Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies.

Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.

International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management.

The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.

International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology.

Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated. Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS. The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology. This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy.

The Role of Emotional Competence in Takotsubo Cardiomyopathy.

OBJECTIVE: The current study examined the role of emotional competences and depression in takotsubo cardiomyopathy (TTC). METHODS: We compared 37 TTC patients who experienced emotion triggers (TTC-t: M (SD) age = 66.4 (12.8) years, 33 women) with 37 TTC patients who did not experience emotion triggers (TTC-nt: M (SD) age = 65.8 (11.1) years, 33 women) and 37 patients with acute myocardial infarction who experienced an emotion trigger (AMI-t: M (SD) age = 66.1 (10.1) years, 33 women). Three aspects of emotional competence (emotional intelligence, metacognitive beliefs, and emotional processing deficits) were assessed using the Trait Meta-Mood Scale (TMMS), the Meta-Cognitions Questionnaire 30, and the Emotional Processing Scale. Differences between-group means were evaluated using multivariate analysis of covariance, adjusting for depressive symptom (Hamilton Rating Scale for Depression). RESULTS: Compared with the TTC-nt and AMI-t comparison groups, TTC-t patients had low scores on emotional intelligence (TMMS Attention: F(2, 184) = 23.10, p < .001; TMMS Repair: F(2, 184) = 11.98, p < .001) and high scores in metacognitive beliefs and emotional processing deficits (e.g., Meta-Cognitions Questionnaire 30 Negative Beliefs about Thoughts: F(2, 184) = 56.93, p < .001), independent of the levels of depressive symptom. TTC-nt patients also had significantly lower scores on the Hamilton Rating Scale for Depression scale compared with AMI-t (p = .021) and TTC-t (p = .004) patients. CONCLUSIONS: TTC-t patients showed a specific dysfunctional profile of emotional competence, even after adjusting for depressive symptom. These results provided a better understanding of the psychological factors that contribute to TTC.

Baseline Characteristics Predict the Presence of Amyloid on Endomyocardial Biopsy.

BACKGROUND: Recent studies have suggested a high prevalence of cardiac amyloidosis (CAm) in heart failure (HF) patients. CAm might be underdiagnosed owing to low clinical suspicion. METHODS AND RESULTS: We performed retrospective analysis of 259 patients with HF and ejection fraction (EF) ≥50% referred for endomyocardial biopsy. Seventy-three (28%) had CAm. Multivariable independent predictors of CAm were identified. Over a mean follow-up of 2.6 ± 3.3 years, CAm patients had worse survival than those without (1.5 y vs 6.3 y; log rank P < .0001). CONCLUSIONS: Clinicians should be suspicious of CAm in patients with EF 50%-75%, >50 years of age, BMI <30 kg/m2, peripheral neuropathy, Sokolow-Lyon index ≤15 mm, and septal wall thickness ≥1.4 cm.

The Sympathetic Nervous System in the Pathogenesis of Takotsubo Syndrome.

Takotsubo syndrome is a unique clinical condition of acute heart failure and reversible left ventricular dysfunction frequently precipitated by sudden emotional or physical stress. There is growing evidence that exaggerated sympathetic stimulation is central to the pathogenesis of this syndrome. Precisely how catecholamines mediate myocardial stunning in takotsubo syndrome remains incompletely understood; but possible mechanisms include epicardial spasm, microvascular dysfunction, direct adrenergic-receptor-mediated myocyte injury, and systemic vascular effects that alter ventricular-arterial coupling. Risk factors that increase sympathetic tone and/or catecholamine sensitivity may render individuals particularly susceptible to takotsubo syndrome during episodes of acute stress.

High Coronary Artery Calcium Score Is Associated With Increased Major Adverse Cardiac Events After Liver Transplantation.

Liver transplantation (LT) candidates frequently have multiple cardiovascular risk factors, and cardiovascular disease is a major cause of morbidity and mortality after LT. Coronary artery calcium (CAC) scores are a noninvasive assessment of coronary artery disease using computed tomography. This study examines CAC scores and cardiac risk factors and their association with outcomes after LT. Methods: Patients who underwent LT between January 2010 and June 2019 with a pretransplant CAC score were included in this study. Patients were divided by CAC score into 4 groups (CAC score 0, CAC score 1-100, CAC score 101-400, CAC score >400). Major adverse cardiovascular events (MACEs) were defined as myocardial infarction, stroke, revascularization, heart failure, atrial fibrillation, and cardiovascular death. Associations between CAC score and MACE or all-cause mortality within the 5-y post-LT follow-up period were analyzed using Cox regression. Statistical significance was defined as P < 0.05. Results: During the study period, 773 adult patients underwent their first LT, and 227 patients met our study criteria. The median follow-up time was 3.4 (interquartile range 1.9, 5.3) y. After 5 y, death occurred in 47 patients (20.7%) and MACE in 47 patients (20.7%). In multivariable analysis, there was no difference in death between CAC score groups. There was significantly higher risk of MACE in the CAC score >400 group, with a hazard ratio 2.58 (95% confidence interval 1.05, 6.29). Conclusions: CAC score was not associated with all-cause mortality. Patients with CAC score >400 had an increase in MACEs within the 5-y follow-up period compared with patients with a CAC score = 0. Further research with larger cohorts is needed to examine cardiac risk stratification in this vulnerable patient population.

Transcriptomic biomarkers for the accurate diagnosis of myocarditis.

BACKGROUND: Lymphocytic myocarditis is a clinically important condition that is difficult to diagnose and distinguish. We hypothesized that the transcriptome obtained from an endomyocardial biopsy would yield clinically relevant and accurate molecular signatures. METHODS AND RESULTS: Microarray analysis was performed on samples from patients with histologically proven lymphocytic myocarditis (n=16) and idiopathic dilated cardiomyopathy (n=32) to develop accurate diagnostic transcriptome-based biomarkers using multiple classification algorithms. We identified 9878 differentially expressed genes in lymphocytic myocarditis versus idiopathic dilated cardiomyopathy (fold change >1.2; false discovery rate <5%) from which a transcriptome-based biomarker containing 62 genes was identified that distinguished myocarditis with 100% sensitivity (95% confidence interval, 46 to 100) and 100% specificity (95% confidence interval, 66 to 100) and was generalizable to a broad range of secondary cardiomyopathies associated with inflammation (n=27), ischemic cardiomyopathy (n=8), and the normal heart (n=11). Multiple classification algorithms and quantitative real-time reverse-transcription polymerase chain reaction analysis further reduced this subset to a highly robust molecular signature of 13 genes, which still performed with 100% accuracy. CONCLUSIONS: Together, these findings demonstrate that transcriptomic biomarkers from a single endomyocardial biopsy can improve the clinical detection of patients with inflammatory diseases of the heart. This approach advances the clinical management and treatment of cardiac disorders with highly variable outcome.

Myocardial recovery in peripartum cardiomyopathy: prospective comparison with recent onset cardiomyopathy in men and nonperipartum women.

BACKGROUND: Whether myocardial recovery occurs more frequently in peripartum cardiomyopathy (PPCM) than in recent onset cardiomyopathies in men and nonperipartum women has not been prospectively evaluated. This was examined through an analysis of outcomes in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) registry. METHODS AND RESULTS: IMAC2 enrolled 373 subjects with recent onset nonischemic dilated cardiomyopathy. Left ventricular ejection fraction (LVEF) was assessed at entry and 6 months, and subjects followed for up to 4 years. Myocardial recovery was compared between men (group 1), nonperipartum women (group 2) and subjects with PPCM (group 3). The cohort included 230 subjects in group 1, 104 in group 2, and 39 in group 3. The mean LVEF at baseline in groups 1, 2, and 3 was 0.23 ± 0.08, 0.24 ± 0.08, and 0.27 ± 0.07 (P = .04), and at 6 months was 0.39 ± 0.12, 0.42 ± 0.11, and 0.45 ± 0.14 (P = .007). Subjects in group 3 had a much greater likelihood of achieving an LVEF >0.50 at 6 months than groups 1 or 2 (19 %, 34%, and 48% respectively, P = .002). CONCLUSIONS: Prospective evaluation confirms myocardial recovery is greatest in women with PPCM, poorest in men, and intermediate in nonperipartum women. On contemporary therapy, nearly half of women with PPCM normalize cardiac function by 6 months.

Left ventricular assist device support and myocardial recovery in recent onset cardiomyopathy.

BACKGROUND: Left ventricular assist device (LVAD) support as bridge to recovery (BTR) is uncommon for subjects with chronic heart failure. Myocardial recovery is more evident in recent onset nonischemic cardiomyopathy (ROCM); however, the prevalence of BTR in this subset has not been addressed. METHODS AND RESULTS: We examined the use of LVAD support for subjects with ROCM in the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC2) study. The overall cohort (n = 373) was 38% female, 21% black, with a mean age of 45 ± 14 years. LVAD support was used in 3.8% (n = 14, 43% female, age 32 ± 10). Of LVAD subjects, 57% (8/14) were BTR, including 73% (8/11) of subjects with symptoms ≤4 months at the time of support. Left ventricular end-diastolic diameter (LVEDD) was smaller in BTR than nonrecovered (NR) subjects (P = .04). Myocardial inflammation was more common in BTR (75% versus 0%, P = .005), whereas fibrosis was less evident (25% versus 100%, P = .005). Of BTR subjects, 7/8 (87.5%) were alive and free of transplant with median follow-up of 19 months. CONCLUSION: In a multicenter registry of ROCM, BTR was common and occurred in the majority of subjects requiring LVAD support. Histology and LVEDD may assist in predicting potential for BTR in ROCM.

Stress cardiomyopathy: a syndrome of catecholamine-mediated myocardial stunning?

During the past few years, a novel syndrome of heart failure and transient left ventricular systolic dysfunction precipitated by acute emotional or physical stress has been described. While patients with "stress cardiomyopathy"(SCM) typically present with signs and symptoms that resemble an acute coronary syndrome, it has become clear that this syndrome has unique clinical features that can readily be distinguished from acute infarction.In particular, in contrast to the irreversible myocardial injury seen with infarction, the myocardial dysfunction of SCM is completely reversible and occurs in the absence of plaque rupture and coronary thrombosis. There is increasing evidence that exaggerated sympathetic stimulation may play a pathogenic role in the development of SCM. Plasma catecholamine levels have been found to be markedly elevated in some patients with SCM, and the syndrome has been observed in other clinical states of catecholamine excess such as central neurologic injury and pheochromocytoma.Further, intravenous catecholamines can precipitate SCM in humans and can reproduce the syndrome in animal models. The precise mechanism in which excessive sympathetic stimulation may result in transient left ventricular dysfunction remains controversial. Abnormal myocardial blood flow due to sympathetically mediated microvascular dysfunction has been suggested and is supported by decreased coronary flow reserve during the acute phase of this syndrome. An alternative explanation is the direct effect of catecholamines on cardiac myocytes, possibly through cyclic AMP-mediated calcium overload. This manuscript will review the clinical and diagnostic features of SCM and will summarize the evidence supporting a sympathetically mediated pathogenesis. Clinical risk factors that appear to increase susceptibility to SCM, possibly by modulating myocyte and microvascular sensitivity to catecholamines, will also be highlighted.

The variable natural history of idiopathic dilated cardiomyopathy.

BACKGROUND: Determining the prognosis of patients with heart failure is essential for patient management and clinical trial conduct. The relative value of traditional prognostic criteria remains unclear and the assessment of long-term prognosis for individual patients is problematic. OBJECTIVES: To determine the ability of clinical, hemodynamic and echocardiographic parameters to predict the long-term prognosis of patients with idiopathic dilated cardiomyopathy. METHODS: We investigated the ability of clinical, hemodynamic and echocardiographic parameters to predict the long-term prognosis of individual patients in a large, representative, contemporary cohort of idiopathic dilated cardiomyopathy (IDCM) patients referred to Johns Hopkins from 1997 to 2004 for evaluation of cardiomyopathy. In all patients a baseline history was taken, and physical examination, laboratory studies, echocardiogram, right heart catheterization and endomyocardial biopsy were performed. RESULTS: In 171 IDCM patients followed for a median 3.5 years, there were 50 long-term event-free survivors (LTS) (median survival 6.4 years) and 34 patients died or underwent ventricular assist device placement or transplantation within 5 years (NLTS; non-long-term survivors) (median time to event 1.83 years. Established risk factors (gender, race, presence of diabetes, serum creatinine, sodium) and the use of accepted heart failure medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers) were similar between the two groups. Although LTS had younger age, higher ejection fraction (EF) and lower New York Heart Association (NYHA) class at presentation, the positive predictive value of an EF < 25% was 64% (95% CI 41%-79%) and that of NYHA class > 2 was 53% (95% CI 36-69%). A logistic model incorporating these three variables incorrectly classified 29% of patients. CONCLUSIONS: IDCM exhibits a highly variable natural history and standard clinical predictors have limited ability to classify IDCM patients into broad prognostic categories. These findings suggest that there are important host-environmental factors still unappreciated in the biology of IDCM.

Stress-Induced (Takotsubo) Cardiomyopathy After Liver Transplant Rescued with Venoarterial Extracorporeal Membrane Oxygenation.

Here, we report the case of a 55 year old male patient without significant preexisting cardiovascular disease who received a deceased donor liver transplant. Intraoperatively, the patient developed cardiogenic shock secondary to stress-induced cardiomyopathy or Takotsubo syndrome (TTS), which was refractory to high-dose vasoactive, inotropic medical therapy. The patient was successfully managed with venoarterial extracorporeal membrane oxygenation (VA-ECMO) for 7 days, with complete recovery of cardiac function and maintenance of the hepatic graft. Given the anticipated need for only a short period of support and the expectation of full myocardial recovery, such patients may represent excellent candidates for the use of VA-ECMO.

Heart transplantation outcomes in arrhythmogenic right ventricular cardiomyopathy: a contemporary national analysis.

AIMS: Heart failure is an increasingly recognized later stage manifestation of arrhythmogenic right ventricular cardiomyopathy (ARVC) that can require heart transplantation (HT) to appropriately treat. We aimed to study contemporary ARVC HT outcomes in a national registry. METHODS AND RESULTS: The United Network for Organ Sharing registry was queried for HT recipients from 1/1994 through 2/2020. ARVC patients were compared with non-ARVC dilated, restrictive, and hypertrophic cardiomyopathy HT patients (HT for ischaemic and valvular disease was excluded from analysis). Post-HT survival was assessed using Kaplan-Meier estimates. A total of 189 of 252 (75%) waitlisted ARVC patients (median age 48 years, 65% male) underwent HT, representing 0.3% of the total 65 559 HT during the study time period. Annual frequency of HT for ARVC increased significantly over time. ARVC patients had less diabetes (5% vs. 17%, P < 0.001), less cigarette use (15% vs. 23%, P < 0.001), lower pulmonary artery and pulmonary capillary wedge pressures, and lower cardiac output than the 33 659 non-ARVC patients (P < 0.001). Ventricular assist device use was significantly lower in ARVC patients (8% vs. 32%, P < 0.001); 1 and 5 year post-HT survival was 97% and 93% for ARVC vs. 95% and 82% for non-ARVC HT recipients (P < 0.001). On adjusted multivariable Cox regression, ARVC had decreased risk of post-HT death compared with non-ARVC aetiologies (hazard ratio 0.48, 95% confidence interval 0.28-0.82, P = 0.008). Patients with ARVC also had lower risk of death or graft failure than non-ARVC patients (hazard ratio 0.51, 95% confidence interval 0.32-0.81, P = 0.004). CONCLUSIONS: In the largest series of HT in ARVC, we found that HT is increasingly performed in ARVC, with higher survival compared with other cardiomyopathy aetiologies. The right ventricular predominant pathophysiology may require unique considerations for heart failure management, including HT.

The gene expression profile of patients with new-onset heart failure reveals important gender-specific differences.

AIMS: We sought to test the hypothesis that inherent biological factors contribute to gender differences in disease pathophysiology of new-onset heart failure (HF), which can be detected from the transcriptome of a single endomyocardial biopsy (EMB). METHODS AND RESULTS: We analysed samples from male (n = 29) and female patients (n = 14) with idiopathic dilated cardiomyopathy (IDCM) and new-onset HF with U133 Plus 2.0 microarrays (Affymetrix) and significance analysis of microarrays (SAM). There were 35 overexpressed and 16 downregulated transcripts in men vs. women [q < 5%, fold change (FC) > 1.2]. In addition to overexpression of Y-chromosome-related transcripts (n = 18), such as USP9Y (FC > 13.1), DDX3Y (FC > 11.3), RPS4Y1 (FC > 9.9), and EIF1AY (FC > 11.8) in males, there was overexpression of CD24 (FC > 5.6) and KCNK1 (FC > 1.5). In females, XIST was highly overexpressed (FC > 28.9), together with X-linked zinc finger proteins (FC > 1.9) and autosomal genes GATAD1 (FC > 1.6), SLC2A12 (FC > 2.9), and PDE6B (FC > 1.5). Analysis of a public data set of end-stage IDCM (n = 15) resulted in approximately 85% overlap with our findings. CONCLUSION: This is the first study that identified gender-specific transcriptomic differences in new-onset HF. Our findings may offer novel insights into fundamental biological differences in the pathophysiology of HF between sexes and provide a platform for personalized medicine.

Capnocytophagia canimorsus sepsis in an asplenic heart transplant candidate with a left ventricular assist system.

Fulminant septic shock associated with Capnocytophagia canimorsus bacteremia developed in a 54-year-old asplenic man, a heart transplantation candidate who was supported with a HeartMate II left ventricular assist system, after he experienced a dog bite. He improved after administration of broad-spectrum antibiotics, which were narrowed to ampicillin/sulbactam for a prolonged 6-week course, and subsequently recovered fully.

Endothelial Stromal PD-L1 (Programmed Death Ligand 1) Modulates CD8+ T-Cell Infiltration After Heart Transplantation.

BACKGROUND: The role of checkpoint axes in transplantation has been partially addressed in animal models but not in humans. Occurrence of fulminant myocarditis with allorejection-like immunologic features in patients under anti-PD1 (programmed death cell protein 1) treatment suggests a key role of the PD1/PD-L1 (programmed death ligand 1) axis in cardiac immune homeostasis. METHODS: We cross-sectionally studied 23 heart transplant patients undergoing surveillance endomyocardial biopsy. Endomyocardial tissue and peripheral blood mononuclear cells were analyzed by flow cytometry. Multivariate logistic regression analyses including demographic, clinical, and hemodynamic parameters were performed. Murine models were used to evaluate the impact of PD-L1 endothelial graft expression in allorejection. RESULTS: We found that myeloid cells dominate the composition of the graft leukocyte compartment in most patients, with variable T-cell frequencies. The CD (cluster of differentiation) 4:CD8 T-cell ratios were between 0 and 1.5. The proportion of PD-L1 expressing cells in graft endothelial cells, fibroblasts, and myeloid leukocytes ranged from negligible up to 60%. We found a significant inverse logarithmic correlation between the proportion of PD-L1+HLA (human leukocyte antigen)-DR+ endothelial cells and CD8+ T cells (slope, -18.3 [95% CI, -35.3 to -1.3]; P=0.030). PD-L1 expression and leukocyte patterns were independent of demographic, clinical, and hemodynamic parameters. We confirmed the importance of endothelial PD-L1 expression in a murine allogeneic heart transplantation model, in which Tie2Crepdl1fl/fl grafts lacking PD-L1 in endothelial cells were rejected significantly faster than controls. CONCLUSIONS: Loss of graft endothelial PD-L1 expression may play a role in regulating CD8+ T-cell infiltration in human heart transplantation. Murine model results suggest that loss of graft endothelial PD-L1 may facilitate alloresponses and rejection.

Dual-Organ Transplantation in a Woman With Right Ventricular Failure Secondary to Arrhythmogenic Right Ventricular Cardiomyopathy.

We report a case of a woman with arrhythmogenic right ventricular cardiomyopathy (ARVC) who presented with severe right-sided heart failure and cardiac cirrhosis that mandated heart-liver transplantation. This case highlights an emerging sex-based difference in ARVC where female sex is associated with a higher risk of heart failure than in male patients with ARVC. (Level of Difficulty: Advanced.).

Transcriptomic biomarkers for individual risk assessment in new-onset heart failure.

BACKGROUND: Prediction of prognosis remains a major unmet need in new-onset heart failure (HF). Although several clinical tests are in use, none accurately distinguish between patients with poor versus excellent survival. We hypothesized that a transcriptomic signature, generated from a single endomyocardial biopsy, could serve as a novel prognostic biomarker in HF. METHODS AND RESULTS: Endomyocardial biopsy samples and clinical data were collected from all patients presenting with new-onset HF from 1997 to 2006. Among a total of 350 endomyocardial biopsy samples, 180 were identified as idiopathic dilated cardiomyopathy. Patients with phenotypic extremes in survival were selected: good prognosis (event-free survival for at least 5 years; n=25) and poor prognosis (events [death, requirement for left ventricular assist device, or cardiac transplant] within the first 2 years of presentation with HF symptoms; n=18). We used human U133 Plus 2.0 microarrays (Affymetrix) and analyzed the data with significance analysis of microarrays and prediction analysis of microarrays. We identified 46 overexpressed genes in patients with good versus poor prognosis, of which 45 genes were selected by prediction analysis of microarrays for prediction of prognosis in a train set (n=29) with subsequent validation in test sets (n=14 each). The biomarker performed with 74% sensitivity (95% CI 69% to 79%) and 90% specificity (95% CI 87% to 93%) after 50 random partitions. CONCLUSIONS: These findings suggest the potential of transcriptomic biomarkers to predict prognosis in patients with new-onset HF from a single endomyocardial biopsy sample. In addition, our findings offer potential novel therapeutic targets for HF and cardiomyopathy.