Background
Heart failure (HF) is the leading cause of death in adults with congenital heart disease (ACHD). Identification of disease progression and timing of referral for advanced therapies is ...often delayed. However, increased awareness and understanding of ACHD and improvements in the approach to treatment have led to improved outcomes. Pulmonary hypertension (PH) is a common barrier to HT. In ACHD, the approach to PH and HT is quite complicated, given the anatomic heterogeneity and lower prevalence and experience. However, in some cases, PH is a result of elevated systemic filling pressures and low output.
Methods
We describe the approach used to successfully transplant an ACHD patient with severe pre‐HT PH performing HT alone. We review the literature and describe the one patient's journey from primarily palliative, to a combined heart‐lung transplant candidate, to successful HT patient.
Results
We discuss the methodology used to successfully transplant a patient, with significantly elevated pulmonary pressures and an initial pulmonary vascular resistance (PVR) > 13 Wood units.
Conclusions
There are a number of complexities associated with the ACHD population and it is of utmost importance to carefully identify the underlying hemodynamic milieu and inform the appropriate treatment course in order to have successful transplant outcomes.
Despite significant advances in the field of genetic cardiomyopathies, the treatment of inherited cardiac disease has long focused on symptom management and therapies geared towards the consequences ...of heart failure. More recently, small molecule therapy has emerged as a targeted approach that seeks to alter the progression of genetic cardiac disease at the molecular level.
To provide a summary of the novel therapeutics in primary genetic cardiomyopathies.
Small molecule myosin inhibitors have been developed to decrease the hypercontractility observed in conditions like hypertrophic cardiomyopathy and myosin activators seek to reverse the reduced left ventricular function seen in dilated cardiomyopathy. Further targeting specific genetic etiologies of cardiomyopathy, P38α MAP kinase inhibition is a therapy developed to counter abnormally upregulated pathways in lamin A/C cardiomyopathy. While trials are still ongoing, these small molecule therapies could alter the treatment landscape of genetic cardiomyopathies for years to come
•Small molecule therapy has emerged as a targeted approach to alter the progression of genetic cardiac disease at the molecular level.•Myosin activation seeks to reverse the reduced left ventricular function seen in heart failure with reduced ejection fraction.•Myosin inhibition aims to decrease the hypercontractility observed in conditions like hypertrophic cardiomyopathy.•Small molecule therapies could alter the treatment landscape of genetic cardiomyopathies for years to come.
Little is known regarding the characteristics and outcomes of patients with hypertrophic cardiomyopathy (HCM) and concomitant pulmonary hypertension (PHTN). Existing data is limited to small ...retrospective cohort studies performed at single centers with considerable HCM experience. In this study, we characterize the incidence and impact of PHTN in HCM patients in the United States.
We performed a retrospective cohort study using the Nationwide/National Inpatient Sample between 2005 and 2014. HCM and PHTN were identified using International Classification of Diseases (ICD)-9 codes. Patients under age 18 were excluded. Demographics, primary payer, hospital length of stay, hospital admission category, hospital region, bed size, location/teaching status, charges, and in-hospital death were collected. We performed univariate and multivariable modeling to find factors associated with mortality in hospitalized HCM patients.
We identified 117,650 patients with hospital admissions for HCM from 2005 to 2014; 14,895 (12.7%) of these patients had concomitant PHTN. The median age of admitted patients with PHTN was higher than those without PHTN (73 years v. 68 years, p <0.001). More women with HCM and PHTN were admitted than with HCM alone (70.0% v. 56.5%, p <0.001). Median length of stay was longer for patients with PHTN (5 days IQR 3-8 v. 4 days IQR 2-7). Patients without PHTN accounted for more elective admissions (18.9% v. 15.3%, p <0.001). There were no differences between the two cohorts with regard to hospital bed size or location/teaching status. In-hospital mortality (5.0% v. 2.8%, p <0.001) and median hospital charges ($34,012 IQR 17,618 - 74,736 v. $29,235 IQR 14,898 - 62,386) were higher for patients with PHTN. In adjusted analysis, the odds (OR) of in-hospital death were significantly higher in patients with PHTN (OR 1.57, 95% CI 1.30 - 1.89). Increasing age and longer length of stay were also associated with higher odds of in-hospital mortality.
In the largest contemporary study of hospitalized patients with HCM and PHTN, we found that patients admitted to U.S. hospitals with HCM and PHTN have a 1.5-fold increased odds of in-hospital mortality relative to patients with HCM without PHTN. As the risk of sudden cardiac death in HCM declines related to the success of primary prevention, the complications of advanced heart failure and PHTN-related morbidity and mortality must be recognized.
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Introduction:
Nonischemic dilated cardiomyopathy (CM) is the most common cause of end stage heart failure (ESHF). Familial/genetic CMs are underdiagnosed CM subtypes, and recognition of ...these CMs has implications for the treatment of patients and their relatives. We aimed to characterize the screening for familial/genetic CM in a cohort of patients with ESHF due to nonischemic CM.
Methods:
Single-center, retrospective analysis of patients with nonischemic CM who underwent left ventricular assist device or heart transplantation (LVAD/HT) from 1992-2019. Demographics, clinical characteristics, family history (FHx), and genetic testing results were collected.
Results:
A total of 248 patients (73 women 29%) were included. Age at CM diagnosis was 23 years (IQR 20.5, 29.5) for patients with suspected or confirmed familial, genetic, or noncompaction CM versus 44 years (IQR 35, 52) for other nonischemic etiologies (p<0.001). A 3-generation FHx was reported for 23% of patients; 25 (18 men 72%) underwent genetic testing. Median time between LVAD/HT and genetic testing was 519 days. Five patients underwent genetic testing prior to LVAD/HT. Cascade screening was recommended in 15/25 (75%). Twelve of 25 (48%) had a disease-causing genetic variant identified (Table). Among these 12, median age at CM diagnosis was 25.5 years (IQR 20.5, 35) compared with 40.5 years (IQR 27, 45.5) for those (n=13) who underwent genetic testing but did not have any causative variants identified.
Conclusion:
In this cohort of patients with ESHF due to nonischemic CM, only 23% had a documented 3-generation FHx, only 10% underwent genetic testing, most patients underwent genetic testing after LVAD/HT, and patients with suspected or confirmed familial/genetic CM presented at significantly younger ages. Our findings highlight opportunities to improve underdiagnosis of familial/genetic CM, especially for those patients who present with advanced HF in the third decade of life.
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Background:
Mavacamten, a first-in-class allosteric reversible inhibitor of cardiac myosin ATPase, was approved by the US Food and Drug Administration for the treatment of symptomatic ...obstructive hypertrophic cardiomyopathy (HCM) in April 2022.
Purpose:
To describe the characteristics of real-world patients initiated on mavacamten at a US HCM center of excellence.
Methods:
All patients started on mavacamten from May 2022 to February 2023 were included. Baseline demographics, clinical characteristics, and echocardiographic data, including left ventricular ejection fraction (LVEF) and left ventricular outflow tract (LVOT) gradients at rest and with Valsalva, were collected. Descriptive statistics were presented as means (standard deviations) and medians (interquartile ranges IQRs) or as counts and percentages as appropriate.
Results:
Of 45 patients initiated on mavacamten in the study period, 47% were female, 13% were non-White, and median age was 63 years (IQR 48, 70). Two-thirds were privately insured. Hypertension was common (56%), and 27% had an implantable cardioverter defibrillator. Median duration of HCM diagnosis was 6 years (IQR 4, 13), and two patients (4%) had undergone septal reduction therapy. At the time of the baseline echocardiogram prior to drug initiation, 42% had NYHA III symptoms, 56% were on background monotherapy with a beta-blocker, 24% with a nondihydropyridine calcium-channel blocker, and 20% were on both. All patients were in either sinus or an atrial-paced rhythm. Median LVEF was 69% (IQR 65, 75), and median septal wall thickness was 19 mm (IQR 18, 22). Median resting LVOT gradient was 57 mmHg (IQR 35, 80), and median Valsalva LVOT gradient was 78 mmHg (IQR 63, 91) (
Table
).
Conclusions:
In this single center experience of patients with obstructive HCM initiated on mavacamten, clinical characteristics were largely similar to those of patients enrolled in the phase 3 randomized trials of mavacamten, EXPLORER-HCM and VALOR-HCM.
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Background:
Mavacamten is a small molecule inhibitor of cardiac myosin that was developed based on insights into the molecular basis of hypertrophic cardiomyopathy (HCM). In the phase 3 ...EXPLORER-HCM trial (NCT03470545), patients showed consistent benefit in the primary endpoint with mavacamten treatment vs placebo while subgroup analysis of patients with pathogenic or likely pathogenic variants in a broad panel of HCM-related genes, revealed a slightly more favorable response. However, it is unknown how patients specifically with sarcomere gene variants responded.
Aims:
To assess the effect of HCM-specific sarcomere gene variants on response to mavacamten.
Methods:
Sequencing using a 60 gene panel (Invitae) was optional in EXPLORER-HCM. In this exploratory analysis, responses to mavacamten vs placebo for the primary, secondary, and exploratory endpoints were analysed. Patients were grouped based on sarcomere gene variant status (positive for pathogenic/likely pathogenic/variants of uncertain significance SARC+, negative SARC–) or no sequencing). Analyses were adjusted for clinically relevant variables.
Results:
Of 190/251 patients sequenced, 73 were SARC+ (mavacamten, n = 33; placebo, n = 40), 117 were SARC– (mavacamten, n = 57; placebo, n = 60) and 61 had no panel sequencing (mavacamten, n = 33; placebo, n = 28). Mavacamten treatment showed a favorable response for the primary endpoint vs placebo, for SARC+ (odds ratio OR, 4.43 95% CI, 1.56-12.58), and for SARC– (OR, 2.52 95% CI, 0.99-6.42) (
Figure
). Improvements with mavacamten vs placebo were observed in both SARC+ and SARC– subgroups for change from baseline to week 30 in post-exercise left ventricular outflow tract gradient, and peak oxygen consumption, and in New York Heart Association class.
Conclusions:
In this exploratory subgroup analysis, mavacamten treatment benefit was observed both in patients with and without sarcomere gene variants.
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Introduction:
There is phenotypic and mechanistic overlap between arrhythmogenic right ventricular cardiomyopathy and cardiac sarcoidosis (CS). Whether CS and arrhythmogenic left ...ventricular cardiomyopathy (ALVC) similarly overlap has not been investigated. We aimed to evaluate the difference in proportions of disease-causing variants in ALVC-associated genes in patients with high clinical suspicion for CS.
Methods:
From a cohort of individuals with whole exome sequencing (WES) with linked electronic health record data in the Penn Medicine BioBank, we identified those who had and had not been referred for FDG-PET and cardiac MRI to evaluate for CS and compared demographics and carrier rates of predicted loss of function (pLOF) variants in genes causal for dilated cardiomyopathy (DCM) and ALVC.
Results:
Among 43,724 unrelated individuals with WES data, we identified 94 who had been referred for imaging to evaluate for CS. Those who had been referred for imaging were more often of self-reported Black race (50% vs. 25%, p<0.001) and had atrial arrhythmias (62% vs. 30%, p<0.001) and systolic heart failure (61% vs. 17%, p<0.001). Among these 94 individuals, six (6.4%) carried a pLOF variant in at least one of 19 genes known to have strong causal evidence for DCM/ALVC, compared with 1.2% of the participants not referred for imaging. After adjustment for age, sex, and five genetic principal components of ancestry, individuals referred for FDG-PET and MRI were more likely to carry a pLOF variant in a DCM gene of interest compared with the remaining PMBB participants (OR 5.96; 95% CI 2.31, 12.6; p<0.001).
Conclusion:
Individuals at high clinical suspicion for having CS have 6-fold higher odds of having a pLOF variant in a gene causal for DCM. There is under-recognized overlap between the clinical presentations of genetic ALVC/DCM and CS, and as such, the differential diagnosis for CS and inflammatory cardiomyopathy should be expanded to include these entities.
The initiation of sacubitril/valsartan (S/V) after hemodynamic stabilization in patients hospitalized for acute decompensated heart failure has been shown to be safe and effective. There are limited ...data suggesting that S/V is safe in patients in cardiogenic shock. The optimal timing of initiation or resumption of therapy remains uncertain.
S/V is safe and tolerable for patients in cardiogenic shock requiring inotropic support.
We identified patients with an ICD 9/10 code diagnosis of heart failure with reduced ejection fraction who had been admitted to the cardiac intensive care unit of a quaternary care medical center between January 1, 2017 and December 31, 2020. Within this cohort, we identified 19 patients who were treated with S/V while receiving inotropic support. Demographics and clinical characteristics (laboratory results and invasive hemodynamics) were collected. Opening hemodynamics were obtained within 24 hours of admission and closing hemodynamics were obtained after weaning off or selecting a stable discharge dose of inotrope. Differences between clinical characteristics were compared using paired Wilcoxon signed rank tests.
19 patients (100%) received milrinone and 3 patients (15.8%) additionally received dobutamine during their hospitalization. Cardiac index increased from 1.70 L/min/m2 interquartile range IQR, 1.50-2.20 L/min/m2 to 2.50 L/min/m2 (IQR, 2.20-2.70 L/min/m2; p<0.001) and systemic vascular resistance decreased from 1490 dynes/sec/cm5 IQR, 1340-1741 dynes/sec/cm5 to 945 dynes/sec/cm5 (IQR, 864-1102 dynes/sec/cm5; p<0.001). Serum creatinine and potassium remained stable from admission to discharge (p for both > 0.05). At discharge, 14 patients (73.7%) were prescribed S/V. Of the patients discharged on S/V, 5 (35.7%) were also discharged on milrinone. S/V was discontinued prior to discharge due to hypotension in 4 patients (21.1%) and acute kidney injury in 1 patient (5.3%). At 3 months post-discharge, a majority of patients (68.4%) remained on S/V.
Patients in cardiogenic shock requiring inotropic support can safely receive S/V without a significant increase in serum creatinine or potassium. Further analyses of larger cohorts should explore the ideal timing for initiating or resuming S/V in patients receiving inotropic support. Establishing the safety and tolerability of this practice may lead to earlier adoption and/or decreased interruption of guideline directed medical therapy.
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