the desired treatment effect of 18%. The change in left ventricular ejection fraction (LVEF) from baseline to Week 12 was selected as the secondary endpoint. Additional exploratory endpoints include changes in hs-troponin, NT-proBNP, markers of inflammation and endothelial function during the 12-week treatment period. The trial is ongoing but is now more than 50% recruited. As enrolment in the trial continues, no interim data are available for inclusion in this Design paper. CONCLUSIONS: The ongoing ARCHER Trial is an international, multicentre, double-blind, randomized, placebo-controlled phase II study, designed to determine the effect of a pharmaceutically produced cannabidiol formulation on CMR parameters in patients presenting with acute myocarditis. Enrolment of 100 patients is expected to conclude in Q3 2024. Study results will be available in early 2025.
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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.
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Cardiomiopatias , Cardiopatias , Insuficiência Cardíaca , Pré-Eclâmpsia , Humanos , Gravidez , Feminino , Camundongos , Animais , Período Periparto , Placenta , Fatores de TranscriçãoRESUMO
BACKGROUND: This study evaluates the clinical trends, risk factors, and effects of post-transplant stroke and subsequent functional independence on outcomes following orthotopic heart transplantation under the 2018 heart allocation system. METHODS: The United Network for Organ Sharing registry was queried to identify adult recipients from October 18, 2018 to December 31, 2021. The cohort was stratified into 2 groups with and without post-transplant stroke. The incidence of post-transplant stroke was compared before and after the allocation policy change. Outcomes included post-transplant survival and complications. Multivariable logistic regression was performed to identify risk factors for post-transplant stroke. Sub-analysis was performed to evaluate the impact of functional independence among recipients with post-transplant stroke. RESULTS: A total of 9,039 recipients were analyzed in this study. The incidence of post-transplant stroke was higher following the policy change (3.8% vs 3.1%, p = 0.017). Thirty-day (81.4% vs 97.7%) and 1-year (66.4% vs 92.5%) survival rates were substantially lower in the stroke cohort (p < 0.001). The stroke cohort had a higher rate of post-transplant renal failure, longer hospital length of stay, and worse functional status. Multivariable analysis identified extracorporeal membrane oxygenation, durable left ventricular assist device, blood type O, and redo heart transplantation as strong predictors of post-transplant stroke. Preserved functional independence considerably improved 30-day (99.2% vs 61.2%) and 1-year (97.7% vs 47.4%) survival rates among the recipients with post-transplant stroke (p < 0.001). CONCLUSIONS: There is a higher incidence of post-transplant stroke under the 2018 allocation system, and it is associated with significantly worse post-transplant outcomes. However, post-transplant stroke recipients with preserved functional independence have improved survival, similar to those without post-transplant stroke.
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Transplante de Coração , Complicações Pós-Operatórias , Acidente Vascular Cerebral , Humanos , Masculino , Feminino , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Acidente Vascular Cerebral/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Fatores de Risco , Estudos Retrospectivos , Obtenção de Tecidos e Órgãos , Incidência , Sistema de Registros , Taxa de Sobrevida/tendências , Adulto , Idoso , SeguimentosRESUMO
OBJECTIVE: This study aimed to investigate the clinical trends and the impact of the 2018 heart allocation policy change on both waitlist and post-transplant outcomes in simultaneous heart-kidney transplantation in the United States. METHODS: The United Network for Organ Sharing registry was queried to compare adult patients before and after the allocation policy change. This study included 2 separate analyses evaluating the waitlist and post-transplant outcomes. Multivariable analyses were performed to determine the 2018 allocation system's risk-adjusted hazards for 1-year waitlist and post-transplant mortality. RESULTS: The initial analysis investigating the waitlist outcomes included 1779 patients listed for simultaneous heart-kidney transplantation. Of these, 1075 patients (60.4%) were listed after the 2018 allocation policy change. After the policy change, the waitlist outcomes significantly improved with a shorter waitlist time, lower likelihood of de-listing, and higher likelihood of transplantation. In the subsequent analysis investigating the post-transplant outcomes, 1130 simultaneous heart-kidney transplant recipients were included, where 738 patients (65.3%) underwent simultaneous heart-kidney transplantation after the policy change. The 90-day, 6-month, and 1-year post-transplant survival and complication rates were comparable before and after the policy change. Multivariable analyses demonstrated that the 2018 allocation system positively impacted risk-adjusted 1-year waitlist mortality (sub-hazard ratio, 0.66, 95% CI, 0.51-0.85, P < .001), but it did not significantly impact risk-adjusted 1-year post-transplant mortality (hazard ratio, 1.03; 95% CI, 0.72-1.47, P = .876). CONCLUSIONS: This study demonstrates increased rates of simultaneous heart-kidney transplantation with a shorter waitlist time after the 2018 allocation policy change. Furthermore, there were improved waitlist outcomes and comparable early post-transplant survival after simultaneous heart-kidney transplantation under the 2018 allocation system.
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Transplante de Coração , Transplante de Rim , Adulto , Humanos , Estados Unidos , Transplante de Rim/efeitos adversos , Transplante de Coração/efeitos adversos , Modelos de Riscos Proporcionais , Listas de Espera , Estudos RetrospectivosRESUMO
BACKGROUND: Genomic variants of the disease are often discovered nowadays through population-based genome-wide association studies (GWAS). Identifying genomic variations potentially underlying a phenotype, such as hypertension, in an individual is important for designing personalized treatment; however, population-level models, such as GWAS, may not capture all the important, individualized factors well. In addition, GWAS typically requires a large sample size to detect the association of low-frequency genomic variants with sufficient power. Here, we report an individualized Bayesian inference (IBI) algorithm for estimating the genomic variants that influence complex traits, such as hypertension, at the level of an individual (e.g., a patient). By modeling at the level of the individual, IBI seeks to find genomic variants observed in the individual's genome that provide a strong explanation of the phenotype observed in this individual. RESULTS: We applied the IBI algorithm to the data from the Framingham Heart Study to explore the genomic influences of hypertension. Among the top-ranking variants identified by IBI and GWAS, there is a significant number of shared variants (intersection); the unique variants identified only by IBI tend to have relatively lower minor allele frequency than those identified by GWAS. In addition, IBI discovered more individualized and diverse variants that explain hypertension patients better than GWAS. Furthermore, IBI found several well-known low-frequency variants as well as genes related to blood pressure that GWAS missed in the same cohort. Finally, IBI identified top-ranked variants that predicted hypertension better than GWAS, according to the area under the ROC curve. CONCLUSIONS: The results support IBI as a promising approach for complementing GWAS, especially in detecting low-frequency genomic variants as well as learning personalized genomic variants of clinical traits and disease, such as the complex trait of hypertension, to help advance precision medicine.
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Estudo de Associação Genômica Ampla , Hipertensão , Humanos , Estudo de Associação Genômica Ampla/métodos , Teorema de Bayes , Polimorfismo de Nucleotídeo Único , Fenótipo , Hipertensão/genética , GenômicaRESUMO
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.
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Cardiomiopatias , Hipertensão , Pré-Eclâmpsia , Transtornos Puerperais , Gravidez , Humanos , Feminino , Pressão Sanguínea/fisiologia , Período Periparto , Período Pós-Parto , Hipertensão/complicaçõesRESUMO
BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P=7.12×10-7). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.
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Cardiomiopatia Dilatada , Insuficiência Cardíaca , Humanos , Cardiomiopatia Dilatada/metabolismo , Volume Sistólico , Estudo de Associação Genômica Ampla , Função Ventricular Esquerda , Fibrose , Antígenos de Neoplasias/uso terapêutico , Moléculas de Adesão Celular/metabolismoRESUMO
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.
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Cardiomiopatias , Insuficiência Cardíaca , Complicações Cardiovasculares na Gravidez , Transtornos Puerperais , Gravidez , Humanos , Feminino , Período Periparto , Proteômica , Transtornos Puerperais/terapia , Complicações Cardiovasculares na Gravidez/terapia , Inflamação , ColesterolRESUMO
BACKGROUND: This study evaluated the current clinical trends, risk factors, and temporal effects of post-transplant dialysis on outcomes following orthotopic heart transplantation after the 2018 United States adult heart allocation policy change. METHODS: The United Network for Organ Sharing (UNOS) registry was queried to analyze adult orthotopic heart transplant recipients after the October 18, 2018 heart allocation policy change. The cohort was stratified according to the need for post-transplant de novo dialysis. The primary outcome was survival. Propensity score-matching was performed to compare the outcomes between 2 similar cohorts with and without post-transplant de novo dialysis. The impact of post-transplant dialysis chronicity was evaluated. Multivariable logistic regression was performed to identify risk factors for post-transplant dialysis. RESULTS: A total of 7,223 patients were included in this study. Out of these, 968 patients (13.4%) developed post-transplant renal failure requiring de novo dialysis. Both 1-year (73.2% vs 94.8%) and 2-year (66.3% vs 90.6%) survival rates were lower in the dialysis cohort (p < 0.001), and the lower survival rates persisted in a propensity-matched comparison. Recipients requiring only temporary post-transplant dialysis had significantly improved 1-year (92.5% vs 71.6%) and 2-year (86.6 % vs 52.2%) survival rates compared to the chronic post-transplant dialysis group (p < 0.001). Multivariable analysis demonstrated low pretransplant estimated glomerular filtration (eGFR) and bridge with extracorporeal membrane oxygenation (ECMO) were strong predictors of post-transplant dialysis. CONCLUSIONS: This study demonstrates that post-transplant dialysis is associated with significantly increased morbidity and mortality in the new allocation system. Post-transplant survival is affected by the chronicity of post-transplant dialysis. Low pretransplant eGFR and ECMO are strong risk factors for post-transplant dialysis.
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Insuficiência Cardíaca , Transplante de Coração , Transplante de Rim , Insuficiência Renal , Adulto , Humanos , Estados Unidos/epidemiologia , Diálise Renal , Transplante de Coração/efeitos adversos , Fatores de Risco , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Since the revision of the United States heart allocation system, increasing use of mechanical circulatory support has been observed as a means to support acutely ill patients. We sought to compare outcomes between patients bridged to orthotopic heart transplantation (OHT) with either temporary (t-LVAD) or durable left ventricular assist devises (d-LVAD) under the revised system. METHODS: The United States Organ Network database was queried to identify all adult OHT recipients who were bridged to transplant with either an isolated t-LVAD or d-LVAD from 10/18/2018 to 9/30/2020. The primary outcome was 1-year post-transplant survival. Predictors of mortality were also modeled, and national trends of LVAD bridging were examined across the study period. RESULTS: About 1,734 OHT recipients were analyzed, 1,580 (91.1%) bridged with d-LVAD and 154 (8.9%) bridged with t-LVAD. At transplant, the t-LVAD cohort had higher total bilirubin levels and greater prevalence of pre-transplant intravenous inotrope usage and mechanical ventilation. Median waitlist time was also shorter for t-LVAD. At 1 year, there was a non-significant trend of increased survival in the t-LVAD cohort (94.8% vs 90.1%; p = 0.06). After risk adjustment, d-LVAD was associated with a 4-fold hazards for 1-year mortality (hazard ratio 3.96, 95% confidence interval 1.42-11.03; p = 0.009). From 2018 to 2021, t-LVAD bridging increased, though d-LVAD remained a more common bridging strategy. CONCLUSIONS: Since the 2018 allocation change, there has been a steady increase in t-LVAD usage as a bridge to OHT. Overall, patients bridged with these devices appear to have least equivalent 1-year survival compared to those bridged with d-LVAD.
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Insuficiência Cardíaca , Transplante de Coração , Coração Auxiliar , Adulto , Humanos , Insuficiência Cardíaca/cirurgia , Insuficiência Cardíaca/etiologia , Coração Auxiliar/efeitos adversos , Resultado do Tratamento , Estudos Retrospectivos , Transplante de Coração/efeitos adversosRESUMO
Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regulate redox signaling in erythrocytes and vascular cells, is essential for cardiomyocyte function. Using a conditional cardiomyocyte-specific CYB5R3-knockout mouse, we discovered that deletion of CYB5R3 in male, but not female, adult cardiomyocytes causes cardiac hypertrophy, bradycardia, and SCD. The increase in SCD in CYB5R3-KO mice is associated with calcium mishandling, ventricular fibrillation, and cardiomyocyte hypertrophy. Molecular studies reveal that CYB5R3-KO hearts display decreased adenosine triphosphate (ATP), increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Finally, from a translational perspective, we reveal that the high-frequency missense genetic variant rs1800457, which translates into a CYB5R3 T117S partial loss-of-function protein, associates with decreased event-free survival (~20%) in Black persons with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a genetic biomarker for persons of African ancestry that may potentially increase the risk of death from HFrEF.
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Insuficiência Cardíaca , Miócitos Cardíacos , Animais , Morte Súbita Cardíaca , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Oxirredução , Volume SistólicoRESUMO
BACKGROUND: Patients admitted with decompensated heart failure (HF) are at risk for hospital readmission and poor quality of life during the discharge period. Lifestyle behavior modifications that promote the self-management of chronic cardiac diseases have been associated with an improved quality of life. However, whether a mobile health (mHealth) program can assist patients in the self-management of HF during the acute posthospital discharge period is unknown. OBJECTIVE: We aimed to develop an mHealth program designed to enhance patients' self-management of HF by increasing knowledge, self-efficacy, and symptom detection. We hypothesized that patients hospitalized with HF would be willing to use a feasibly deployed mHealth program after their hospital discharge. METHODS: We employed a patient-centered outcomes research methodology to design a stakeholder-informed mHealth program. Adult patients with HF admitted to a large academic hospital were enrolled and randomized to receive the mHealth intervention versus usual care. Our feasibility outcomes included ease of program deployment, use of the clinical escalation process, duration of participant recruitment, and participant attrition. Surveys assessing the demographics and clinical characteristics of HF were measured at baseline and at 30 and 90 days after discharge. RESULTS: The study period was between July 1, 2019, and April 7, 2020. The mean cohort (N=31) age was 60.4 (range 22-85) years. Over half of the participants were men (n=18, 58%) and 77% (n=24) were White. There were no significant differences in baseline measures. We determined that an educational mHealth program tailored for patients with HF is feasibly deployed and acceptable by patients. Though not significant, we found notable trends including a higher mean quality of life at 30 days posthospitalization among program users and a longer duration before rehospitalization, which are suggestive of better HF prognosis. CONCLUSIONS: Our mHealth tool should be further assessed in a larger comparative effectiveness trial. Our pilot intervention offers promise as an innovative means to help HF patients lead healthy, independent lives. These preliminary data suggest that patient-centered mHealth tools can enable high-risk patients to play a role in the management of their HF after discharge. TRIAL REGISTRATION: ClinicalTrials.gov NCT03982017; https://clinicaltrials.gov/ct2/show/NCT03982017.
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Aims: The goal of this study was to determine whether sex and age differences exist for soluble ST2 (sST2) for several cardiovascular diseases (CVDs). Methods: We examined sST2 levels using an ELISA kit for myocarditis (n = 303), cardiomyopathy (n = 293), coronary artery disease (CAD) (n = 239), myocardial infarct (MI) (n = 159), and congestive heart failure (CHF) (n = 286) and compared them to controls that did not have CVDs (n = 234). Results: Myocarditis occurred in this study in relatively young patients around age 40 while the other CVDs occurred more often in older individuals around age 60. We observed a sex difference in sST2 by age only in myocarditis patients (men aged 38, women 46, p = 0.0002), but not for other CVDs. Sera sST2 levels were significantly elevated compared to age-matched controls for all CVDs: myocarditis (p ≤ 0.0001), cardiomyopathy (p = 0.0009), CAD (p = 0.03), MI (p = 0.034), and CHF (p < 0.0001) driven by elevated sST2 levels in females for all CVDs except myocarditis, which was elevated in both females (p = 0.002) and males (p ≤ 0.0001). Sex differences in sST2 levels were found for myocarditis and cardiomyopathy but no other CVDs and were higher in males (myocarditis p = 0.0035; cardiomyopathy p = 0.0047). sST2 levels were higher in women with myocarditis over 50 years of age compared to men (p = 0.0004) or women under 50 years of age (p = 0.015). In cardiomyopathy and MI patients, men over 50 had significantly higher levels of sST2 than women (p = 0.012 and p = 0.043, respectively) but sex and age differences were not detected in other CVDs. However, women with cardiomyopathy that experienced early menopause had higher sST2 levels than those who underwent menopause at a natural age range (p = 0.02). Conclusion: We found that sex and age differences in sera sST2 exist for myocarditis, cardiomyopathy, and MI, but were not observed in other CVDs including CAD and CHF. These initial findings in patients with self-reported CVDs indicate that more research is needed into sex and age differences in sST2 levels in individual CVDs.
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Bicuspid aortic valve (BAV) with ~1%-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13-1.92; p = 4.2 × 10-3) for LVOTO, 1.47 (95% CI, 1.10-1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75-13.7; p = 9.7 × 10-6) for CoA, and 1.49 (95% CI, 1.07-2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.
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BACKGROUND: Immune dysregulation is implicated in the development and clinical outcomes of peripartum cardiomyopathy (PPCM). METHODS AND RESULTS: 98 women with PPCM were enrolled and followed for 1 year postpartum (PP). LVEF was assessed at entry, 6-, and 12-months PP by echocardiography. Serum levels of soluble interleukin (IL)-2 receptor (sIL2R), IL-2, IL-4, IL-17, IL-22, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by ELISA at entry. Cytokine levels were compared between women with PPCM by NYHA class. Outcomes including myocardial recovery and event-free survival were compared by cytokine tertiles. For cytokines found to impact survival outcomes, parameters indicative of disease severity including baseline LVEF, medications, and use of inotropic and mechanical support were analyzed. Levels of proinflammatory cytokines including IL-17, IL-22, and sIL2R, were elevated in higher NYHA classes at baseline. Subjects with higher IL-22 levels were more likely to require inotropic or mechanical support. Higher levels of TNF-α and IL-22 were associated with poorer event-free survival. Higher TNF-α levels were associated with lower mean LVEF at entry and 12 months. In contrast, higher levels of immune-regulatory cytokines such as IL-4 and IL-2 were associated with higher LVEF during follow up. CONCLUSION: Proinflammatory cytokines IL-22 and TNF-α were associated with adverse event-free survival. IL-17 and IL-22 were associated with more severe disease. In contrast, higher levels of IL-2 and IL-4 corresponded with higher subsequent LVEF. Increased production of TH17 type cytokines in PPCM correlated with worse disease and outcomes, while an increased immune-regulatory response seems to be protective.
Assuntos
Cardiomiopatias , Período Periparto , Cardiomiopatias/diagnóstico por imagem , Citocinas , Feminino , Humanos , Índice de Gravidade de Doença , Células Th17RESUMO
Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB.
Assuntos
Insuficiência Cardíaca , Transplante de Coração , Biópsia , Endocárdio , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Humanos , Japão/epidemiologia , MiocárdioRESUMO
Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples have significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (i) an overview of the practical approach to EMB, (ii) an update on indications for EMB, (iii) a revised plan for HTx rejection surveillance, (iv) the impact of multimodality imaging on EMB, and (v) the current clinical practice in the worldwide use of EMB.
Assuntos
Insuficiência Cardíaca , Transplante de Coração , Biópsia , Endocárdio , Insuficiência Cardíaca/diagnóstico , Humanos , Japão , MiocárdioRESUMO
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.