Traditional approaches to the assessment of new treatments for heart failure have generally evaluated individual components of the syndrome at fixed points in time or have relied on surrogate physiological measures that are poorly correlated with the clinical status of patients. Conventional time-to-event trials that focus on morbidity and mortality represent an important methodological advance, but they generally assign undue weight to clinical events of less importance and are insensitive to difference in functional capacity among individuals who do not experience a clinical event during follow-up. Twenty years ago, a hierarchical clinical composite was developed to address these limitations; it aims to assess the clinical course of patients as a physician would in practice by combining a symptomatic assessment of the patient at each visit with an evaluation of the clinical stability of the patient between visits. The composite does not generate a numeric score by summing arbitrarily assigned weights to certain symptoms or events; instead, the composite ranks relevant measures and outcomes according to clinical priority. In doing so, the clinical composite minimizes the biases created by noncompleting patients in the assessment of symptoms or exercise tolerance while expanding the range of patients who contribute to the treatment difference in a typical morbidity and mortality trial. When applied appropriately, the hierarchical clinical composite end point has reliably distinguished effective from ineffective treatments. The composite may have particular advantages in the evaluation of new devices and transcatheter interventions in chronic heart failure and of new drugs for acute heart failure. Recent modifications enhance its discriminant characteristics and its ability to accurately assess the efficacy of novel interventions for heart failure.

Dr James (also known as Jamie) N. Topper, MD, PhD, serves as Managing General Partner at Frazier Healthcare Partners, where he leads the Life Science Venture practice. In 2011, and 2016, he was named to the Midas List of leading venture capitalists, and, in 2013, he was recognized by Forbes as one of the top 10 healthcare investors. He has >25 years of experience working with entrepreneurs to found and build successful therapeutics-focused companies. Dr Topper holds a BS from the University of Michigan. He received an MD and PhD (in biophysics) from Stanford University School of Medicine. He completed postgraduate training in internal medicine and cardiovascular disease at the Brigham and Women's Hospital in Boston and is board certified in both disciplines.

Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies and linkage studies only partially explain the influence of genetics on KD susceptibility.

The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive.

Heart rate turbulence (HRT) has been proposed as a candidate marker of altered autonomic tone, and some studies showed its prognostic value for both cardiac death (CD) and sudden death. Nevertheless, HRT is not currently used in the clinical practice.

Serine and glycine interconversion and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1)-mediated 1-carbon transfer are the major sources of methyl groups for 1-carbon metabolism. Recently, plasma glycine and a common polymorphism in MTHFD1 have been associated with risk of acute myocardial infarction (AMI). It is, therefore, of interest to explore if these 2 pathways interact in relation to AMI.

The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease.