Publications by authors named "Hugh Watkins"
Background: Cardiomyopathies are an important cause of heart failure in Africa yet there are limited data on etiology and clinical phenotypes.
Objectives: The IMHOTEP (African Cardiomyopathy and Myocarditis Registry Program) was designed to systematically collect data on individuals diagnosed with cardiomyopathy living in Africa.
Methods: In this multicenter pilot study, patients (age ≥13 years) were eligible for inclusion if they had a diagnosis of cardiomyopathy or myocarditis.
Background: Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition that can lead to atrial fibrillation, heart failure, and sudden cardiac death in many individuals but mild clinical impact in others. The mechanisms underlying this phenotypic heterogeneity are not well defined. The aim of this study was to use plasma proteomic profiling to help illuminate biomarkers that reflect or inform the heterogeneity observed in HCM.
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- Hypertrophic cardiomyopathy (HCM) is a diverse heart condition that can lead to severe health issues and traditionally managed through symptom relief and the use of defibrillators to prevent sudden cardiac death.
- There is a recognized need for treatments that modify the disease itself, and recently, new therapies like mavacamten, a myosin inhibitor, have gained regulatory approval.
- Clinical trials for HCM face unique challenges, which include selecting patients based on their genetic and symptom profiles, measuring outcomes effectively, and considering factors like trial duration and sample size when interpreting results.
Background: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined.
Objectives: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten.
Article Synopsis
- Genetic studies have highlighted the need for more diverse research on plasma fibrinogen levels, as previous studies largely focused on Europeans, leading to gaps in understanding and missing heritability.
- By analyzing data from whole-genome sequencing and genotype data from large cohorts, researchers identified 18 genetic loci related to fibrinogen levels, some of which are more common in African populations and include variants that may impact protein function.
- The study's findings indicate a connection between fibrinogen levels and various health conditions, emphasizing the importance of whole-genome sequencing in discovering genetic factors in diverse populations and enhancing knowledge about fibrinogen regulation.
Article Synopsis
- The study analyzed the role of biomarkers NT-proBNP and hs-cTnI in managing obstructive hypertrophic cardiomyopathy (oHCM) and how they relate to treatment effects of aficamten.
- Baseline levels of NT-proBNP correlated with the left ventricular outflow tract gradient (LVOT-G) and diastolic function, while hs-cTnI correlated with left ventricular thickness.
- After 8 weeks of aficamten treatment, NT-proBNP decreased by 79% and hs-cTnI by 41%, with these reductions linked to improvements in heart function, health status, and exercise capacity, suggesting that these biomarkers are useful for tracking treatment response.
Aims: Recently, deep learning artificial intelligence (AI) models have been trained to detect cardiovascular conditions, including hypertrophic cardiomyopathy (HCM), from the 12-lead electrocardiogram (ECG). In this external validation study, we sought to assess the performance of an AI-ECG algorithm for detecting HCM in diverse international cohorts.
Methods And Results: A convolutional neural network-based AI-ECG algorithm was developed previously in a single-centre North American HCM cohort (Mayo Clinic).
Article Synopsis
- Aficamten is a new drug that helps reduce heart issues in patients with obstructive hypertrophic cardiomyopathy by targeting heart muscle contractility and maintaining safe blood flow levels.
- * In a clinical trial involving 282 patients, those receiving aficamten were able to maintain effective heart function with minimal side effects, including a stable reduction in heart muscle contraction without significant adverse events.
- * The findings suggest that using a tailored dosing strategy for aficamten is effective and safe, improving cardiovascular health without worsening conditions like heart failure.
Cardiomyopathies are a group of inherited heart muscle disorders. Expressivity is variable and while sometimes mild, complications can result in sudden cardiac death (SCD) at any age, heart failure and stroke. In around a third of patients a monogenic cause is identifiable, and development of genetic therapies that aim to correct the underlying genetic defect is underway.
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- - The text discusses Calcium Release Deficiency Syndrome (CRDS), a serious genetic heart condition that can cause sudden cardiac arrest without clear reasons and is not detectable through standard tests.
- - The study aimed to analyze electrocardiogram (ECG) responses after brief periods of fast heart rates followed by pauses in order to develop a diagnostic test for CRDS.
- - Findings showed that patients with CRDS had a significantly greater change in T-wave amplitude on their ECG after a pause compared to control groups, indicating a potential diagnostic marker for this syndrome.
Background: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility.
Methods: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results.
Article Synopsis
- * The research showed that individuals with high polygenic risk scores have significantly higher blood pressure (almost 17 mmHg more) and over seven times the risk of developing hypertension compared to those with low scores.
- * Incorporating these genetic risk scores into hypertension prediction models improved their accuracy, and excitingly, similar genetic associations were found in a large African-American sample, underscoring the potential of these findings for precision health initiatives.
Aims: Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM.
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- Nonobstructive hypertrophic cardiomyopathy (nHCM) currently lacks approved treatments, but a new drug, ninerafaxstat, aims to improve heart energy and alleviate symptoms.
- A clinical trial with 67 patients showed that ninerafaxstat led to better ventilatory efficiency after 12 weeks compared to a placebo, despite similar peak exercise levels.
- Overall, ninerafaxstat was safe, well tolerated, and particularly beneficial for patients with more severe symptoms, indicating potential for improving their health and exercise capacity.
Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing).
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- This phase 2 trial assessed the safety and effectiveness of a medication called aficamten in patients suffering from nonobstructive hypertrophic cardiomyopathy (nHCM).
- 41 patients participated, and after 10 weeks of treatment, over half showed improvement in heart failure symptoms, with many reaching a better functional class.
- While some patients experienced a slight decrease in heart function (LVEF), the overall results indicated that aficamten is generally safe and effective in improving symptoms and relevant heart health markers.
Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM).
View Article and Find Full Text PDFBackground: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.
Methods: We enrolled 436 patients with HCM (median age, 60 years; 28.
Article Synopsis
- Whole genome sequencing (WGS) is being increasingly used to diagnose rare diseases, but traditional methods often have low diagnostic yields, typically 25-30%.
- In a study involving 122 rare disease patients and their relatives, a comprehensive bioinformatics approach led to a diagnostic yield of 35%, with 39% solved when including novel gene candidates.
- The study also identified several novel genes, expanded the phenotypic understanding of existing conditions, and resulted in critical changes to clinical diagnoses and treatments for some patients.
Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals.
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- * The study involved analyzing data from over 10,000 individuals with HCM and around 2,500 with DCM, revealing significant penetrance rates: 23% for HCM and 35% for DCM by late adulthood for rare, pathogenic variants.
- * Results indicate that certain variant subgroups, particularly loss-of-function ones, show higher penetrance, especially in males, and the findings will help guide the management and screening of individuals for genetic risks associated with cardi
Article Synopsis
- Genetic studies on plasma fibrinogen levels primarily focused on Europeans, revealing numerous associated regions, but there are gaps in understanding due to missing heritability and representation of non-Europeans.
- The researchers utilized whole genome sequencing (WGS) and array-based genotyping data from large cohorts to identify 18 new genetic loci linked to fibrinogen levels, with some variants more common in African populations.
- The study highlights the importance of WGS in discovering genetic variations across diverse populations, linking fibrinogen polygenic risk scores to increased risk for thrombotic and inflammatory diseases like gout.