Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators.

BACKGROUND: We determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure. METHODS AND RESULTS: One hundred forty-six patients with New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) who had a pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index

Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure.

BACKGROUND: Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET(A) receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET(A) receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy. METHODS AND RESULTS: This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index

Veterans Affairs Quality Enhancement Research Initiative in chronic heart failure.

Chronic heart failure (CHF) is a highly prevalent condition associated with serious morbidity, intense levels of health services use, and shortened survival. It is also a condition for which ameliorative therapies exist. The evidence indicates that there is substantial need to change clinical practice and health care delivery for people with CHF and thereby improve their outcomes. The goal of the Veterans Affairs (VA) Quality Enhancement Research Initiative in CHF (CHF QUERI) is to create measurable, rapid, and sustainable improvements in quality of care and health outcomes of veterans with heart failure. This article describes the current state of knowledge and practice in care for people with CHF. Using the framework of the 5 steps of the QUERI process, we point out the gaps in research and practice that must be filled if the CHF QUERI is to achieve its goal. We relate our recommendations for how the VA can put its research and administrative infrastructure to work to fill the gaps. Lessons learned about CHF in the course of the CHF QUERI will be applicable to all people with heart failure and to all health care systems--VA as well as non-VA--that care for them.

Effect of angiotensin-converting enzyme inhibition on myocardial fibrosis and function in hypertrophied and failing myocardium from the spontaneously hypertensive rat.

BACKGROUND: After a period of stable hypertrophy, male spontaneously hypertensive rats (SHR) develop heart failure between 18 to 24 months of age, with depression of active myocardial function and increased passive stiffness. We tested the hypothesis that chronic ACE inhibition by captopril would prevent and possibly reverse impairment of myocardial function. METHODS AND RESULTS: Male SHR and normotensive Wistar-Kyoto rats (WKY) were assigned to no treatment or captopril treatment (2 g/L in drinking water) begun at ages 12, 18, and 21 months; animals were studied at 24 months of age, or earlier when evidence of heart failure was found in SHR (mean age, 19+/-2 months). In an additional group, captopril treatment was begun when SHR developed heart failure; surviving animals were studied at 24 months of age. In untreated SHR, relative to WKY, isometric stress development at Lmax, maximum rate of stress development, and shortening velocity were depressed, whereas passive stiffness was increased, in association with the development of myocardial fibrosis. In the SHR treated before cardiac dysfunction, captopril administration attenuated hypertrophy and prevented contractile dysfunction, fibrosis, and increased passive stiffness. Captopril treatment begun after cardiac function was impaired reduced left ventricular hypertrophy but did not restore intrinsic contractile function or reduce fibrosis or passive stiffness. CONCLUSIONS: In the male SHR, early treatment with captopril was associated with the most marked attenuation of dysfunction relative to the untreated SHR. Treatment initiated after the onset of heart failure improved clinical signs of heart failure and decreased left ventricular hypertrophy in surviving animals but did not reverse the fibrosis and contractile dysfunction associated with heart failure.

The spontaneously hypertensive rat as a model of the transition from compensated left ventricular hypertrophy to failure.

Studies of hemodynamics and intrinsic left ventricular myocardial function are carried out to investigate the transition from stable hypertrophy to cardiac decompensation in the aging (18-24 months) spontaneously hypertensive rat (SHR). Echocardiographic data in awake animals demonstrate increased end-diastolic and end-systolic volumes and depressed ejection fractions in left ventricles from SHR with failure (SHR-F) as compared to age matched hypertensive (SHR-NF) and non-hypertensive control animals (WKY). Cardiac catheterization data in anesthetized animals demonstrate depression of both systolic pressure and +dP/dt, and elevated end-diastolic pressure in the SHR-F relative to the two control groups. Since loading conditions and altered demand states may contribute to altered ventricular function, studies of isolated perfused hearts were carried out which demonstrate impaired systolic stress development in the SHR-F group under conditions in which loading conditions are controlled; in addition, it is observed that increasing perfusion pressure by 30 mm Hg has little effect on function. Depression of systolic function and increases in passive stiffness of isolated muscle preparations from the SHR-F indicate impairment of systolic and diastolic function at the tissue level. While all of the preparations studied have potential shortcomings, an integration of findings from these complementary approaches supports the conclusion that heart failure develops in the aging SHR. Furthermore, these data suggest that impaired function is due to changes in the intrinsic properties of the myocardium and that the connective tissue response may play an important role. These studies, in conjunction with the findings of others who have studied the aging SHR, provide support for the use of the aging SHR as a model of the transition from compensated hypertrophy to failure.

K+ channel blocking actions of flecainide compared with those of propafenone and quinidine in adult rat ventricular myocytes.

The K+ channel blocking action of the class Ic antiarrhythmic agent flecainide was compared with that of propafenone and quinidine in isolated adult rat ventricular myocytes by using the whole-cell patch-clamp technique. In rat ventricular myocytes, depolarization activates both an inactivating (ITO) and a maintained (IK) outward K+ current. Flecainide, propafenone and quinidine all were potent inhibitors of ITO with IC50s of 3.7, 3.3 and 3.9 microM, respectively. Flecainide and quinidine were less potent inhibitors of IK than was propafenone with IC50s of 15 and 14 microM compared with an IC50 of 5 microM for propafenone. By contrast with their effects on outward currents, these agents produced little or no inhibition of the inward rectifier K+ current, even when present at 300 microM. All three agents produced a concentration-dependent increase in the rate of inactivation of ITO but they only produced minor hyperpolarizing shifts (approximately 3 mV) in the voltage dependence of steady-state inactivation. Although propafenone had little effect on the rate of ITO recovery from inactivation (tau CONTROL = 64 +/- 5 ms; tau PROPAFENONE = 84 +/- 9 ms), ITO recovery in the presence of flecainide and quinidine was biexponential; it exhibited an additional slow component (tau FAST = 67 +/- 5 ms and tau SLOW = 2580 +/- 1500 ms for flecainide; tau FAST = 55 +/- 5 ms and tau SLOW = 871 +/- 99 ms for quinidine). Consistent with these observations, flecainide and quinidine, but not propafenone, produced use-dependent block of ITO at a stimulation frequency of 1 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of 4-aminopyridine block of the transient outward K+ current in adult rat ventricular myocytes.

The blocking action of 4-aminopyridine (4-AP) on the transient outward K+ current (ITO) in isolated rat ventricular myocytes was studied using the whole-cell configuration of the patch-clamp technique. 4-AP inhibition of ITO was concentration-dependent with half-maximal block occurring at 0.2 mM. At high concentrations (> 1 mM), 4-AP appeared to slow both the activation and inactivation phases of ITO. This resulted in a crossover phenomenon where in the presence of 4-AP the outward current was less than control at the beginning of a depolarizing pulse but crossed over during the pulse to become greater than control. Inhibition of ITO by 4-AP was voltage-dependent. Steady-state block of ITO by 4-AP was greatest at or near resting membrane potentials (i.e., -70 mV) but decreased with membrane depolarization. The voltage-dependence of block was steep and was well described by a Boltzmann relationship with a slope factor of approximately 4 mV. The midpoint potential for block was dependent on the concentration of 4-AP, being -41.6 +/- 0.4 mV (n = 9), -40.7 +/- 1.3 mV (n = 6), -34.0 +/- 1.6 mV (n = 5) and -30.1 +/- 0.2 (n = 15) at 0.3, 1, 3 and 10 mM, respectively. The midpoint potential for activation was -12.6 mV and was -46.9 mV for inactivation. The concentration-dependence of the voltage-dependence of 4-AP block can be explained by assuming that the sequential closed states through which the channel passes during activation exhibit successively lower affinities for 4-AP. Onset of ITO block by 4-AP was slow. The association (kON) and dissociation. (kOFF) rate constants for binding at -70 mV were: kON = 207 M-1 s-1 and kOFF = 0.090 s-1. The time constant for unblock (tau UNBLOCK) of ITO at 0 mV was independent of 4-AP concentration indicating that there was no binding of 4-AP at this potential. kOFF (1/tau UNBLOCK) at 0 mV was 2.4 s-1 which is approximately 25-fold faster then at -70 mV. The results suggest that 4-AP binds most strongly to closed channels with the inactivation gate open. The conformational changes that occur during channel opening induce a decrease in affinity for 4-AP so that when the channel is in the open state, 4-AP binding is at its weakest. The processes of 4-AP block and inactivation appear to be mutually exclusive.

Effect of exercise conditioning on excitation-contraction coupling in aged rats.

We studied aged (24-26 mo) Fischer 344 rats after they underwent 8 wk of moderate exercise conditioning. Right ventricular papillary muscles were loaded with the calcium indicator aequorin. Electrophysiological recordings were also performed. Time to peak isometric tension in muscles from exercised aged rats (EAR) was shorter than in those from unexercised aged rats (UAR) (126 +/- 7 vs. 167 +/- 7 ms; P less than 0.01). Time to 50% relaxation from peak isometric tension was also shorter in EAR than in UAR (88 +/- 3 vs. 119 +/- 12 ms; P less than 0.05). There was a trend toward decrease in time to peak light and a significant decrease in time to 50% decline from peak light (33 +/- 4 ms in EAR vs. 59 +/- 17 ms in UAR; P = 0.001). Action potential amplitude was smaller in EAR than in UAR (67 +/- 4 vs. 82 +/- 3 mV; P = 0.003); however, action potential duration was longer (137 +/- 6 ms in EAR vs. 100 +/- 10 ms in UAR; P = 0.005). Right ventricular-to-body weight ratios revealed no evidence of hypertrophy in EAR compared with UAR. Cardiac tissue norepinephrine content was significantly greater in EAR than in UAR (1,212 +/- 25 vs. 630 +/- 105 ng/tissue; P = 0.02). In summary, exercise reversed the age-related prolongation of isometric contraction and associated intracellular calcium transient in the aged rat while it prolonged the transmembrane action potential. In addition, exercise in aged rats resulted in an increase in cardiac norepinephrine content.

Role of intracellular calcium handling in force-interval relationships of human ventricular myocardium.

Experiments were performed in human working myocardium to investigate the relationship of intracellular calcium handling and availability to alterations in the strength of contraction produced by changes in stimulation rate and pattern. Both control and myopathic muscles exhibited potentiation of peak isometric force during the postextrasystolic contraction which was associated with an increase in the peak intracellular calcium transient. Frequency-related force potentiation was attenuated in myopathic muscles compared to controls. This occurred despite an increase in resting intracellular calcium and in the peak amplitude of the calcium transient as detected with aequorin. Therefore, abnormalities in contractile function of myopathic muscles during frequency-related force potentiation are not due to decreased availability of intracellular calcium, but more likely reflect differences in myofibrillar calcium responsiveness. Sarcolemmal calcium influx may also contribute to frequency-related changes in contractile force in myopathic muscles as suggested by a decrease in action potential duration with increasing stimulation frequency which is associated with fluctuations in peak calcium transient amplitude.

Role of intracellular sodium in the regulation of intracellular calcium and contractility. Effects of DPI 201-106 on excitation-contraction coupling in human ventricular myocardium.

Experiments were performed to investigate the mechanism of action of DPI 201-106 on human heart muscle. In both control and myopathic muscles, DPI produced concentration-dependent increases in action potential duration, resting muscle tension, peak isometric tension, and duration of isometric tension. These changes were associated with increases in resting intracellular calcium and peak calcium transients as measured by aequorin. At higher concentrations of DPI, a second delayed Ca2+ transient (L') appeared. L' was inhibited by tetrodotoxin and ryanodine, suggesting that DPI acts at both the sarcolemma and the sarcoplasmic reticulum. DPI toxicity was manifested by after-glimmers and after-contractions reflecting a Ca2+-overload state: DPI effects were mimicked by veratridine, a Na+ channel agonist, and reversed by tetrodotoxin, yohimbine, and cadmium, Na+ channel antagonists. These results suggest that DPI acts primarily as a Na+ channel agonist. DPI may produce an increase in intracellular Ca2+ by increasing intracellular Na+ and altering Na+-Ca2+ exchange across the sarcolemma. DPI may also increase intracellular Ca2+ by directly altering sarcoplasmic reticulum Ca2+ handling.