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Acute heart failure (AHF) is a syndrome defined as the new onset (de novo heart failure (HF)) or worsening (acutely decompensated heart failure (ADHF)) of symptoms and signs of HF, mostly related to systemic congestion. In the presence of an underlying structural or functional cardiac dysfunction (whether chronic in ADHF or undiagnosed in de novo HF), one or more precipitating factors can induce AHF, although sometimes de novo HF can result directly from the onset of a new cardiac dysfunction, most frequently an acute coronary syndrome. Despite leading to similar clinical presentations, the underlying cardiac disease and precipitating factors may vary greatly and, therefore, the pathophysiology of AHF is highly heterogeneous. Left ventricular diastolic or systolic dysfunction results in increased preload and afterload, which in turn lead to pulmonary congestion. Fluid retention and redistribution result in systemic congestion, eventually causing organ dysfunction due to hypoperfusion. Current treatment of AHF is mostly symptomatic, centred on decongestive drugs, at best tailored according to the initial haemodynamic status with little regard to the underlying pathophysiological particularities. As a consequence, AHF is still associated with high mortality and hospital readmission rates. There is an unmet need for increased individualization of in-hospital management, including treatments targeting the causative factors, and continuation of treatment after hospital discharge to improve long-term outcomes. Acute heart failure (AHF) is a syndrome characterized by signs and symptoms of heart failure (typically systemic congestion) that occurs in the presence of an underlying cardiac dysfunction (previously diagnosed, undiagnosed or new-onset) and precipitating factors. AHF is associated with high mortality and hospital readmission rates.

Hypertrophic cardiomyopathy (HCM) is widely recognized as one of the most common inheritable cardiac disorders. Since its initial description over 60 years ago, advances in multimodality imaging and translational genetics have revolutionized our understanding of the disorder. The diagnosis and management of patients with HCM are optimized with a multidisciplinary approach. This, along with increased safety and efficacy of medical, percutaneous, and surgical therapies for HCM, has afforded more personalized care and improved outcomes for this patient population. In this review, we will discuss our modern understanding of the molecular pathophysiology that underlies HCM. We will describe the range of clinical presentations and discuss the role of genetic testing in diagnosis. Finally, we will summarize management strategies for the hemodynamic subtypes of HCM with specific emphasis on the rationale and evidence for the use of implantable cardioverter defibrillators, septal reduction therapy, and cardiac myosin inhibitors.

Purpose “Genome-first” approaches, in which genetic sequencing is agnostically linked to associated phenotypes, can enhance our understanding of rare variants’ contributions to disease. Loss-of-function variants in LMNA cause a range of rare diseases, including cardiomyopathy. Methods We leveraged exome sequencing from 11,451 unselected individuals in the Penn Medicine Biobank to associate rare variants in LMNA with diverse electronic health record (EHR)–derived phenotypes. We used Rare Exome Variant Ensemble Learner (REVEL) to annotate rare missense variants, clustered predicted deleterious and loss-of-function variants into a “gene burden” ( N  = 72 individuals), and performed a phenome-wide association study (PheWAS). Major findings were replicated in DiscovEHR. Results The LMNA gene burden was significantly associated with primary cardiomyopathy ( p  = 1.78E-11) and cardiac conduction disorders ( p  = 5.27E-07). Most patients had not been clinically diagnosed with LMNA cardiomyopathy. We also noted an association with chronic kidney disease ( p  = 1.13E-06). Regression analyses on echocardiography and serum labs revealed that LMNA variant carriers had dilated cardiomyopathy and primary renal disease. Conclusion Pathogenic LMNA variants are an underdiagnosed cause of cardiomyopathy. We also find that LMNA loss of function may be a primary cause of renal disease. Finally, we show the value of aggregating rare, annotated variants into a gene burden and using PheWAS to identify novel ontologies for pleiotropic human genes.

Background Hypertrophic cardiomyopathy (HCM) is characterized by increased left ventricular wall thickness, cardiomyocyte hypertrophy, and fibrosis. Adverse cardiac risk characterization has been performed using late gadolinium enhancement (LGE), native T1, and extracellular volume (ECV). Relaxation time constants are affected by background field inhomogeneity. T1ρ utilizes a spin-lock pulse to decrease the effect of unwanted relaxation. The objective of this study was to study T1ρ as compared to T1, ECV, and LGE in HCM patients. Methods HCM patients were recruited as part of the Novel Markers of Prognosis in Hypertrophic Cardiomyopathy study, and healthy controls were matched for comparison. In addition to cardiac functional imaging, subjects underwent T1 and T1ρ cardiovascular magnetic resonance imaging at short-axis positions at 1.5T. Subjects received gadolinium and underwent LGE imaging 15–20 min after injection covering the entire heart. Corresponding basal and mid short axis LGE slices were selected for comparison with T1 and T1ρ. Full-width half-maximum thresholding was used to determine the percent enhancement area in each LGE-positive slice by LGE, T1, and T1ρ. Two clinicians independently reviewed LGE images for presence or absence of enhancement. If in agreement, the image was labeled positive (LGE + +) or negative (LGE −−); otherwise, the image was labeled equivocal (LGE + −). Results In 40 HCM patients and 10 controls, T1 percent enhancement area (Spearman’s rho = 0.61, p < 1e-5) and T1ρ percent enhancement area (Spearman’s rho = 0.48, p < 0.001e-3) correlated with LGE percent enhancement area. T1 and T1ρ percent enhancement areas were also correlated (Spearman’s rho = 0.28, p = 0.047). For both T1 and T1ρ, HCM patients demonstrated significantly longer relaxation times compared to controls in each LGE category (p < 0.001 for all). HCM patients also showed significantly higher ECV compared to controls in each LGE category (p < 0.01 for all), and LGE −− slices had lower ECV than LGE + + (p = 0.01). Conclusions Hyperenhancement areas as measured by T1ρ and LGE are moderately correlated. T1, T1ρ, and ECV were elevated in HCM patients compared to controls, irrespective of the presence of LGE. These findings warrant additional studies to investigate the prognostic utility of T1ρ imaging in the evaluation of HCM patients.

Purpose The purpose of this review is to provide an update on the recent advances in the research and clinical care of patients with the major phenotypes of inherited cardiomyopathies—hypertrophic, dilated, and arrhythmogenic. Developments in genetics, risk stratification, therapies, and disease modeling will be discussed. Recent Diagnostic, prognostic, and therapeutic tools which incorporate genetic and genomic data are being steadily incorporated into the routine clinical care of patients with genetic cardiomyopathies. Human pluripotent stem cells are a breakthrough model system for the study of genetic variation associated with inherited cardiovascular disease. Summary Next-generation sequencing technology and molecular-based diagnostics and therapeutics have emerged as valuable tools to improve the recognition and care of patients with hypertrophic, dilated, and arrhythmogenic cardiomyopathies. Improved adjudication of variant pathogenicity and management of genotype-positive/phenotype-negative individuals are imminent challenges in this realm of precision medicine.

Extracorporeal membrane oxygenation (ECMO) is an increasingly used supportive measure for patients with refractory cardiogenic shock (CS). Despite its increasing use, there remain minimal data regarding which patients with refractory CS are most likely to benefit from ECMO. We retrospectively studied all patients (n = 123) who underwent initiation of ECMO for CS from February 2009 to September 2014 at a single center. Baseline patient characteristics, including demographics, co-morbid illness, cause of CS, available laboratory values, and patient outcomes were analyzed. Overall, 69 patients (56%) were weaned from ECMO, with 48 patients (39%) surviving to discharge. Survivors were younger (50 vs 60 years; p ≤0.0001), had a lower rate of previous smoking (27 vs 56%; p = 0.01) and chronic kidney disease (2% vs 13%; p = 0.03), and had lower lactate measured soon after ECMO initiation (3.1 vs 10.2 mmol/l; p = 0.01). Patients with pulmonary embolism (odds ratio 8.0, 95% confidence interval 2.00 to 31.99; p = 0.01) and acute cardiomyopathy (odds ratio 7.5, 95% confidence interval 1.69 to 33.27; p = 0.01) had a higher rate of survival than acute myocardial infarction, chronic cardiomyopathy, and miscellaneous etiologies compared to postcardiotomy CS as a referent. In conclusion, survival after ECMO initiation differs based on underlying cause of CS. Survival may be lower in older patients and those with early evidence of persistent hypoperfusion after initiation of ECMO for CS.

There are limited data describing the prevalence of mental health disorders (MHDOs) in patients with ventricular assist devices (VADs), or associations between MHDOs and resource use or outcomes. We used the Nationwide Emergency Department Sample administrative database to analyze 44,041 ED encounters for VAD-supported adults from 2010 to 2017, to assess the relationship between MHDOs and outcomes in this population. MHDO diagnoses were present for 23% of encounters, and were associated with higher charges and rates of admission, but lower mortality.

Background/Objectives: Mavacamten is a first-in-class cardiac myosin inhibitor approved for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM). Long-term data regarding its real-world safety and effectiveness are limited. We aimed to describe the real-world experience of mavacamten in a large obstructive HCM cohort at a high-volume HCM center in the United States. Methods: Adult patients initiated on mavacamten between 29 April 2022 and 19 January 2025 at a single HCM center (n = 163) were retrospectively identified. Clinical effectiveness and safety data were collected through 108 weeks of treatment. Results: Rapid and sustained reductions in resting (baseline mean 53.0 ± 36.7 mm Hg to 10.0 ± 11.0 mm Hg) and Valsalva left ventricular outflow tract gradients (baseline mean 79.7 ± 33.2 mm Hg to 16.6 ± 15.4 mm Hg) were observed during treatment throughout the study period along with substantial improvements in New York Heart Association (NYHA) class (75% with >1 NYHA class improvement by Week 12). Mean maximal left ventricular wall thickness significantly decreased (β = 0.01 mm per week). Ten patients (6.1%) required temporary drug interruption due to decrement in left ventricular ejection fraction, and mavacamten was discontinued in six patients (3.7%). Doses of background beta blocker and nondihydropyridine calcium channel blocker were significantly reduced during the study period (p < 0.001). Conclusions: In this large single-center real-world experience of mavacamten therapy, mavacamten was highly effective and maintained an acceptable safety profile, comparable to the clinical trial long-term extension experience.

Background: Variants in the desmoplakin (DSP) gene have been recognized in association with the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) for nearly 20 years. More recently, genetic variation in DSP has also been associated with left-dominant arrhythmogenic cardiomyopathy. Data regarding the cardiac phenotypes associated with genetic variation in DSP have been largely accumulated from phenotype-first studies of ARVC. Methods: We aimed to evaluate the clinical manifestations of cardiac disease associated with variants in DSP through a genotype-first approach employed in the University of Pennsylvania Center for Inherited Cardiovascular Disease registry. We performed a retrospective study of 19 individuals with “pathogenic” or “likely pathogenic” variants in DSP identified by clinical genetic testing. Demographics and clinical characteristics were collected. Results: Among individuals with disease-causing variants in DSP, nearly 40% had left ventricular enlargement at initial assessment. Malignant arrhythmias were prevalent in this cohort (42%) with a high proportion of individuals undergoing primary and secondary prevention implantable cardioverter defibrillator implantation (68%) and ablation of ventricular arrhythmias (16%). Probands also experienced end-stage heart failure requiring heart transplantation (11%). Conclusions: Our data suggest DSP cardiomyopathy may manifest with a high burden of heart failure and arrhythmic events, highlighting its importance in the pathogenesis of dilated and arrhythmogenic cardiomyopathies. Targeted strategies for diagnosis and risk stratification for DSP cardiomyopathy should be investigated.