Volume Overload Heart Failure Research Articles

Differential alteration of cardiotonic effects of EMD 57033 and β-adrenoceptor agonists in volume-overload rabbit ventricular myocytes

Background: We investigated the effects of EMD 57033, a prototype Ca 2+ sensitizer, and β-adrenoceptor agonists in ventricular myocytes isolated from the volume-overload (V-O) heart failure model of the rabbit. Methods and Results: V-O cardiac hypertrophy was induced in rabbits by the formation of an arterio-venous shunt between the carotid artery and jugular vein 12 to 15 weeks after the operation. Ventricular myocytes were enzymically isolated from normal and V-O rabbit hearts. The myocyte was loaded with a fluorescence Ca 2+ dye, indo-1, and Ca 2+ transients, and cell lengths were measured simultaneously. V-O myocytes were significantly larger than control myocytes. Duration of Ca 2+ transients and cell shortening was significantly longer in the V-O myocytes than in control myocytes. Effects of cardiotonic interventions, including EMD 57033, isoproterenol, and dobutamine, on Ca 2+ transients and cell shortening in V-O myocytes were compared with those in control rabbit myocytes. Isoproterenol and dobutamine increased the systolic cell shortening and peak Ca 2+ transients and abbreviated the duration of cell shortening and Ca 2+ transients. These responses were markedly attenuated in V-O myocytes. By contrast, the response of cell shortening to EMD 57033 was unaltered, and the Ca 2+ sensitizing effect of EMD 57033 was rather enhanced in V-O myocytes. Conclusion: Our results indicate that the effectiveness of Ca 2+ sensitizers is maintained in the V-O rabbit hypertrophy and heart failure model in contrast to the blunted response to β-adrenoceptor agonists, which provides an insight on therapeutic strategy with Ca 2+ sensitizers for the treatment of contractile dysfunction in congestive heart failure.

Altered tension-frequency relation of human myocardium in volume overload heart failure

Altered tension-frequency relation of human myocardium in volume overload heart failure

Decreased levels of oxygen free radical scavengers in chronic volume overload heart failure

Decreased levels of oxygen free radical scavengers in chronic volume overload heart failure

Oxygen free radicals in volume overload heart failure.

It has been suggested that oxygen free radicals (OFR) depress the excitation-contraction coupling in cardiac muscle. It is possible that a decrease in the cardiac contractility in the failing heart may be due to an increased OFR producing activity of polymorphonuclear (PMN) leukocytes. We studied the OFR producing activity (chemiluminescence) of PMN leukocytes from blood in dogs with heart failure due to chronic volume overload. The animals were divided into two groups: I) normal, (n = 10): II) dogs with mitral insufficiency (MI) of 6 to 9 months duration, (n = 10). Hemodynamic studies were done to establish the presence of heart failure. Blood samples were collected to measure PMN leukocyte chemiluminescence. There was a decrease in the cardiac index and index of myocardial contractility (dp/dt/IIP) and an increase in the left ventricular end-diastolic pressure in dogs with MI indicating left ventricular failure. The peak chemiluminescent activity of the PMN leukocytes in blood of dogs with failure was about four folds greater than that in the blood from normal dogs. These results suggest that there may be an increased OFR generation in dogs with volume overload heart failure. The decrease in the myocardial contractility in the failing heart might be due to an increase in the OFR produced by the PMN leukocytes.

Oxygen free radicals and heart failure.

We hypothesize that oxygen free radicals are involved in the genesis and maintenance of volume and pressure overload heart failure. Pressure and volume overload would produce myocardial ischemia. During ischemia there will be an increase in xanthine and xanthine oxidase; and a decrease in the superoxide dismutase and glutathione peroxidase activity leading to an increase in the oxygen free radicals. A decrease in the cellular pH during ischemia would release phospholipase which would, in turn, release arachidonic acid from phospholipids. Leukotrienes and prostaglandins will be synthesized through arachidonic acid metabolism. During this synthesis not only oxygen free radicals will be produced but also there will be formation of leukotriene, LTB4, which is known to activate neutrophil and hence increased secretion of oxygen free radicals. Increased circulatory catecholamines due to compensatory mechanism would also lead to an increase in the oxygen free radicals. Oxygen free radicals are known to depress Ca++ binding and uptake of sarcoplasmic reticulum which would lead to a decrease in the myocardial contractility. We have shown that oxygen free radicals depress cardiac function and cardiac contractility. It is, therefore, suggested that oxygen free radicals might be involved in the development of heart failure. The use of agents that reduce the amount of oxygen free radicals would be of value in the prevention and treatment of heart failure.

Usefulness of calcium antagonists for congestive heart failure

In patients with congestive heart failure (CHF) due to dilated cardiomyopathy, nifedipine, diltiazem and several of the newer calcium antagonists including nicardipine, nitrendipine, felodipine and PN 200-110 (isradipine) improve left ventricular function. Because of its relatively more pronounced negative inotropic and chronotropic actions, verapamil is generally not tolerated by patients with left ventricular failure. In addition, even relatively vascular-selective agents such as nifedipine can occasionally cause significant left ventricular depression, particularly if combined with β-adrenergic blocking agents. Comparative studies using nitroprusside to cause an equivalent decrease in arterial pressure indicate that nifedipine acts predominantly on the arterial vasculature, and that a small but significant decrease in contractility occurs, apparently due to a direct myocardial action. Although diltiazem causes a depression in myocardial contractility in dogs with volume overload heart failure, limited data show no significant negative inotropic action in patients with heart failure. The negative inotropic effects, if any, of newer and possibly more vascular-selective agents are not yet known. Calcium antagonists appear to act predominantly on the limb and coronary vasculature, with relatively less effect on renal and hepatic vessels. In patients with CHF, nifedipine causes an increase in coronary blood flow and a decrease in the aorto-coronary sinus oxygen difference indicating an improvement in myocardial energetics. Although nifedipine causes an increase in cardiac index and decreases in systemic vascular resistance and pulmonary capillary wedge pressure during exercise, the limited data available fail to show a short- or long-term increase in exercise capacity. Nifedipine causes an increase in plasma renin activity, possibly due to a direct action on the kidney. In the Syrian hamster, microvascular spasm, myocyte necrosis and development of heart failure can be prevented by verapamil, suggesting that calcium antagonists could have a role in preventing the development of some cardiomyopathies. The ultimate role of calcium antagonists in the treatment of patients with CHF is not yet clear. These agents are most likely to be of value in patients with both CHF and symptoms of myocardial ischemia, and in many cases, combination with nitrates or converting enzyme inhibitors may substantially improve the clinical response to the calcium antagonist.

Increased myocardial adenosine release in heart failure

Volume overload congestive heart failure in dogs is associated with a reduced myocardial inotropic responsiveness to the exogenous administration of beta-adrenergic agonists [10, 11]. This same blunted inotropic responsiveness to beta-agonists has now been identified in the failing human myocardium [2]. Volume overload congestive heart failure in dogs is also associated with a reduced resting coronary vascular resistance [7, 12] suggesting the possibility of increased myocardial production of a metabolic vasodilator in the failing heart. Adenosine is a metabolic coronary vasodilator [1] and also has recently been shown to antagonize the inotropic action of beta-adrenergic agonists through a mechanism involving action on the sarcolemmal adenylate cyclase system [4, 13]. Given the findings of blunted inotropic responsiveness of the failing myocardium to beta-adrenergic agonists and reduced coronary vascular resistance in heart failure, we hypothesized that heart failure was associated with elevated myocardial production of adenosine. Accordingly we measured myocardial adenosine release in normal dogs and dogs with volume overload heart failure. Basal levels of myocardial adenosine release were found to be elevated three-fold above normal in dogs with heart failure. It is possible that elevated adenosine release in the failing myocardium contributes both to abnormalities of coronary blood flow and to the blunted inotropic responsiveness of the failing heart to catecholamines.

Persistence of myocardial failure following removal of chronic volume overload.

Length-contractile force curves and dose-response curves of heart rate, blood pressure, and contractile force were recorded from the left ventricle of six anesthetized dogs in a control state. These measurements were repeated at an average of 56 days following creation of an atrioventricular fistula when signs of heart failure were present. The fistula was then closed and the dogs restudied after an additional 57 days. Heart failure was associated with a shift up the ascending limb of a depressed length-contractile force curve and a depressed contractile response to isoproterenol. For instance, 0.1 micrograms/kg of isoproterenol produced a 173 +/- 8% increase in contractile force in control and 42 +/- 7% in failure. The contractile response to ouabain (30 micrograms/kg) was unchanged in heart failure, i.e., 36 +/- 5% in control vs. 39 +/- 4% in heart failure. When the dogs were restudied following fistula closure, the length-contractile force curve was still depressed as was the contractile response to isoproterenol, whereas the response to ouabain was again unchanged from control. Plasma norepinephrine and renin levels increased 5- and 10-fold, respectively, during heart failure and then returned to control following closure of the fistula. The data support the view that myocardial dysfunction associated with volume-overload heart failure is not reversible within the same time frame as its onset.

Cardiovascular effects of AR-L115 BS in conscious dogs with and without chronic congestive heart failure.

AR-L115 BS is a phenyl-imidazo-pyridine derivative that combines positive inotropic and vasodilator properties. To analyze the mechanisms of action of AR-L115 in the presence or absence of heart failure, we administered it intravenously to conscious dogs (seven normals and eight with a volume-overload heart failure). In normals, at a plasma level around 1,000 ng/ml, AR-L115 BS increased left ventricular (LV) peak (+) dP/dt (+48%; p less than 0.02) and heart rate (+29 beats/min; p less than 0.05) without altering significantly cardiac filling pressures or cardiac output. The mean aortic pressure and the systemic vascular resistances (-20%; p less than 0.02) were reduced, but plasma renin activity (PRA) was unchanged. In heart failure, the same plasma level increased peak (+) dP/dt by 36% (p less than 0.01), but heart rate stayed unchanged. Mean aortic pressure, systemic vascular resistances (-20%; p less than 0.01), and LV end-diastolic pressure (-9.1 mm Hg; p less than 0.01) all dropped significantly, while cardiac output increased slightly; PRA did not rise significantly. After beta-blockade, the increases in peak (+) dP/dt and the changes in systemic vascular resistances were markedly reduced. In conclusion, AR-L115 BS has strong positive inotropic and vasodilator effects, both of which are partially dependent on the level of the sympathetic tone in the intact animal. These combined properties improve hemodynamics in heart failure; this improvement is already significant at relatively low plasma levels, at which deleterious changes in heart rate or PRA are absent.

Comparative hemodynamic effects of digoxin vs nitroprusside in conscious dogs with aortocaval fistula-induced chronic left ventricular volume overload and normal systolic performance

We compared the effects of IV digoxin (0.04 mg/kg) and nitroprusside (NP) (1.2 and 1.8 μg/kg/min) on left ventricular (LV) performance in six preinstrumented conscious dogs with chronic volume overload and congestive heart failure (CHF) produced by an aortocaval fistula. At 3 and 6 hours after digoxin administration (serum level, 3.5 ± 0.6 ng/ml), there were no changes in heart rate, LV systolic (LVSP) and end-diastolic (LVEDP) pressures, LV dimensions, LV dP dt max , or percent minor diameter shortening as compared to control values in the resting state, after beta blockade, or during phenylephrine infusion. By contrast, NP produced a significant reduction ( p < 0.05) in LVEDP (16 ± 3 to 10 ± 3 mm Hg) at the smaller dose which caused no change in mean aortic pressure. The larger dose of NP further reduced LVEDP and evoked significant ( p < 0.05) decreases in LVSP (124 ± 5 to 117 ± 7 mm Hg), mean aortic pressure (85 ± 3 to 78 ± 5 mm Hg), and LV end-diastolic dimension (LVEDD) (53.0 ± 5.5 to 52.0 ± 5.7 mm), while augmenting LV dP dt max (3288 ± 266 to 3647 ± 130 mm Hg/sec). Beta blockade with IV propranolol (2.0 mg/kg) prevented the rise in LV dP dt max after high-dose NP administration but did not alter the reductions in mean aortic pressure, LVEDP, and LVEDD. This study indicates that NP, but not digitalis, has a favorable effect on LV hemodynamics in the volume-overloaded heart with normal LV systolic contraction and high-output CHF resulting from increased blood volume and reduced LV diastolic compliance. At least part of the apparent improvement in LV performance observed with high-dose NP is sympathetically mediated since it can be attenuated by beta blockade.

Cardiac responses to beta-adrenergic stimulation in anesthetized dogs with chronic congestive heart failure.

The cardiac responses to i. v. bolus injections of norepinephrine (NE, 5 and 10 μg) and isoproterenol (ISO, 2 and 5 μg) were compared in dogs with and without chronic congestive heart failure (CHF) induced by construction of a large infrarenal aortacaval fistula. Prior to establishing the shunt there was a significant increase in left ventricular pressure (LVSP), dp/dtmax cardiac output (CO) and stroke volume (SV) to both doses of NE. Pre-shunt there was a significant increase, in dp/dtmax, heart rate (HR), CO and SV to both doses of ISO. Following establishment of the shunt and CHF, there was a significantly depressed response of LVSP and dp/dtmax to both doses of NE compared to pre-shunt changes. Following the shunt and CHF, the response of LVSP was significantly greater at the 2 μg dose of ISO while there was a depressed response of dp/dtmax at both, doses of ISO and a depressed chronotropic response of ISO at both doses. In eight dogs with ligated A-V fistulas and a return of hemodynamic variables as well as heart size to pre-shunt level, there was a reversal of inotropic and chronotropic response to ISO while the inotropic responses to NE were more variable and appeared to remain depressed. In a group of seven normal dogs which were volume expanded with isotonic, isooncotic dextran to similar levels of end diastolic pressures as the CHF dogs, the responses to ISO were not depressed. NE responses were not tested in this group. It is concluded that dogs with chronic volume overload heart failure have a reduced capacity to respond to exogenous catecholamines and that this phenomenon is not related to the volume expanded state of these animals.

Volume overload heart failure: length-tension curves, and response to beta-agonists, Ca2+, and glucagon.

Left ventricular force-generating capacity was determined in 19 anesthetized dogs with heart failure (HF) from aortocaval fistula. At the time of study all dogs had ascites, edema, and elevated pulmonary wedge pressure. Length-contractile force (CF) curves recorded from the left ventricle (LV) with a modified Walton-Brodie arch indicated that the LV was operating on the ascending limb of the length-CF curve at 62.4 +/- 0.1% Lmax in the normal group and in the HF group at 83.4 +/- 2.7% Lmax. In HF the length-CF curve was depressed when compared to normal and was further depressed when CF in grams was normalized for changes in LV wall thickness and expressed as g/cm2. Additionally, dose-response curves of CF in response to injected norepinephrine, isoproterenol, glucagon, and calcium were depressed when compared to the normal group while the response of heart rate and blood pressure was not different. These findings indicate that volume overload HF is associated with depressed ventricular muscle function and a depressed response to inotropic drugs.