Novel therapies in acute and chronic heart failure

Aronson, Doron; Krum, Henry

doi:10.1016/j.pharmthera.2012.03.002

Cited by 45 publications

(36 citation statements)

References 189 publications

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“…In recent ADHF trials, moderately or marked improvement in dyspnea was achieved in only 25% to 65% of patients within 24 hours. 9,10,12,13 These studies demonstrate that contemporary ADHF therapy is suboptimal not only with respect to outcomes, 21 but also with respect to symptom relief. 22 Therefore, it is important to understand the reasons for the failure to improve dyspnea.…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic Determinants of Dyspnea Improvement in Acute Decompensated Heart Failure

Solomonica

Burger

Aronson

2013

Circ: Heart Failure

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Background— Dyspnea relief constitutes a major treatment goal and a key measure of treatment efficacy in decompensated heart failure. However, there are no data with regard to the relationship between hemodynamic measurements during treatment and dyspnea improvement. Methods and Results— We studied 233 patients assigned to right heart catheterization in the Vasodilation in the Management of Acute Congestive Heart Failure trial. Dyspnea (assessed using a 7-point Likert scale) and hemodynamic parameters were measured simultaneously at 15 and 30 minutes and 1, 2, 3, 6, and 24 hours. Dyspnea relief was defined as moderate or marked improvement. There was a time-dependent association between the reductions in pulmonary capillary wedge pressure (PCWP; 25.4, 24.6, 24.0, 23.5, 23.4, 21.5, and 19.9 mm Hg) and the percentage of patients achieving dyspnea relief (17.7%, 24.6%, 32.2%, 36.2%, 37.8%, 47.4%, and 66.1%, in the respective time points). Multivariable logistic generalized estimating equations modeling demonstrated that reductions of both PCWP and mean pulmonary artery pressure were independently associated with dyspnea relief. Compared with the highest PCWP quartile, the adjusted odds ratios for dyspnea relief were 0.92 (95% confidence interval [CI], 0.67–1.29), 1.07 (95% CI, 0.75–1.55), and 1.80 (95% CI, 1.22–2.65) in the third, second, and first PCWP quartiles, respectively ( P trend =0.003). Compared with the highest mean pulmonary artery pressure quartile, the adjusted odds ratios for dyspnea relief were 2.0 (95% CI, 1.41–2.82), 2.23 (95% CI, 1.52–3.27), and 2.98 (95% CI, 1.91–4.66) in the third, second, and first mean pulmonary artery pressure quartiles, respectively ( P trend <0.0001). Conclusions— A clinically significant improvement in dyspnea is associated with a reduction in both PCWP and mean pulmonary artery pressure.

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Section: Discussionmentioning

confidence: 99%

Hemodynamic Determinants of Dyspnea Improvement in Acute Decompensated Heart Failure

Solomonica

Burger

Aronson

2013

Circ: Heart Failure

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“…Notably, heart failure is associated with abnormal Ca 2+ handling, deficient SR Ca 2+ uptake and inefficient energy usage, leading to impairments in both the systolic and diastolic function of the heart (Arai et al 1993;Kawase and Hajjar 2008). The underlying dysfunction that commonly characterizes patients with heart failure has been attributed to impaired SERCA2a function (Aronson and Krum 2012;Park and Oh 2013). These cardiac abnormalities may be a result of reductions in the mRNA, protein expression, or activity of SERCA2a (Mercadier et al 1990; Kawase and Hajjar 2008;Park and Oh 2013).…”

Section: Serca2a Expression and Activity Is Reduced In Heart Failurementioning

confidence: 99%

The regulation of sarco(endo)plasmic reticulum calcium-ATPases (SERCA)

Stammers

Susser

Hamm

et al. 2015

Can. J. Physiol. Pharmacol.

132

106

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The sarco(endo)plasmic reticulum calcium ATPase (SERCA) is responsible for transporting calcium (Ca(2+)) from the cytosol into the lumen of the sarcoplasmic reticulum (SR) following muscular contraction. The Ca(2+) sequestering activity of SERCA facilitates muscular relaxation in both cardiac and skeletal muscle. There are more than 10 distinct isoforms of SERCA expressed in different tissues. SERCA2a is the primary isoform expressed in cardiac tissue, whereas SERCA1a is the predominant isoform expressed in fast-twitch skeletal muscle. The Ca(2+) sequestering activity of SERCA is regulated at the level of protein content and is further modified by the endogenous proteins phospholamban (PLN) and sarcolipin (SLN). Additionally, several novel mechanisms, including post-translational modifications and microRNAs (miRNAs) are emerging as integral regulators of Ca(2+) transport activity. These regulatory mechanisms are clinically relevant, as dysregulated SERCA function has been implicated in the pathology of several disease states, including heart failure. Currently, several clinical trials are underway that utilize novel therapeutic approaches to restore SERCA2a activity in humans. The purpose of this review is to examine the regulatory mechanisms of the SERCA pump, with a particular emphasis on the influence of exercise in preventing the pathological conditions associated with impaired SERCA function.

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“…54 Over time, collagen-associated AGEs accumulate within the ECM attributable to their slow turnover rate and exert detrimental effects on cardiovascular function. 55 Accumulation of AGEs within the myocardium diminishes compliance leading to diastolic LV stiffness.…”

Section: Advanced Glycation End Productsmentioning

confidence: 99%

“…55 Accumulation of AGEs within the myocardium diminishes compliance leading to diastolic LV stiffness. 54 Specific cross-linking of AGEs with matrix proteins has been detected on type I collagen and elastin. 56 AGEs monitored in the circulation positively correlate with heart failure severity and progression of disease.…”

Section: Advanced Glycation End Productsmentioning

confidence: 99%

Dynamic Changes in Myocardial Matrix and Relevance to Disease

Liu

Villarreal

et al. 2014

Circulation Research

110

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T he extracellular matrix (ECM) provides structural support and organization for cardiomyocytes and the vasculature of the heart. Under normal conditions, the ECM scaffold facilitates efficient force transduction for mechanical work, while mediating intercellular communication and metabolic exchange. This follows the unique 3-dimensional disposition of myocyte bundles and fibrillar collagens within the myocardium (Figure 1). With stress, injury, or disease, the ECM undergoes changes that potentiate inflammatory processes, myocardial protein turnover, tissue repair, and regeneration, which leads to organ remodeling and functional adaptation. However, sustained ECM remodeling can compromise proper diastolic and contractile functions as seen with fibrosis. This review will discuss the complex dynamics of the ECM in the setting of cardiovascular conditions of myocardial infarction (MI), pressure overload (PO), and volume overload (VO) as both participant and contributor to the disease pathophysiology. Subsequent sections will focus on the translational aspects of identifying biomarkers that can prognosticate or identify disease progression in patients and the current status of ECM-focused antifibrotic therapies.

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Novel therapies in acute and chronic heart failure

Cited by 45 publications

References 189 publications

Hemodynamic Determinants of Dyspnea Improvement in Acute Decompensated Heart Failure

Hemodynamic Determinants of Dyspnea Improvement in Acute Decompensated Heart Failure

The regulation of sarco(endo)plasmic reticulum calcium-ATPases (SERCA)

Dynamic Changes in Myocardial Matrix and Relevance to Disease

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