Search

Aims: The trajectories of systolic function after admission for acute heart failure (HF) and their effect on clinical outcomes have not been fully elucidated. We aimed to assess changes in left ventricular ejection fraction (LVEF) between the index and 1 year after discharge and to examine their prognostic implications. Methods and results: We extracted data from a prospective multicentre registry of patients hospitalized for acute HF and identified 1636 patients with LVEF data at admission and 1 year after discharge. We categorized them into five groups based on LVEF changes: HF with unchanged‐preserved EF [HFunc‐pEF (EF ≥ 50%); N = 527, 32.2%], unchanged‐mildly reduced EF [HFunc‐mrEF (EF 41–49%); N = 86, 5.3%], unchanged‐reduced EF [HFunc‐rEF (EF ≤ 40%); N = 377, 23.0%], worsened EF (HFworEF; N = 83, 5.1%), and improved EF (HFimpEF; N = 563, 34.4%). We then evaluated the subsequent composite outcome of cardiovascular death and HF readmission. During 1 year after discharge, 53% of patients with HF with reduced EF and 67% of those with HF with mildly reduced EF (HFmrEF) transitioned to other categories, whereas 92% of those with HF with preserved EF (HFpEF) remained within the same category. Patients with HFimpEF were more likely to be younger and had relatively preserved renal function, whereas those with HFworEF were the oldest and had more comorbidities among the five groups. After multivariable adjustment, patients with HFimpEF and HFunc‐pEF had a lower risk for composite outcomes when referenced to patients with HFunc‐rEF [hazard ratio (95% confidence interval), P‐value: 0.28 (0.16–0.49), P < 0.001, and 0.40 (0.25–0.63), P < 0.001, respectively]. Conversely, patients with HFunc‐mrEF and HFworEF had a comparable risk [0.44 (0.18–1.07), P = 0.07, and 0.63 (0.29–1.39), P = 0.26, respectively]. Conclusions: A substantial number of patients with HF experienced transitions to other categories after discharge. Notably, patients with decreased EF experienced a worse prognosis, even with slight decreases (e.g. HFpEF transitioning to HFmrEF). These findings emphasize the significance of longitudinal assessments of systolic function to better manage patients following acute decompensation. [ABSTRACT FROM AUTHOR]

Heart failure in children and adults is often the consequence of myocarditis associated with Coxsackievirus (CV) infection. Upon CV infection, enteroviral protease 2A cleaves a small number of host proteins including dystrophin, which links actin filaments to the plasma membrane of muscle fiber cells (sarcolemma). It is unknown whether protease 2A-mediated cleavage of dystrophin and subsequent disruption of the sarcolemma play a role in CV-mediated myocarditis. We generated knockin mice harboring a mutation at the protease 2A cleavage site of the dystrophin gene, which prevents dystrophin cleavage following CV infection. Compared with wild-type mice, we found that mice expressing cleavage-resistant dystrophin had a decrease in sarcolemmal disruption and cardiac virus titer following CV infection. In addition, cleavage-resistant dystrophin inhibited the cardiomyopathy induced by cardiomyocyte-restricted expression of the CV protease 2A transgene. These findings indicate that protease 2A-mediated cleavage of dystrophin is critical for viral propagation, enteroviral-mediated cytopathic effects, and the development of cardiomyopathy.

The response of cardiomyocytes to biomechanical stress can determine the pathophysiology of hypertrophic cardiac disease, and targeting the pathways regulating these responses is a therapeutic goal. However, little is known about how biomechanical stress is sensed by the cardiomyocyte sarcomere to transduce intracellular hypertrophic signals or how the dysfunction of these pathways may lead to disease. Here, we found that four-and-a-half LIM domains 1 (FHL1) is part of a complex within the cardiomyocyte sarcomere that senses the biomechanical stress--induced responses important for cardiac hypertrophy. Mice lacking Fhl1 displayed a blunted hypertrophic response and a beneficial functional response to pressure overload induced by transverse aortic constriction. A link to the G[alpha]q (Gq) signaling pathway was also observed, as Fhl1 deficiency prevented the cardiomyopathy observed in Gq transgenic mice. Mechanistic studies demonstrated that FHL1 plays an important role in the mechanism of pathological hypertrophy by sensing biomechanical stress responses via the N2B stretch sensor domain of titin and initiating changes in the titin- and MAPK-mediated responses important for sarcomere extensibility and intracellular signaling. These studies shed light on the physiological regulation of the sarcomere in response to hypertrophic stress., Introduction Cardiovascular disease and ensuing heart failure is the leading cause of human morbidity and mortality worldwide. Biomechanical stress--induced growth responses have been shown to play a pivotal role in [...]

The coxsackievirus and adenovirus receptor (CAR) is a transmembrane protein that belongs to the family of adhesion molecules. In the postnatal heart, it is localized predominantly at the intercalated disc, where its function is not known. Here, we demonstrate that a first degree or complete block of atrioventricular (AV) conduction developed in the absence of CAR in the adult mouse heart and that prolongation of AV conduction occurred in the embryonic heart of the global CAR-KO mouse. In the cardiac-specific CAR-KO (CAR-cKO) mouse, we observed the loss of connexin 45 localization to the cell-cell junctions of the AV node but preservation of connex-in 40 and 43 in contracting myocardial cells and connexin 30.2 in the AV node. There was also a marked decrease in [beta]-catenin and zonula occludens-1 (ZO-1) localization to the intercalated discs of CAR-cKO mouse hearts at 8 weeks before the mice developed cardiomyopathy at 21 weeks of age. We also found that CAR formed a complex with connexin 45 via its PSD-95/DigA/ZO-l-binding (PDZ-binding) motifs. We conclude that CAR expression is required for normal AV-node conduction and cardiac function. Furthermore, localization of connexin 45 at the AV-node cell-cell junction and of [beta]-catenin and ZO-1 at the ventricular intercalated disc are dependent on CAR, Introduction The coxsackievirus and adenovirus receptor (CAR) was initially identified as a common receptor of the viruses for which it was named (1), (2). It is expressed in various organs [...]

The present study tested the hypothesis that murine (m)IFN-[beta] or mIFN-[[alpha].sub.2] can eliminate cardiac viral load and protect cardiomyocytes from injury in animals infected with coxsackievirus B3 (CVB3). CVB3-inoculated male Balb/c mice exhibited signs of illness, including lethargy, progressive weight loss, and death (10% on day 3 and 100% on day 8). Cardiac viral load was high [4,277 [+ or -] 1,009 plaque-forming units and 25 [+ or -] 5 copies CVB3/hypoxanthine guanine phosphoribosyl transferase 1 mRNA] on day 4. The cardiac tissue exhibited severe inflammatory infiltration and myocyte damage with an average myocarditis integrated pathology score of 2.1 [+ or -] 0.2 on day 7. Most of the mice infected with CVB3 also developed epicarditis, and 55% had intraventricular thrombi present. Treatment with mIFN-[beta] [2.5 to 10 million international units (MIU)/kg] dose-dependently improved the general health status in CVB3-inoculated mice, as evidenced by reduction in weight loss, prevention of death, elimination of cardiac viral load, protection of myocytes from injury, decrease in inflammatory cell infiltration, and attenuation of intraventricular thrombus formation. Treatment with 10 MIU/kg mIFN-[[alpha].sub.2] resulted in a similar level of efficacy as that induced by 5 MIU/kg mIFN-[beta], with the exception that mIFN-[[alpha].sub.2] did not reduce cardiac CVB3 mRNA. However, mIFN-[[beta].sub.2] , but not any dose group of mIFN-[beta], significantly attenuated CVB3-induced epicarditis. These data demonstrate antiviral effects for both mIFN-[beta] and mIFN-[[alpha].sub.2], which lead to protection of the mice from CVB3-induced myocarditis. However, the potential mechanisms leading to a differential host response for the two isoforms of mIFN remain to be elucidated. viral cardiomyopathy; myocyte infection; antiviral action; immunomodulation doi:10.1152/ajpheart.00154.2007