Simvastatin Therapy Normalizes Sympathetic Neural Control in Experimental Heart Failure

Gao, Lie; Wang, Wei; Li, Yu Long; Schultz, Harold D.; Li, Dongmei; Cornish, Kurtis G.; Zucker, Irving H.

doi:10.1161/circulationaha.105.552174

Cited by 123 publications

(118 citation statements)

References 56 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…In addition, beta-blockers can impact on the relationship between venous congestion and renal function, by blocking SNS activation. Also, as observed in a study of experimental heart failure [38], statins can indirectly influence SNS activation by down-regulation of angiotensin II receptor expression. Other new therapies to preserve renal function and to reduce venous congestion have effects on the cardiorenal interaction.…”

Section: Clinical Implications For Therapymentioning

confidence: 70%

Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction

Damman

Navis

Smilde

et al. 2007

European J of Heart Fail

411

284

View full text Add to dashboard Cite

Background: Renal failure in heart failure is related to decreased cardiac output. However, little is known about its association with venous congestion. Aims: To investigate the relationship between venous congestion and glomerular filtration rate (GFR) in patients with cardiac dysfunction. Methods and results: Right atrial pressure (RAP) and cardiac index (CI) were determined by right heart catheterisation in 51 patients with cardiac dysfunction, secondary to pulmonary hypertension. GFR and renal blood flow (RBF) were measured as 125 I-Iothalamate and 131 IHippuran clearances, respectively. Mean age was 40 ± 11 years and 69% of patients were female. GFR was 73 ± 19 ml/min/1.73 m 2 with a CI of 2.1 ± 0.7 l/min/m 2 . In multivariate analysis, RBF (r = 0.664, p b 0.001) and RAP (r = − 0.367, p = 0.020) were independently associated with GFR. In patients in the lower ranges of RBF, venous congestion was an important determinant of renal function. Conclusion: RBF is the main factor determining GFR in patients with cardiac dysfunction. Venous congestion, characterised by an increased RAP, adjusted for RBF is also related to GFR. Treatment to preserve GFR should not only focus on improvement of renal perfusion, but also on decreasing venous congestion.

show abstract

Section: Clinical Implications For Therapymentioning

confidence: 70%

Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction

Damman

Navis

Smilde

et al. 2007

European J of Heart Fail

411

284

View full text Add to dashboard Cite

show abstract

“…[16][17][18][19][20][21] In addition, several studies in animal and human models found strong interactions between statins and the neurohumoral system, which could be clinically significant. 11,[22][23][24] Previously, convincing data suggested the involvement of enhanced sympathetic activity in the pathogenesis of cardiovascular diseases, including hypertension and hypertension-related complications. [25][26][27] Sympathetic overactivity might be partly explained by peripheral mechanisms, including elevated peripheral chemoreceptor activity, reduced baroreceptor sensitivity and reduced nitric oxide synthesis.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin reduces sympathetic activity in men with hypertension and hypercholesterolemia

et al. 2010

View full text Add to dashboard Cite

Beyond their hypolipidemic effect, statins reduce cardiovascular risk in hypertensive subjects via various mechanisms; one suggested mechanism is that they reduce sympathetic activity. We investigated the hypothesis that simvastatin decreased muscle sympathetic nerve activity (MSNA) in 31 hypertensive subjects with hypercholesterolemia (aged 38.7±10 years). In this randomized, placebocontrolled, double-blinded study, patients were treated with simvastatin (40 mg day À1 ; n¼15) or placebo (n¼16) for 8 weeks. Before and after treatment, we measured MSNA, blood pressure and heart rate. Baroreceptor control of the heart rate, or baroreceptor sensitivity (BRS), was computed by the sequence method, a cross-analysis of systolic blood pressure and the electrocardiogram R-R interval. Blood samples were tested for plasma levels of catecholamines, neuropeptide Y, aldosterone, endothelin and renin activity. Simvastatin significantly reduced MSNA (from 36.5 ± 5 to 27.8 ± 6 bursts per min, P¼0.001), heart rate (from 77 ± 6.7 to 71 ± 6.1 beats per min, P¼0.01) and both total and low-density lipoprotein cholesterol (from 249±30.6 to 184±28.3 mg dl À1 , P¼0.001 and from 169±30.6 to 117±31.2 mg dl À1 , P¼0.01, respectively). Simvastatin also improved BRS (from 10.3 ± 4.1 to 17.1 ± 4.3 ms per mm Hg, P¼0.04). No changes were observed in systolic or diastolic blood pressures, or in plasma levels of catecholamines, neuropeptide Y, endothelin, aldosterone and renin activity. After simvastatin therapy, MSNA and BRS were inversely related (r¼À0.94, Po0.05). In conclusion, we found that, in patients with hypertension and hypercholesterolemia, simvastatin reduced MSNA, and this was related to increased baroreceptor sensitivity.

show abstract

“…Furthermore, simvastatin down-regulated mRNA and protein expression of angiotensin II type I receptor and NADPH oxidase subunits in the medulla of heart failure rabbits. 112 Lee et al 113 once more demonstrated hyperinnervation in rats with MI as shown by an increase in tyrosine hydroxylase and myocardial norepinephrine levels. But they subsequently went on to show that rats treated with pravastatin had lower arrhythmic scores in programed electrical stimulation studies than controls not treated with a statin or treated with a K-channel blocker.…”

Section: Medical Therapies Modulating Cardiac Autonomicsmentioning

confidence: 99%

The Role of the Autonomic Nervous System in Sudden Cardiac Death

Vaseghi

Shivkumar²

2008

Progress in Cardiovascular Diseases

318

225

View full text Add to dashboard Cite

The cardiac autonomic nervous system consists of 2 branches-the sympathetic and the parasympathetic systems-that work in a delicately tuned, yet opposing fashion in the heart. This extrinsic control mechanism can dominate intrinsic regulatory mechanisms that modulate heart rate and cardiac output. These branches differ in their neurotransmitters (norepinephrine and acetylcholine) and exert stimulatory or inhibitory effects on target tissue via adrenergic and muscarinic receptors. Stimulation of the sympathetic branch exerts facilitatory effects on function, increasing heart rate and myocardial contractility, whereas the stimulation of the parasympathetic branch exerts inhibitory effects that decrease heart rate and contractility. The interplay between these two branches is complex and susceptible to control at several levels, from centrally mediated baroreceptors and chemoreceptors to local interneuronal interactions.Alterations in autonomic function occur in several interrelated cardiac conditions including sudden cardiac death, congestive heart failure, diabetic neuropathy, and myocardial ischemia. Although the full extent of these changes has not been elucidated, multiple autonomic remodeling mechanisms have been observed at both the neuronal fiber and myocardial cellular level that contribute to an arrhythmogenic substrate. We describe the anatomy of both systems in this review. However, the review will premdominantly focus on the sympathetic system, whose role in the modulation of cardiac arrhythmias is slightly better delineated. Cardiac Autonomic Innervation: NeuroanatomyBoth branches of the autonomic nervous system are composed of both afferent and efferent as well interneuronal fibers (Fig 1). Sympathetic innervation originates mainly in the right and left stellate ganglia. These fibers travel along the epicardial vascular structures of the heart and penetrate into the underlying myocardium similar to coronary vessels and end as sympathetic nerve terminals reaching the endocardium. Based on norepinephrine content studies, a gradient exists in sympathetic innervation from atria to the ventricles and from base to apex of the heart. Therefore, the atria are most densely innervated, but the ventricles are also supplied with a sympathetic network, most densely at the base. 1 Parasympathetic effects are carried by the right and left vagus nerves, originating in the medulla. The vagus nerve further divides into the superior and inferior cardiac nerves, finally merging with the postganglionic sympathetic neurons to form a plexus of nerves at the base of the heart, known as the cardiac plexus. In contrast to sympathetic neurons, after parasympathetic fibers cross the atrioventricular (AV) groove along the surface of the heart,

show abstract

Simvastatin Therapy Normalizes Sympathetic Neural Control in Experimental Heart Failure

Cited by 123 publications

References 56 publications

Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction

Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction

Simvastatin reduces sympathetic activity in men with hypertension and hypercholesterolemia

The Role of the Autonomic Nervous System in Sudden Cardiac Death

Contact Info

Product

Resources

About