In end-stage heart failure, no significant change of I(f) could be found, although there was a trend toward increased I(f). Together with an elevated plasma norepinephrine concentration and a previously reported reduction in I(K1) in human heart failure, I(f) might favor diastolic depolarization in individual myopathic cells.

The increased expression of the Na(+)-Ca2+ exchanger is a possible explanation for the increased inotropic potency of the Na+ channel activator BDF 9148 in failing human myocardium. The increase in exchanger molecules could be of functional relevance for the modulation of cardiac contractility by agents that increase the intracellular Na+ concentration. Enhancement of Na(+)-Ca2+ exchanger activity might be a powerful mechanism for increasing cardiac contractility in chronic heart failure.

1 Clinical studies have shown di erent e ects of b-blockers on the b-adrenergic system, tolerability and outcome in patients with heart failure. 2 The study examines b-adrenoceptor-G-protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium. 3 Radioligand binding studies ([ 125 I]-Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Functional experiments were carried out in isolated muscle preparations of human left ventricular myocardium from failing hearts. 4 Bucindolol and carvedilol bound non-selectively to b 1 -and b 2 -adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35-fold b 1 -selective and lacked guanine nucleotide modulatable binding. 5 All b-blockers antagonized isoprenaline-induced enhancement of contractility. 6 In preparations in which the coupling of the stimulatory G-protein to adenylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in ®ve experiments. Carvedilol increased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89.4+2.2% (P50.01 metoprolol vs carvedilol and bucindolol). The negative inotropic e ect of metoprolol was antagonized by bucindolol. 7 It is concluded that di erences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ventricular myocardium, bucindolol displays substantially higher intrinsic activity than metoprolol and carvedilol. Bucindolol can behave as partial agonist or partial inverse agonist depending on the examined tissue. 8 Di erences in intrinsic activity may contribute to di erences in b-adrenoceptor regulation and possibly to di erences in tolerability and outcomes of patients with heart failure.

Background-The pacemaker current I f is present in atrial and ventricular myocytes. However, it remains controversial whether I f overexpression in diseased states might play a role for arrhythmogenesis, because first I f activation in whole-cell recordings hardly overlapped the diastolic voltage of working myocardium.

OH. radicals induce an impairment of contraction and relaxation and an attenuation of the force-frequency relationship in human myocardium accompanied by an inhibition of SERCA. Carvedilol and BM-910228 partly prevented OH.-induced contractile dysfunction. These observations could explain the improvement of ejection fraction in heart failure trials with carvedilol without a restoration of beta-adrenergic receptor density.

BackgroundProfilin-1 is an ubiquitous actin binding protein. Under pathological conditions such as diabetes, profilin-1 levels are increased in the vascular endothelium. We recently demonstrated that profilin-1 overexpression triggers indicators of endothelial dysfunction downstream of LDL signaling, and that attenuated expression of profilin-1 confers protection from atherosclerosis in vivo.MethodologyHere we monitored profilin-1 expression in human atherosclerotic plaques by immunofluorescent staining. The effects of recombinant profilin-1 on atherogenic signaling pathways and cellular responses such as DNA synthesis (BrdU-incorporation) and chemotaxis (modified Boyden-chamber) were evaluated in cultured rat aortic and human coronary vascular smooth muscle cells (VSMCs). Furthermore, the correlation between profilin-1 serum levels and the degree of atherosclerosis was assessed in humans.Principal FindingsIn coronary arteries from patients with coronary heart disease, we found markedly enhanced profilin expression in atherosclerotic plaques compared to the normal vessel wall. Stimulation of rat aortic and human coronary VSMCs with recombinant profilin-1 (10−6 M) in vitro led to activation of intracellular signaling cascades such as phosphorylation of Erk1/2, p70S6 kinase and PI3K/Akt within 10 minutes. Furthermore, profilin-1 concentration-dependently induced DNA-synthesis and migration of both rat and human VSMCs, respectively. Inhibition of PI3K (Wortmannin, LY294002) or Src-family kinases (SU6656, PP2), but not PLCγ (U73122), completely abolished profilin-induced cell cycle progression, whereas PI3K inhibition partially reduced the chemotactic response. Finally, we found that profilin-1 serum levels were significantly elevated in patients with severe atherosclerosis in humans (p<0.001 vs. no atherosclerosis or control group).ConclusionsProfilin-1 expression is significantly enhanced in human atherosclerotic plaques compared to the normal vessel wall, and the serum levels of profilin-1 correlate with the degree of atherosclerosis in humans. The atherogenic effects exerted by profilin-1 on VSMCs suggest an auto-/paracrine role within the plaque. These data indicate that profilin-1 might critically contribute to atherogenesis and may represent a novel therapeutic target.

Voltage-gated calcium channels are key components in cardiac electrophysiology. We demonstrate that Ca(v)2.3 is expressed in mouse and human heart and that mice lacking the Ca(v)2.3 voltage-gated calcium channel exhibit severe alterations in cardiac function. Amplified cDNA fragments from murine heart and single cardiomyocytes reveal the expression of three different Ca(v)2.3 splice variants. The ablation of Ca(v)2.3 was found to be accompanied by a compensatory upregulation of the Ca(v)3.1 T-type calcium channel, while other voltage-gated calcium channels remained unaffected. Telemetric ECG recordings from Ca(v)2.3 deficient mice displayed subsidiary escape rhythm, altered atrial activation patterns, atrioventricular conduction disturbances and alteration in QRS-morphology. Furthermore, time domain analysis of heart rate variability (HRV) in Ca(v)2.3(-/-) mice exhibited a significant increase in heart rate as well as in the coefficient of variance (CV) compared to control mice. Administration of atropin/propranolol revealed that increased heart rate was due to enhanced sympathetic tonus and that partial decrease of CV in Ca(v)2.3(-/-) mice after autonomic block was in accordance with a complete abolishment of 2(nd) degree atrioventricular block. However, escape rhythms, atrial activation disturbances and QRS-dysmorphology remained unaffected, indicating that these are intrinsic cardiac features in Ca(v)2.3(-/-) mice. We conclude that the expression of Ca(v)2.3 is essential for normal impulse generation and conduction in murine heart.

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