The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.

Heart failure (HF), the leading cause of death in the western world, develops when a cardiac injury or insult impairs the ability of the heart to pump blood and maintain tissue perfusion. It is characterized by a complex interplay of several neurohormonal mechanisms that become activated in the syndrome to try and sustain cardiac output in the face of decompensating function. Perhaps the most prominent among these neurohormonal mechanisms is the adrenergic (or sympathetic) nervous system (ANS), whose activity and outflow are enormously elevated in HF. Acutely, and if the heart works properly, this activation of the ANS will promptly restore cardiac function. However, if the cardiac insult persists over time, chances are the ANS will not be able to maintain cardiac function, the heart will progress into a state of chronic decompensated HF, and the hyperactive ANS will continue to push the heart to work at a level much higher than the cardiac muscle can handle. From that point on, ANS hyperactivity becomes a major problem in HF, conferring significant toxicity to the failing heart and markedly increasing its morbidity and mortality. The present review discusses the role of the ANS in cardiac physiology and in HF pathophysiology, the mechanisms of regulation of ANS activity and how they go awry in chronic HF, methods of measuring ANS activity in HF, the molecular alterations in heart physiology that occur in HF, along with their pharmacological and therapeutic implications, and, finally, drugs and other therapeutic modalities used in HF treatment that target or affect the ANS and its effects on the failing heart.

Adrenergic nervous system in heart failure: pathophysiology and therapy.

The sympathetic nervous system and heart failure.

Aims It is generally accepted that post-MI heart failure (HF) changes a variety of aspects of sarcoplasmic reticular Ca2+ fluxes but for some aspects there is disagreement over whether there is an increase or decrease. The commonest statistical approach is to treat data collected from each cell as independent, even though they are really clustered with multiple likely similar cells from each heart. In this study, we test whether this statistical assumption of independence can lead the investigator to draw conclusions that would be considered erroneous if the analysis handled clustering with specific statistical techniques (hierarchical tests). Methods and results Ca2+ transients were recorded in cells loaded with Fura-2AM and sparks were recorded in cells loaded with Fluo-4AM. Data were analysed twice, once with the common statistical approach (assumption of independence) and once with hierarchical statistical methodologies designed to allow for any clustering. The statistical tests found that there was significant hierarchical clustering. This caused the common statistical approach to underestimate the standard error and report artificially small P values. For example, this would have led to the erroneous conclusion that time to 50% peak transient amplitude was significantly prolonged in HF. Spark analysis showed clustering, both within each cell and also within each rat, for morphological variables. This means that a three-level hierarchical model is sometimes required for such measures. Standard statistical methodologies, if used instead, erroneously suggest that spark amplitude is significantly greater in HF and spark duration is reduced in HF. Conclusion Ca2+ fluxes in isolated cardiomyocytes show so much clustering that the common statistical approach that assumes independence of each data point will frequently give the false appearance of statistically significant changes. Hierarchical statistical methodologies need a little more effort, but are necessary for reliable conclusions. We present cost-free simple tools for performing these analyses.

/pdf/hierarchical-statistical-techniques-are-necessary-to-draw-44icfh6bks.pdf

Hierarchical statistical techniques are necessary to draw reliable conclusions from analysis of isolated cardiomyocyte studies.

Regulation of Connective Tissue Growth Factor Gene Expression and Fibrosis in Human Heart Failure

Aims Combined left ventricular assist device (LVAD) and pharmacological therapy has been proposed to favour myocardial recovery in patients with end-stage heart failure (HF). Clenbuterol (Clen), a b2adrenoceptor (b2-AR) agonist, has been used as a part of this strategy. In this study, we investigated the direct effects of clenbuterol on unloaded myocardium in HF. Methods and results Left coronary artery ligation or sham operation was performed in male Lewis rats. After 4–6 weeks, heterotopic abdominal transplantation of the failing hearts into normal recipients was performed to induce LV unloading (UN). Recipient rats were treated with saline (Sal) or clenbuterol (2 mg/kg/day) via osmotic minipumps (HF þ UN þ Sal or HF þ UN þ Clen) for 7 days. Non-transplanted HF animals were treated with Sal (Sham þ Sal, HF þ Sal) or clenbuterol (HF þ Clen). LV myocytes were isolated and studied using optical, fluorescence, and electrophysiological techniques. Clenbuterol treatment improved in vivo LV function measured with echocardiography (LVEF (%): HF 35.9+ 2 [16], HF þ Clen 52.1+ 1.4 [16]; P , 0.001; mean+ SEM [n]). In combination with unloading, clenbuterol increased sarcomere shortening (amplitude (mm): HF þ UN þ Clen 0.1+ 0.01 [50], HF þ UN þ Sal 0.07+ 0.01 [38]; P , 0.001) by normalizing the depressed myofilament sensitivity to Ca 2þ (slope of the linear relationship between Ca 2þ transient and sarcomere shortening hysteresis loop during relaxation (mm/ ratio unit): HF þ UN þ Clen 2.13+ 0.2 [52], HF þ UN þ Sal 1.42+ 0.13 [38]; P , 0.05). Conclusion Clenbuterol treatment of failing rat hearts, alone or in combination with mechanical unloading, improves LV function at the whole-heart and cellular levels by affecting cell morphology, excitation–contraction coupling, and myofilament sensitivity to calcium. This study supports the use of this drug in the strategy to enhance recovery in HF patients treated with LVADs and also begins to elucidate some of the possible cellular mechanisms responsible for the improvement in LV function.

Role and possible mechanisms of clenbuterol in enhancing reverse remodelling during mechanical unloading in murine heart failure.

Background Prolonged unloading using left ventricular (LV) assist devices (LVADs) leads to unloading-induced atrophy with altered cardiomyocyte contractility. The causes for this time-dependent deterioration of myocardial function are unclear. Our aim was to determine the effects of prolonged mechanical unloading on cardiomyocyte function and, more specifically, on Ca 2+ cycling and myofilament sensitivity to Ca 2+ . Methods LV unloading was induced by heterotopic abdominal transplantation (UN) in rats for 5 weeks. Recipient hearts were used as controls (REC). LV myocytes were isolated and cardiomyocyte area measured by planimetry, sarcomere length measured by Fourier analysis of digitized cardiomyocyte images, and cytoplasmic [Ca 2+ ] monitored using Indo-1. Myofilament sensitivity to Ca 2+ was assessed as the slope of the linear relationship between Indo-1 ratio and sarcomere shortening during relaxation. Results UN cardiomyocyte area was smaller compared with REC (mean ± SEM: UN 2,503 ± 78 μm 2 [ n = 132], REC 3,856 ± 89 μm 2 [ n = 116]; p n = 37], REC 0.11 ± 0.01 μm [ n = 38]; p 2+ transient amplitude (UN 0.13 ± 0.01 Indo-1 ratio units [ n = 37], REC 0.11 ± 0.01 Indo-1 ratio units [ n = 38]; p = non-significant). Myofilament sensitivity to Ca 2+ was reduced in UN (UN 2.0 ± 1.2 μm/ratio unit [ n = 20], REC 3.7 ± 0.4 μm/ratio unit [ n = 22]; p 2+ uptake (assessed by 20 mmol/liter caffeine) was also reduced in UN (UN 84.3 ± 0.79% relative contribution [ n = 22], REC 89.8 ± 0.67% relative contribution [ n = 24]; p Conclusions Prolonged myocardial unloading causes depressed contractility due to reduced SR Ca 2+ uptake and myofilament sensitivity to Ca 2+ . These effects may be relevant with regard to myocardial performance after prolonged LVAD support.

Prolonged mechanical unloading reduces myofilament sensitivity to calcium and sarcoplasmic reticulum calcium uptake leading to contractile dysfunction.

Adult progenitor cell transplantation has been proposed for the treatment of heart failure, but the mechanisms effecting functional improvements remain unknown. The aim of this study was to test the hypothesis that, in failing hearts treated with cell transplantation, the mechanical properties and excitation-contraction coupling of recipient cardiomyocytes are altered. Adult rats underwent coronary artery ligation, leading to myocardial infarction and chronic heart failure. After 3 wk, they received intramyocardial injections of either 107 green fluorescence protein (GFP)-positive bone marrow mononuclear cells or 5 × 106 GFP-positive skeletal myoblasts. Four weeks after injection, both cell types increased ejection fraction and reduced cardiomyocyte size. The contractility of isolated GFP-negative cardiomyocytes was monitored by sarcomere shortening assessment, Ca2+ handling by indo-1 and fluo-4 fluorescence, and electrophysiology by patch-clamping techniques. Injection of either bone marrow cells or skeletal myoblasts normalized the impaired contractile performance and the prolonged time to peak of the Ca2+ transient observed in failing cardiomyocytes. The smaller and slower L-type Ca2+ current observed in heart failure normalized after skeletal myoblast, but not bone marrow cell, transplantation. Measurement of Ca2+ sparks suggested a normalization of sarcoplasmic reticulum Ca2+ leak after skeletal myoblast transplantation. The increased Ca2+ wave frequency observed in failing myocytes was reduced by either bone marrow cells or skeletal myoblasts. In conclusion, the morphology, contractile performance, and excitation-contraction coupling of individual recipient cardiomyocytes are altered in failing hearts treated with adult progenitor cell transplantation.

Adult progenitor cell transplantation influences contractile performance and calcium handling of recipient cardiomyocytes

[ Cardiovascular Research, Volume 77, Issue 4, 1 March 2008, Pages 695–706 ]

When this article was originally published, it should have been published as an open access article with the following copyright line:

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Corrigendum to: Role and possible mechanisms of clenbuterol in enhancing reverse remodelling during mechanical unloading in murine heart failure

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Role and possible mechanisms of clenbuterol in enhancing reverse remodelling during mechanical unloading in murine heart failure.

Prolonged mechanical unloading reduces myofilament sensitivity to calcium and sarcoplasmic reticulum calcium uptake leading to contractile dysfunction.

Adult progenitor cell transplantation influences contractile performance and calcium handling of recipient cardiomyocytes

Corrigendum to: Role and possible mechanisms of clenbuterol in enhancing reverse remodelling during mechanical unloading in murine heart failure