The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo

OBJECTIVE: The endogenous peptide apelin is differentially regulated in cardiovascular disease but the nature of its role in cardiac function remains unclear. METHODS: We investigated the functional relevance of this peptide using ECG and respiration gated magnetic resonance imaging, conductance catheter pressure-volume hemodynamic measurements, and echocardiography in vivo. In addition, we carried out histology and immunohistochemistry to assess cardiac hypertrophy and to localize apelin and APJ in the adult and embryonic mouse heart. RESULTS: Intraperitoneal injection of apelin (300 microg/kg) resulted in a decrease in left ventricular end diastolic area (pre: 0.122+/-0.007; post: 0.104+/-0.005 cm(2), p=0.006) and an increase in heart rate (pre: 537+/-20; post: 559+/-19 beats per minute, p=0.03). Hemodynamic measurements revealed a marked increase in ventricular elastance (pre: 3.7+/-0.9; post: 6.5+/-1.4 mm Hg/RVU, p=0.018) and preload recruitable stroke work (pre: 27.4+/-8.0; post: 51.8+/-3.1, p=0.059) with little change in diastolic parameters following acute infusion of apelin. Chronic infusion (2 mg/kg/day) resulted in significant increases in the velocity of circumferential shortening (baseline: 5.36+/-0.401; 14 days: 6.85+/-0.358 circ/s, p=0.049) and cardiac output (baseline: 0.142+/-0.019; 14 days: 0.25+/-0.019 l/min, p=0.001) as determined by 15 MHz echocardiography. Post-mortem corrected heart weights were not different between apelin and saline groups (p=0.5) and histology revealed no evidence of cellular hypertrophy in the apelin group (nuclei per unit area, p=0.9). Immunohistochemistry studies revealed APJ staining of myocardial cells in all regions of the adult mouse heart. Antibody staining, as well as quantitative real time polymerase chain reaction identified expression of both APJ and apelin in embryonic myocardium as early as embryonic day 13.5. CONCLUSIONS: Apelin reduces left ventricular preload and afterload and increases contractile reserve without evidence of hypertrophy. These results associate apelin with a positive hemodynamic profile and suggest it as an attractive target for pharmacotherapy in the setting of heart failure.     

Right ventricular function under acute cor pulmonale

Many investigators have reported the hemodynamics in acute cor pulmonale clinically and experimentally. However, earlier studies have not made quantitative evaluations of the effects of coronary perfusion pressure and hypoxia on right ventricular contractility. We simulated acute cor pulmonale in nine isolated canine hearts and investigated the relationship of the process to cardiac deterioration and restoration. The afterload and preload of the right ventricle were controlled with a computer-assisted load control servosystem. Coronary perfusion pressure (COPP) was also controlled at either normal or variable levels identical to products of measured cardiac output and assumed values of systemic vascular resistance. Critical state (CS) was defined as a condition with an initial decrease in peak systolic pressure despite increased afterload. Within the normal range of PaO2 (105 +/- 5.3 mmHg), CS developed at a COPP of 51 +/- 5.1 mmHg, while under low PaO2 (51 +/- 2.3 mmHg), it developed at a COPP of 59 +/- 8.8 mmHg. As long as the COPP was normal (90 mmHg), the contractility of the right ventricle did not decrease despite hypoxia (PaO2 51 +/- 2.3 mmHg). An increase in systemic vascular resistance or administration of a beta-stimulant at CS restored the contractility of the right ventricle. However, an increase in preload decreased the contractility of the right ventricle.     

Functional and morphological characteristics of compensated and decompensated cardiac hypertrophy in dogs with chronic infrarenal aorto-caval fistulas

The relation between cardiac hypertrophy, shunt size, myocardial contractility, capillary density, adrenergic responsiveness, and neurohumoral stimulation was evaluated in dogs with compensated and decompensated cardiac hypertrophy caused by an infrarenal aorto-caval shunt. Shunt size varied from 5 to 35 mm2 due to an inability to create a uniform size. Dogs that developed heart failure within 4 months had 25 +/- 2 mm2 shunts, whereas those that developed it after 4 months had 19 +/- 3 mm2 shunts; those that did not develop heart failure had 10 +/- 1 mm2 shunts. Hypertrophy developed at the same rate in all the dogs that developed heart failure, which occurred at a critical heart weight (hypertrophy) for a given load (shunt size). In the dogs with heart failure there was a decrease in myocardial contractility (tension = 5.7 +/- 0.6 vs. 7.3 +/- 0.3 g/mm2, p less than 0.05), a decrease in adrenergic responsiveness (maximal heart rate with isoproterenol = 203 +/- 7 vs. 249 +/- 5 beats/min, p less than 0.01), an increase in circulating neurohormones, and a decrease in urinary sodium excretion (0.4 +/- 0.1 vs. 5.0 +/- 1.3 meq/3 hr, p less than 0.01). None of these abnormalities occurred in dogs with compensated hypertrophy. There were no differences in cardiac capillary density between the control dogs and the dogs with compensated cardiac hypertrophy or heart failure. Thus, it would appear that if heart failure is to develop after an initial toleration of a sudden volume overload, it will develop at a given combination of cardiac hypertrophy and volume overload, with cardiac hypertrophy developing at the same rate in all cases. In this model, once heart failure develops, myocardial contractility and cardiac adrenergic responsiveness are decreased and there is pronounced neurohumoral activation. All these changes are absent in hearts with compensated hypertrophy.     

Response of the pulmonary circulation to acetylcholine, calcitonin gene-related peptide, substance P and oral nicardipine in patients with primary pulmonary hypertension.

Endothelium-dependent vasodilation of the pulmonary vascular bed was investigated in five patients with primary pulmonary hypertension. Three endothelium-dependent vasodilators (acetylcholine, calcitonin gene-related peptide and substance P [in two patients]) were infused sequentially into the right atrium, followed by nicardipine given orally during full hemodynamic monitoring. Acetylcholine, calcitonin gene-related peptide and substance P had no effect on pulmonary artery pressure, total pulmonary vascular resistance or cardiac output, although calcitonin gene-related peptide significantly decreased systemic arterial systolic pressure from 132 +/- 34 to 113 +/- 33 mm Hg. In contrast, oral nicardipine decreased total pulmonary vascular resistance from 23 +/- 12 to 13 +/- 8 U, with a concomitant increase in cardiac output from 3.1 +/- 1 to 4.7 +/- 2 liters.min-1 and decrease in systemic vascular resistance from 30 +/- 9 to 13 +/- 4 U. Thus, despite the presence of a reversible component in these five patients with primary pulmonary hypertension, pulmonary vascular resistance did not decrease in response to the infused endothelium-dependent vasodilator agents, indicating that endothelium-dependent vasodilation is impaired in these patients.     

Organ failure in the ICU: cardiac alterations

Cardiac alterations may be defined as changes that lead to abnormal cardiac function. They include decrease in preload, increase in afterload, and depressed cardiac contractility. Cardiac dysfunction differs from cardiac failure: cardiac performance is altered, but this does not necessarily mean that the cardiovascular system is failing. Several tools are available to detect cardiac alterations. Some may continuously assess cardiac performance by mainly or exclusively measuring cardiac output, but no information is given about the mechanisms underlying the cardiac output decrease. Doppler echocardiography allows noncontinuous cardiac monitoring, but it is perfectly adapted to evaluation of cardiac performance. It directly visualizes cardiac contractility and assesses cardiac preload. Only when there is an imbalance between oxygen demand and oxygen transport is correction of cardiac alterations required. But the truth is that no study supports the use of one treatment rather than another. Changes in respiratory settings or in respiratory mechanics induce changes in cardiac function and must then be considered in the strategy.     

Contrasting preload-dependent hemodynamic and neurohumoral effects of isomazole, a partial phosphodiesterase inhibitor and calcium sensitizer

Background: Currently evaluated positive inotropic agents that act predominantly through phosphodiesterase III-inhibiting properties, have been disappointing in the treatment of heart failure. Lack of efficacy as a result of diminished cellular cyclic adenosine monophosphate and vasodilating tolerance and side effects are prevalent. In contrast, calcium sensitization is preserved in heart failure and agents that combine phosphodiesterase-inhibiting and calcium-sensitizing properties may be more efficacious. Isomazole is such a novel agent with combined properties. This study investigated the acute hemodynamic and neurohormonal effects of intravenous isomazole (3 μg/kg/min for 30 minutes).Methods and Results: The effects of preexisting preload were evaluated in 18 patients with heart failure, New York Heart Association class II/III, and elevated (>15 mmHg, n = 11, group I) and normal (n = 7, group II) pulmonary wedge pressure at baseline. In the overall group, isomazole increased myocardial contractility and relaxation and decreased systemic resistance by 20%. Left and right filling pressures fell by 35–45%, accompanied by a 69% reduction in cardiac atrial natriuretic peptide release. In contrast, levels of arterial norepinephrine and renin both increased by 27%. Cardiac output increased in group I (23%), but fell in group II (18%), accompanied by a 51% increase in arterial norepinephrine. Cardiac atrial natriuretic peptide decreased in group I, but not in group II.Conclusions: Isomazole induced positive inotropic and lusitropic effects and arterial vasodilation in all patients. Cardiac pump function improved only in group I, accompanied by a reduction in sympathetic activity and renin-angiotensin and aldosterone levels and a more pronounced decrease in cardiac atrial natriuretic peptide release. In contrast, in patients with normal to low preload, the further reduction in preload led to a deterioration of pump function and increased sympathetic tone.     

Cardiac performance in rats with renal hypertension.

To evaluate cardiac performance in renal hypertension more precisely we determined cardiac function curves for 12 normotensive rats and 11 other rats with two-kidney Goldblatt hypertension. The hypertensive group (BP = 134 +/- 8 mm Hg) showed significant cardiac hypertrophy (44 +/- 1% increased ratio of heart weight to body weight, P less than 0.01) and markedly increased left ventricular stroke work with a moderate but not significant increase in left ventricular end-diastolic pressure (LVEDP) (5.9 +/- 0.8 vs. 4.7 +/- 0.4 mm Hg). We evaluated cardiac function by recording left ventricular end-diastolic pressure, stroke volume (SV), and cardiac output (CO) (by electromagnetic flowmeter) during rapid alteration in venous return. Analysis of variations of stroke volume vs. left ventricular end-diastolic pressure showed that renal hypertension is accompanied by a significant decrease in ventricular performance [SV = 0.0190 + 0.0509 LVEDP - 0.0025 (LVEDP)2 + 0.0001 (LVEDP)3] compared to the normotensive group [SV = 0.0430 + 0.0644 LVEDP - 0.0040 (LVEDP)2 + 0.001 (LVEDP)3]. The alterations in stroke volume and cardiac output were associated with a lack of significant changes in the work performed at matched end-diastolic pressures. The data indicate that chronic renal hypertension is accompanied by a depression of cardiac reserve which is not revealed by measurements of cardiac output and left ventricular end-diastolic pressure at rest. This impairment in cardiac function might be related to either diminished cardiac contractility or reduced left ventricular compliance; the latter possibility is in accord with our finding of a 2-fold increase in the hydroxyproline content (P less than 0.001) and a significant decrease in the DNA concentration of ventricular tissue.     

Mechanics of left ventricular systolic and diastolic function in physiologic hypertrophy of the athlete heart.

Due to a number of factors, there is tremendous diversity in the pattern of cardiac mechanics encountered in athletes. Nevertheless, there are several trends that can be identified and several conclusions are possible. Hypertrophy of a mild-to-moderate degree and out of proportion to body size is a common finding. Some athletes experience ventricular dilation with appropriate hypertrophy and preservation of the ventricular mass-to-volume ratio, whereas others manifest concentric hypertrophy with an increased mass-to-volume ratio. The functional changes that are encountered appear to be secondary to the structural alterations, and there is no evidence of altered myocardial systolic or diastolic properties. Some athletes with hypertrophy have reduced wall stress when they are evaluated at rest, and the velocity of shortening is augmented due to the reduced afterload. Due to adaptation to a high output state, some athletes appear preload reduced when evaluated at rest. Although velocity of shortening is not affected by preload status, fractional shortening is inversely related to preload. The magnitude of systolic shortening is therefore the net result of altered preload and afterload and cannot be understood without assessing both of these parameters. When the various determinants of systolic shortening are included, contractility appears to be normal. There have been several reports of depressed contractility immediately following extreme exertion, but the significance of this remains to be determined.     

Isoproterenol stimulates rapid extrusion of sodium from isolated smooth muscle cells.

beta-Agonists cause an inhibition of contractility and a transient stimulation of Na+/K+ pumping in smooth muscle cells of the stomach from the toad Bufo marinus. To determine if the stimulation of Na+/K+ pumping causes changes in intracellular [Na+] ([Na+]i) that might link Na+ pump stimulation to decrease Ca2+ availability for contraction, [Na+]i was measured in these cells with SBFI, a Na(+)-sensitive fluorescent indicator. Basal [Na+]i was 12.8 +/- 4.2 mM (n = 32) and was uniform throughout the cell. In response to isoproterenol, [Na+]i decreased an average of 7.1 +/- 1.1 mM in 3 sec. Since this decrease in [Na+]i could be completely blocked by inhibition of the Na+ pump, or by blockade of the beta-receptor, [Na+]i reduction is the result of occupation of the beta-receptor by isoproterenol and subsequent stimulation of the Na+ pump. 8-Bromoadenosine 3',5'-cyclic monophosphate and forskolin mimicked the effect of isoproterenol, indicating that the sequence of events linking beta-receptor occupation to Na+ pump stimulation most likely includes activation of adenylate cyclase, production of cAMP, and stimulation of cAMP-dependent protein kinase. The decrease in [Na+]i is sufficiently large and fast that it is expected to stimulate turnover of the Na+/Ca2+ exchanger in the Ca2+ extrusion mode, thereby accounting for the observed linkage between stimulation of the Na+/K+ pump and inhibition of contractility in response to beta-adrenergic agonists.     

Effect of prazosin treatment on the cardiac sarcolemmal ATPase in failing heart due to mitral insufficiency in dogs

Prazosin has been used in the treatment of congestive heart failure. It is, however, not known whether prazosin gives only haemodynamic benefit or if it also produces a decrease in the cardiac sarcolemmal Na+-K+-ATPase which has been reported to be increased in the failing heart. The present investigation deals with the effect of 3 months of prazosin treatment in dogs with 3 months of induced mitral insufficiency (MI) on the sarcolemmal Na+-K+-ATPase activity. The dogs were divided into four groups each comprising of five dogs. A--normal; B--3 months of MI; C--6 months of MI; D--3 months of prazosin treatment after 3 months of MI. Three months of MI produced a decrease in the dp/dt and an increase in the end-diastolic pressure of left ventricle but no change in the index of left ventricular contractility and cardiac index. Also there was no change in the sarcolemmal Na+-K+-ATPase. There was a significant decrease in the index of left ventricular contractility and cardiac index and an increase in the LVEDP associated with a significant increase in the left ventricular sarcolemmal Na+-K+-ATPase at 6 months of MI. Sarcolemmal Mg2+-ATPase of both ventricles increased after 6 months of MI the significance of which is not known as yet. There was no change in the sarcolemmal Na+-K+-ATPase of the nonfailing right ventricle. Prazosin treatment prevented the deterioration of the left ventricular contractility and function and also prevented the increase in the sarcolemmal Na+-K+-ATPase observed in failing heart.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of Na+/H+ exchange in norepinephrine-induced protein synthesis in neonatal cultured rat cardiomyocytes

It is reported that Na+ influx contributes to stretch-induced cardiac hypertrophy. Na+ influx may also be involved in cardiac hypertrophy induced by catecholamine. In the present study, to test whether Na+/H+ exchange plays an important role in norepinephrine-induced cardiac hypertrophy, the effect of Na+/H+ exchange inhibitor, amiloride on protein synthesis was studied in cultured neonatal rat cardiomyocytes in serum free medium. [3H]Phenylalanine uptake was determined 24 and 48 hours after administration of norepinephrine with and without amiloride. In the control, norepinephrine increased [3H]phenylalanine uptake in a dose dependent manner (10(-5)-10(-7) M). Prazosin (10(-7) M) and amiloride (10(-5)-10(-4) M) significantly attenuated the norepinephrine mediated protein synthesis. These results indicate that alpha 1-adrenergic stimulation enhances the protein synthesis through activation of Na+/H+ exchange. Therefore, Na+ influx and/or PH increase may play a key role in cardiac hypertrophy.     

Cellular mechanisms of altered contractility in the hypertrophied heart: big hearts, big sparks

To investigate the cellular mechanisms for altered Ca2+ homeostasis and contractility in cardiac hypertrophy, we measured whole-cell L-type Ca2+ currents (ICa,L), whole-cell Ca2+ transients ([Ca2+]i), and Ca2+ sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) and from age- and sex-matched Wistar-Kyoto and Sprague-Dawley control rats. By echocardiography, SHR hearts had cardiac hypertrophy and enhanced contractility (increased fractional shortening) and no signs of heart failure. SHR cells had a voltage-dependent increase in peak [Ca2+]i amplitude (at 0 mV, 1330+/-62 nmol/L [SHRs] versus 836+/-48 nmol/L [controls], P<0.05) that was not associated with changes in ICa,L density or kinetics, resting [Ca2+]i, or Ca2+ content of the sarcoplasmic reticulum (SR). SHR cells had increased time of relaxation. Ca2+ sparks from SHR cells had larger average amplitudes (173+/-192 nmol/L [SHRs] versus 109+/-64 nmol/L [control]; P<0.05), which was due to redistribution of Ca2+ sparks to a larger amplitude population. This change in Ca2+ spark amplitude distribution was not associated with any change in the density of ryanodine receptors, calsequestrin, junctin, triadin 1, Ca2+-ATPase, or phospholamban. Therefore, SHRs with cardiac hypertrophy have increased contractility, [Ca2+]i amplitude, time to relaxation, and average Ca2+ spark amplitude ("big sparks"). Importantly, big sparks occurred without alteration in the trigger for SR Ca2+ release (ICa,L), SR Ca2+ content, or the expression of several SR Ca2+-cycling proteins. Thus, cardiac hypertrophy in SHRs is linked with an alteration in the coupling of Ca2+ entry through L-type Ca2+ channels and the release of Ca2+ from the SR, leading to big sparks and enhanced contractility. Alterations in the microdomain between L-type Ca2+ channels and SR Ca2+ release channels may underlie the changes in Ca2+ homeostasis observed in cardiac hypertrophy. Modulation of SR Ca2+ release may provide a new therapeutic strategy for cardiac hypertrophy and for its progression to heart failure and sudden death.     

Transesophageal two-dimensional echocardiographic evaluation of biventricular dimension and function during positive end-expiratory pressure ventilation after coronary artery bypass grafting

Transesophageal 2-dimensional echocardiography was performed in 21 patients soon after uncomplicated coronary artery bypass grafting to determine the mechanism of positive end-expiratory pressure (PEEP) ventilation-induced decreased cardiac output. End-diastolic and end-systolic short-axis area and percent area reduction of right and left ventricles were determined during 5-cm H2O stepwise increments of PEEP ventilation. Simultaneously, cardiac output and right- and left-sided hemodynamic values were determined. Cardiac output, mean arterial pressure and end-diastolic area of both ventricles gradually decreased, and right and left atrial and pulmonary arterial pressures (mainstem and capillary wedge) increased. Left ventricular end-systolic area did not change, whereas right ventricular area decreased. Percent area reduction of both ventricles decreased (p less than 0.01). Thus, decrease in cardiac output during PEEP ventilation is primarily caused by decrease of preload rather than compromised contractility.     

Evaluation of maintenance of cardiac output during DDD and VVI pacing by exercise Doppler echocardiography]

To evaluate the efficacy of DDD pacing for cardiac reserve, we assessed increases in the stroke volume and cardiac output during randomized treadmill exercise in 16 patients by DDD and fixed-rate ventricular (VVI) pacing. The stroke volume index and cardiac index were determined using suprasternal Doppler measurements. Ten patients who showed sinus rhythm during exercise were excluded from this study. Compared with the findings during VVI pacing, those during DDD pacing showed: 1) a greater exercise-induced positive chronotropic response (mean maximum heart rate 122 +/- 22 beats/min vs 70 beats/min, p < 0.01), 2) a lesser increase in the stroke volume index (34 +/- 7 to 39 +/- 9 ml/m2 vs 31 +/- 7 to 49 +/- 11 ml/m2, p < 0.05), 3) a greater increase in the cardiac index (2.43 +/- 0.45 to 4.48 +/- 1.36 L/min/m2 vs 2.22 +/- 0.47 to 3.43 +/- 0.45 L/min/m2, p < 0.05), and 4) prolongation of exercise duration (6.35 +/- 2.00 min vs 5.97 +/- 1.81 min, NS). These findings indicated that VVI pacing promoted a greater stroke volume than DDD pacing, which provides a compensatory increase in contractility and the preload in cases without an increase in heart rate during exercise, however, the increase in cardiac output was insufficient due to the absence of a chronotropic response. In conclusion, a DDD pacemaker could effectively increase heart rate, causing a significant increase in cardiac output and extending exercise duration.     

Vasodilators and regression of left ventricular hypertrophy. Hydralazine versus prazosin in hypertensive humans

Long-term treatment of hypertensive rats with arterial vasodilators may further increase left ventricular hypertrophy. Since left ventricular hypertrophy may be an important determinant of outcome in hypertension, the long-term effects of arterial vasodilation with hydralazine on left ventricular mass and function were compared with those of an alternative third-line drug, the alpha1 blocker prazosin, in patients still hypertensive despite combined diuretic and beta blocker therapy. A single-blind, randomized, two-group parallel design was employed. Both treatments induced a sustained antihypertensive effect, with hydralazine showing more effect on supine blood pressure, and prazosin having more effect on standing pressure. Heart rate, cardiac output, and volume status showed only minor changes. Plasma norepinephrine showed a sustained increase when measured in both the supine and standing positions, but the increases were similar for the two treatments. Supine and standing plasma renin activity increased only during long-term treatment with hydralazine. Prazosin induced a progressive decrease in left ventricular mass over time (-34 +/- 15 g/m2 at 12 months), but hydralazine did not (-9 +/- 10 g/m2 after 12 months). Stepwise regression indicated that a decrease in systolic blood pressure was associated with a decrease in left ventricular mass with both treatments, but an increase in plasma norepinephrine was associated with an increase in left ventricular mass only with hydralazine, suggesting that increased sympathetic activity may affect left ventricular mass via cardiac alpha1 receptors. Thus, if regression of left ventricular hypertrophy is a worthwhile therapeutic goal, hydralazine and analogous arterial vasodilators are not drugs of choice.     

Inhibition of Na(+)-H(+) exchange prevents hypertrophy, fibrosis, and heart failure in beta(1)-adrenergic receptor transgenic mice

Chronic stimulation of the beta(1)-adrenergic receptor leads to hypertrophy and heart failure in beta(1)-adrenergic receptor transgenic mice and contributes to disease progression in heart failure patients. The cellular mechanisms underlying these detrimental effects are largely unknown. In this study, we have identified the cardiac Na(+)-H(+) exchanger (NHE1) as a novel mediator of adrenergically induced heart failure. beta(1)-Adrenergic receptor transgenic mice showed upregulation of both NHE1 mRNA (+140+/-6%) and protein (+42+/-19%). In order to test whether increased NHE1 is causally related to beta(1)-adrenergic-induced hypertrophy, fibrosis, and heart failure, beta(1)-adrenergic receptor transgenic (TG) and wild-type (WT) littermates were treated with a diet containing 6000 ppm of the NHE1 inhibitor cariporide or control chow for 8 months. There was significant hypertrophy of cardiac myocytes in beta(1)-adrenergic receptor transgenic mice (2.3-fold increase in myocyte cross-sectional area), which was virtually absent in cariporide-fed animals. Interstitial fibrosis was prominent throughout the left ventricular wall in nontreated beta(1)-adrenergic receptor transgenic mice (4.8-fold increase in collagen volume fraction); cariporide treatment completely prevented this development of fibrosis. Left ventricular catheterization showed that cariporide also prevented the loss of contractile function in beta(1)-adrenergic receptor transgenic mice: whereas untreated transgenic mice showed a significant decrease in left ventricular contractility (5250+/-570 mm Hg/s TG versus 7360+/-540 mm Hg/s WT, dp/dt(max)), this decrease was completely prevented by cariporide (8150+/-520 mm Hg/s TG cariporide). Inhibition of NHE1 prevented the development of heart failure in beta(1)-receptor transgenic mice. We conclude that the cardiac Na(+)-H(+) exchanger 1 is essential for the detrimental cardiac effects of chronic beta(1)-receptor stimulation in the heart.     

Effect of positive end-expiratory pressure on right and left ventricular function in patients with the adult respiratory distress syndrome

The predominant mechanism of the cardiac output reduction associated with positive end-expiratory pressure (PEEP) is unclear. Reported possibilities include decreased systemic venous return, increased pulmonary vascular resistance, or change in ventricular contractility. We investigated this question by studying 9 patients with the adult respiratory distress syndrome (ARDS) during PEEP application. We used an equilibrium radionuclide angiography method modified for improved right ventricular imaging to evaluate changes in left and right ventricular volume and contractility. Thermodilution cardiac output and stroke volume progressively declined (27 and 33% mean decrease, respectively) with increasing increments of PEEP. Right and left ventricular end diastolic counts, reflecting volume, also progressively diminished as PEEP increased (38 and 27% mean decrease in RV and LV counts, respectively; p less than 0.001 for both ventricles). A slight upward trend in ejection fraction was found for both ventricles. These findings support the concept that during PEEP application the reduction in cardiac output is due to biventricular reduction in blood volume. This biventricular volume reduction is compatible with either preload reduction to both ventricles because of impeded venous return or to change in ventricular configuration caused by external compression of both ventricles.     

Mechanisms of Ca2+-dependent calcineurin activation in mechanical stretch-induced hypertrophy

Pressure overload is the major stimulus for cardiac hypertrophy. Accumulating evidence suggests an important role for calcium-induced activation of calcineurin in mediating hypertrophic signaling. Hypertrophy is an important risk factor for cardiovascular morbidity and mortality. We therefore employed an in vitro mechanical stretch model of cultured neonatal cardiomyocytes to evaluate proposed mechanisms of calcium-induced calcineurin activation in terms of inhibition of calcineurin activity and hypertrophy. The protein/DNA ratio and ANP gene expression were used as markers for stretch-induced hypertrophy. Stretch increased the calcineurin activity, MCIP1 gene expression and DNA binding of NFATc as well as the protein/DNA ratio and ANP mRNA in a significant manner. The specific inhibitor of calcineurin, cyclosporin A, inhibited the stretch-induced increase in calcineurin activity, MCIP1 gene expression and hypertrophy. The L-type Ca2+ channel blocker nifedipine and a blocker of the Na+/H+ exchanger (cariporide) both suppressed stretch-dependent enhanced calcineurin activity and hypertrophy. Also application of a blocker of the Na+/Ca2+ exchanger (KB-R7943) was effective in preventing calcineurin activation and increases in the protein/DNA ratio. Inhibition of capacitative Ca2+ entry with SKF 96365 was also sufficient to abrogate calcineurin activation and hypertrophy. The blocker of stretch-activated ion channels, streptomycin, was without effect on stretch-induced hypertrophy and calcineurin activity. The present work suggests that of the proposed mechanisms for the calcium-induced activation of calcineurin (L-type Ca2+ channels, capacitative Ca2+ entry, Na+/H+ exchanger, Na+/Ca2+ exchanger and stretch-activated channels) all but stretch-activated channels are possible targets for the inhibition of hypertrophy.     

The Na+/Ca2+ exchanger/SR Ca2+ ATPase transport capacity regulates the contractility of normal and hypertrophied feline ventricular myocytes

BACKGROUND: Pressure overload leads to cardiac hypertrophy, which is often followed by heart failure. We tested the hypothesis that depressed contractility in this process results from an imbalance in Ca 2+ transport by the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) and the sarcolemmal Na+/Ca2+ exchanger (NCX). METHODS AND RESULTS: Left ventricular (LV) myocytes (n = 79) from 12 normal (N) and 5 hypertrophied (LVH, by aortic banding) feline hearts were studied. Adenoviral gene transfer was used to introduce green fluorescent protein (GFP), SERCA2, and NCX into N and LVH myocytes. Contraction (videomicroscopy) and Ca2+ transients (Fluo-3) were measured in steady state and after rest periods of 2 to 120 seconds (rest decay and potentiation). LVH hearts were significantly larger than N (7.1 +/- 1.4 versus 4.2 +/- 0.2 g/kg). SERCA protein was significantly less abundant in LVH versus N. Steady state contractions and Ca2+ transients of LVH-GFP myocytes decayed more slowly and rest decay of contractility was more pronounced compared with N-GFP. Infection of LVH (and N) myocytes with SERCA increased basal contractility and reduced rest decay. Infection of LVH myocytes with NCX almost abolished contraction and in N myocytes reduced contractility and increased rest decay. CONCLUSION: These findings suggest that an imbalance of Ca2+ transport by SERCA and the NCX produces the characteristic contractile abnormalities of hypertrophied cardiac myocytes.     

Increased contractility and calcium sensitivity in cardiac myocytes isolated from endurance trained rats

OBJECTIVE: Regular exercise enhances cardiac function and modulates myocyte growth in healthy individuals. The purpose of the present study was to assess contractile function and expression of selected genes associated with intracellular Ca2+ regulation after intensity controlled aerobic endurance training in the rat. METHODS: Female Sprague-Dawley rats were randomly assigned to sedentary control (SED) or treadmill running (TR) 2 h per day, 5 days per week for 2, 4 or 13 weeks. Rats ran 8-min intervals at 85-90% of VO2max separated by 2 min at 50-60%. Myocyte length, intracellular Ca2+ (Fura-2), and intracellular pH (BCECF) were measured in dissociated cells in response to electrical stimulation at a range of stimulation rates. RESULTS: The increase in VO2max plateaued after 6-8 weeks, 60% above SED. After 13 weeks, left and right ventricular weights were 39 and 36% higher than in SED. Left ventricular myocytes were 13% longer, whereas width remained unchanged. After 4 weeks training, myocyte contractility was approximately 20% higher in TR. Peak systolic intracellular Ca2+ and time for the decay from systole were 20-35 and 12-17% lower, respectively. These results suggest that increased myofilament Ca2+ sensitivity is the dominant effect responsible for enhanced myocyte contractility in TR. Intracellular pH progressively decreased as stimulation frequency was increased in the SED group. This decrease was markedly attenuated in TR and the intracellular pH was significantly higher in the TR group at a stimulation rate of 5-10 Hz. This effect may contribute to the increased contractility observed at the higher stimulation frequencies in TR. A higher intrinsic myofilament Ca2+ sensitivity was observed in permeabilised myocytes from the TR group under conditions of constant pH and [Ca2+]. Western blot analysis indicated 21 and 46% higher myocardial SERCA-2 and phospholamban, but unaltered Na+/Ca(2+)-exchanger levels. Competitive RT-PCR revealed that TR significantly increased Na+/H(+)-exchanger mRNA. CONCLUSION: Intensity controlled interval training increases cardiomyocyte contractility. Higher myofilament Ca(2+)-sensitivity, and enhanced Ca(2+)-handling and pH-regulation are putative mechanisms. Our results suggest that physical exercise induces adaptive hypertrophy in cardiac myocytes with improved contractile function.