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.

Antiplatelet Therapy for Secondary Prevention of Vascular Disease Complications.

PURPOSE OF REVIEW: Platelets are activated upon interaction with injured vascular endothelium to form a primary hemostatic plug. Pathogenic thrombosis driven by platelet aggregation can occur in the setting of vascular disease leading to ischemic events. The use of antiplatelet agents has become a mainstay for prevention of the secondary complications of vascular disease. This review summarizes seminal and recent literature related to this area. RECENT FINDINGS: Aspirin is a cornerstone of antiplatelet therapy for coronary artery disease and cerebrovascular disease for prevention of myocardial infarction, stroke, and vascular death. Alternative antiplatelet agents have shown promise for use in patients with peripheral artery disease though further validation is necessary. Dual antiplatelet therapy (DAPT) with clopidogrel, prasugrel, or ticagrelor, and aspirin demonstrates benefit in patients with higher thrombotic risk. However, use of DAPT predictably increases bleeding risk, thus limiting mortality benefit. Individualization of DAPT to patient-specific features is an area of active research with the development the DAPT score and pharmacogenomic approaches. Application of pharmacogenetic data could allow for a precision medicine approach to tailoring antiplatelet therapy. Recommendations for management of cardiovascular, cerebrovascular, and peripheral artery disease are largely based on large-scale randomized control trials and meta-analyses. Seminal trials have largely focused on prevention of vascular events including non-fatal MI, stroke, and vascular death in subsets of patients with cardiovascular disease. Data from these trials along with smaller studies have driven recommendations for secondary prevention management in patients with cerebrovascular and peripheral artery disease.

Treatment of left main coronary artery compression in the setting of unpalliated congenital heart disease: a case series.

Background: Left main coronary artery compression syndrome (LMCS) is a well-characterized phenomenon resulting from compression of the left main coronary artery (LMCA) between the aorta and an enlarged pulmonary arterial trunk. The development of LMCS is usually described in the context of severe pulmonary arterial hypertension. Cases of LMCS, in the context of unpalliated congenital heart disease (CHD), are complex clinical scenarios that challenge traditional treatment paradigms. Case summary: Here, we discuss two thought-provoking patients with unpalliated CHD complicated by severe pulmonary hypertension (PH). Both patients developed LMCS, one with severe non-ST elevation myocardial infarction and the other with refractory angina. Their pulmonary vascular resistance was severely elevated despite pulmonary vasodilator therapy, and concomitant surgical correction of their CHD in addition to bypass grafting was deemed high risk. They underwent successful percutaneous coronary intervention (PCI) of the LMCA with drug-eluting stents. Discussion: Pulmonary hypertension can develop in the setting of long-standing unpalliated CHD. Surgical correction of congenital heart defects may be performed in select patients with systemic-to-pulmonary shunts, contingent on the status of PH severity. Pulmonary vasodilator therapy modulates haemodynamics to ensure surgical correction without risk of cardiopulmonary demise-termed the 'treat and repair' strategy. LMCS, an increasingly recognized phenomenon in patients with long-standing PH, is a notable complicating factor in the 'treat and repair' strategy. We introduce the concept that PCI of the LMCA may bridge patients to corrective surgery for CHD by allowing time for optimization of their pulmonary vasodilator therapy.

NT-proBNP and predictors of event free survival and left ventricular systolic function recovery in peripartum cardiomyopathy.

OBJECTIVE: To determine predictors of adverse outcomes in peripartum cardiomyopathy (PPCM). METHODS AND RESULTS: We conducted a multi-center cohort study across four centers to identify subjects with PPCM with the following criteria: LVEF <40%, development of heart failure within the last month of pregnancy or within 5 months of delivery and no other identifiable cause of heart failure with reduced ejection fraction. Outcomes included 1) survival free from major adverse events (need for extra-corporeal membrane oxygenation, ventricular assist device, orthotopic heart transplantation or death) and 2) LVEF recovery ≥ 50%. Using a univariate logistic regression analysis, we identified significant clinical predictors of these outcomes, which were then used to create multivariable models. NT-proBNP at the time of diagnosis was examined both as a continuous variable (log transformed) in logistic regression and as a dichotomous variable (values above and below the median) using the log-rank test. In all, 237 women (1993 to 2017) with 736.4 person-years of follow-up, met criteria for PPCM. Participants had a mean age of 32.4 ± 6.7 years, mean BMI 30.6 ± 7.8 kg/m2; 63% were White. After median follow-up of 3.6 years (IQR 1.1-7.8), 113 (67%) had LVEF recovery, and 222 (94%) had survival free from adverse events. Significant predictors included gestational age, gravidity, systolic blood pressure, smoking, heart rate, initial LVEF, and diuretic use. In a subset of 110 patients with measured NTproBNP levels, we found a higher event free survival for women with NTproBNP <2585 pg/ml (median) as compared to women with NTproBNP ≥2585 pg/ml (log-rank test p-value 0.018). CONCLUSION: Gestational age, gravidity, current or past tobacco use, systolic blood pressure, heart rate, initial LVEF and diuretic requirement at the time of diagnosis were associated with survival free from adverse events and LVEF recovery. Initial NT-proBNP was significantly associated with event free survival.

Hypoxia as a therapy for mitochondrial disease.

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction.