No abstract

*Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply; see Appendix 1 for recusal information. †ACC/AHA Representative.

Context Heart failure increases with advancing age, and approximately half of patients have preserved left ventricular ejection fraction. Although diastolic dysfunction plays a role in heart failure with preserved ejection fraction, little is known about age-dependent longitudinal changes in diastolic function in community populations. Objective To measure longitudinal change in diastolic function and heart failure incidence in a population-based cohort. Design 2042 randomly selected participants underwent clinical evaluation, medical record abstraction, and echocardiography (1997–2000). Diastolic left ventricular function was graded as mild, moderate, or severe by validated Doppler techniques. After four years participants were invited to return for re-examination, and 1402 did so (2001–2004). The cohort was then followed for ascertainment of new onset heart failure (2004–2010). Setting Community population; Olmsted County, Minnesota Participants Population-based cohort of persons ≥45 years old Main Outcome Measures Incident heart failure Results Over 4 ± 0.3 years diastolic dysfunction prevalence increased from 23.8% (95% CI 21.2–26.4) to 39.2% (95% CI 36.3–42.2) (P <0.001). Diastolic function grade worsened in 23.4% (95% CI 20.9–26.0) of participants, was unchanged in 67.8% (95% CI 64.9–70.6), and improved in 8.8% (95% CI 7.1–10.5). Worsened diastolic dysfunction was associated with age ≥65 years (OR 2.85; 95% CI 1.77–4.72). During 6.3 ± 2.3 years of additional follow-up, heart failure occurred in 2.6% (95% CI 1.4–3.8), 7.8% (95% CI 5.8–13.0), and 12.2% (95% CI 8.5–18.4) of persons whose diastolic function normalized or remained normal, remained or progressed to mild dysfunction, or remained or progressed to moderate-severe dysfunction, respectively. (P <0.001) Diastolic dysfunction was associated with incident heart failure after adjustment for age, hypertension, diabetes, and coronary disease (HR 1.81; 95% CI 1.01–3.48). Conclusion In a population-based cohort followed for four years, diastolic dysfunction prevalence increased. Diastolic dysfunction was associated with development of heart failure during six years of subsequent follow-up.

*Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply; see Appendix 1 for recusal information. †ACC/AHA Representative.

Reaction to stress requires feedback adaptation of cellular functions to secure a response without distress, but the molecular order of this process is only partially understood. Here, we report a previously unrecognized regulatory element in the general adaptation syndrome. Kir6.2, the ion-conducting subunit of the metabolically responsive ATP-sensitive potassium (KATP) channel, was mandatory for optimal adaptation capacity under stress. Genetic deletion of Kir6.2 disrupted KATP channel-dependent adjustment of membrane excitability and calcium handling, compromising the enhancement of cardiac performance driven by sympathetic stimulation, a key mediator of the adaptation response. In the absence of Kir6.2, vigorous sympathetic challenge caused arrhythmia and sudden death, preventable by calcium-channel blockade. Thus, this vital function identifies a physiological role for KATP channels in the heart. I on channels control the electrical potential across the cell membrane of all living organisms. The profile of channel expression within the cell is defined by evolution through natural selection (1, 2). Developed as channel͞enzyme multimers, K ATP channels combine properties of two different classes of protein to adjust rapidly and precisely membrane excitability according to the metabolic state of the cell (3-7). Identified in metabolically active tissues of a broad range of species, K ATP channels were discovered originally in heart muscle where they are expressed in high density (8, 9). Functional cardiac K ATP channels can be formed only through physical association of the pore-forming Kir6.2 subunit with the regulatory sulfonylurea receptor SUR2A (10-12). In this complex, which harbors an intrinsic ATPase activity, nucleotide interaction at SUR2A gates potassium permeation through Kir6.2, a property believed to be responsible for the fine metabolic modulation of membrane potential-dependent cellular functions (7,(13)(14)(15)(16).The physiological role of K ATP channels as metabolic sensors has been understood best in the regulation of hormone secretion in pancreatic ␤-cells and more recently in the hypothalamus (17-21). In the heart, definition of the function of this protein complex thus far has been limited to acute protection against ischemic events (22). In fact, under ischemia, the opening of as few as 1% of K ATP channels is sufficient to produce significant shortening of the cardiac action potential (23), manifested globally by ST-segment elevation on the electrocardiogram (24). Yet, beyond the impact in pathophysiology, a physiological role for the cardiac K ATP channel that supports its maintenance in hearts of many species is lacking (25).The general adaptation syndrome is a ubiquitous reaction vital for self-preservation under conditions of stress such as exertion or fear (26-28). Mediated by a catecholamine surge, this syndrome generates an alteration of physiologic and biochemical functions to sustain a superior level of bodily performance and allows confrontation or escape in response to threat...

Members of the transforming growth factor beta1 (TGF-beta) superfamily--namely, TGF-beta and BMP2--applied to undifferentiated murine embryonic stem cells up-regulated mRNA of mesodermal (Brachyury) and cardiac specific transcription factors (Nkx2.5, MEF2C). Embryoid bodies generated from stem cells primed with these growth factors demonstrated an increased potential for cardiac differentiation with a significant increase in beating areas and enhanced myofibrillogenesis. In an environment of postmitotic cardiomyocytes, stem cells engineered to express a fluorescent protein under the control of a cardiac promoter differentiated into fluorescent ventricular myocytes beating in synchrony with host cells, a process significantly enhanced by TGF-beta or BMP2. In vitro, disruption of the TGF-beta/BMP signaling pathways by latency-associated peptide and/or noggin prevented differentiation of stem cells. In fact, only host cells that secrete a TGF-beta family member induced a cardiac phenotype in stem cells. In vivo, transplantation of stem cells into heart also resulted in cardiac differentiation provided that TGF-beta/BMP2 signaling was intact. In infarcted myocardium, grafted stem cells differentiated into functional cardiomyocytes integrated with surrounding tissue, improving contractile performance. Thus, embryonic stem cells are directed to differentiate into cardiomyocytes by signaling mediated through TGF-beta/BMP2, a cardiac paracrine pathway required for therapeutic benefit of stem cell transplantation in diseased heart.

Background Diagnosis of heart failure (HF) with preserved ejection fraction (HFpEF) is challenging and relies largely on demonstration of elevated cardiac filling pressures (pulmonary capillary wedge pressure, PCWP). Current guidelines recommend use of natriuretic peptides (NT-proBNP) and rest/exercise echocardiography (E/e’ ratio) to make this determination. Data to support this practice is conflicting. Methods Simultaneous echocardiographic-catheterization studies were prospectively conducted at rest and during exercise in subjects with invasively-proven HFpEF (n=50) and participants with dyspnea but no identifiable cardiac pathology (n=24). Results NT-proBNP levels were below the level considered to exclude disease (≤125 pg/ml) in 18% of subjects with HFpEF. E/e’ ratio was correlated with directly measured PCWP at rest (r=0.63, p<0.0001) and during exercise (r=0.57, p<0.0001). While specific, current guidelines were poorly sensitive, identifying only 34–60% of subjects with invasively-proven HFpEF based upon resting echocardiographic data alone. Addition of exercise echocardiographic data (E/e’ ratio>14) improved sensitivity (to 90%) and thus negative predictive value, but decreased specificity (71%). Conclusions Currently proposed HFpEF diagnostic guidelines based upon resting data are poorly sensitive. Adding exercise E/e’ data improves sensitivity and negative predictive value but compromises specificity, suggesting that exercise echocardiography may help rule out HFpEF. These results question the accuracy of current approaches to exclude HFpEF based upon resting data alone and reinforce the value of exercise testing using invasive and noninvasive hemodynamic assessments to definitively confirm or refute the diagnosis of HFpEF. Clinical trial registration NCT01418248 https://clinicaltrials.gov/ct2/results?term=NCT01418248&Search=Search

A unique and highly versatile technique, stress echocardiography (SE) is increasingly recognized for its utility in the evaluation of non-ischaemic heart disease. SE allows for simultaneous assessment of myocardial function and haemodynamics under physiological or pharmacological conditions. Due to its diagnostic and prognostic value, SE has become widely implemented to assess various conditions other than ischaemic heart disease. It has thus become essential to establish guidance for its applications and performance in the area of non-ischaemic heart disease. This paper summarizes these recommendations.