Systemic and renal hemodynamics in oliguric hepatic failure: effect of volume expansion.

Systemic and renal hemodynamics were studied by indicator dilution techniques before and after infusion of 500 ml of dextran 40 in 21 patients with renal failure developing in the course of decompensated cirrhosis. Cardiac index was directly correlated with total blood volumes. Renal blood flow was low and renal vascular resistance elevated in 13 of 15 patients. Renal vascular resistance was directly related to total systemic nonrenal vascular resistance. Two patients with the highest cardiac outputs in the group were oliguric with high renal blood flow. Plasma volume expansion increased cardiac output in 19 of 21 patients and increased renal blood flow in 12 of 14. The patients were divided into two groups on the basis of control cardiac index. Those with lower cardiac index had lower blood volumes and responded to dextran with a 73% increase in cardiac output, a 148% increase in renal blood flow, and a rise in renal fraction. Those with high control cardiac index had significantly higher blood volumes and responded to dextran with only a small average rise in cardiac output and renal blood flow. Systolic arterial pressure was less than 100 mm Hg in 12 patients. When compared to the normotensive subjects, this hypotension was characterized by a lower vascular resistance, a tendency for a lesser rise in renal blood flow after volume expansion, and a more rapid demise. The prompt circulatory improvement after volume expansion in many of these patients indicates that functional plasma volume depletion may be an important factor in the renal vasoconstriction of oliguric hepatic failure. In an attempt to sustain volume expansion, reinfusion of ascitic fluid was accomplished in four patients. Normal renal blood flow was maintained during reinfusion and a diuresis always occurred, but the response usually was not maintained after the infusion was terminated.

Left ventricular function in acute myocardial infarction.

Left ventricular catheterization was carried out in 40 patients with acute myocardial infarction. Left ventricular end-diastolic pressure (LVEDP) was elevated in 85% of the patients studied. In 14 patients with apparently uncomplicated infarcts, LVEDP averaged 15 mm Hg, and cardiac index (2.98 liter/min/m(2)), stroke volume (38.3 ml/m(2)), and stroke work (49.2 g-m/m(2)) were within normal limits. In 12 patients with clinical signs of left ventricular failure, LVEDP averaged 29.9 mm Hg, cardiac index was at the lower limit of normal (2.79 liter/min/m(2)), but stroke volume (31.6 ml/m(2)) and stroke work (37.3 g-m/m(2)) were reduced. In 14 patients with clinical signs of shock, LVEDP averaged significantly lower than in the heart failure group (21.1 mm Hg), but cardiac index (1.59 liter/min/m(2)), stroke volume (16.5 ml/m(2)), and stroke work (11.1 g-m/m(2)) were markedly reduced. A large presystolic atrial "kick" (average amplitude 9.5 mm Hg) was an important factor in the high LVEDP in the patients with heart failure but not in those with shock. The first derivative of left ventricular pressure was significantly lower in shock than in the nonshock group. Although right atrial pressure (RAP) and LVEDP were significantly correlated (r = 0.49), wide discrepancies in individual patients rendered the RAP an unreliable indicator of the magnitude of left ventricular filling pressure. THESE DATA SHOW THE FOLLOWING: (a) LVEDP is usually elevated in acute myocardial infarction, even in absence of clinical heart failure; (b) cardiac output apparently is supported by increased LVEDP and compensatory tachycardia; (c) in patients with shock, left ventricular function usually is markedly impaired, but inadequate compensatory cardiac dilatation or tachycardia could contribute to the reduced cardiac output in some individuals; (d) lower LVEDP in shock than in heart failure may represent differences in left ventricular compliance.

Mechanism of pulsus paradoxus in clinical shock.

An inspiratory fall in systolic arterial pressure of more than 10 mm Hg (pulsus paradoxus) was noted in 30 of 61 patients with shock. Inspiratory right atrial pressures and total blood volumes were significantly lower in patients with pulsus paradoxus. Rapid infusion of dextran in 22 patients usually was effective in reversing the exaggerated inspiratory fall in systolic pressure. Total peripheral vascular resistance tended to be higher in the patients with pulsus paradoxus and administration of vasoconsrictor drugs often accentuated the respirator pressure variation. Respiratory effects on blood flow in the aorta, pulmonary artery, and venae cavae were studied in anesthetized, closed-chest dogs. In the control state, pulmonary arterial flow increased during inspiration but aortic flow remained nearly constant. After hemorrhage a sharp inspiratory fall in aortic flow was associated with decreased central blood volume and attenuation of the usual inspiratory increase in venae caval and pulmonary arterial flows. The respiratory changes in aortic flow after hemorrhage could be attributed both to depletion of the pulmonary reservoir and to alterations in pulmonary inflow related to changes in systemic venous return. These data indicate that blood volume depletion may precipitate pulsus paradoxus both in the anesthetized dog and in the critically ill patient. The occurrence of pulsus paradoxus may aid in the clinical recognition of the common syndrome of occult hypovolemia in patients with shock in the absence of signs of blood loss.

Studies in clinical shock and hypotension: VI. Relationship between left and right ventricular function.

Left ventricular end diastolic (LVEDP) and mean right atrial (RAP) pressures were recorded simultaneously in 30 patients with shock (14 acute myocardial infarction, 10 acute pulmonary embolism or severe bronchopulmonary disease, and 6 sepsis). Myocardial infarction was characterized by a predominant increase in LVEDP, pulmonary disease by a predominant increase in RAP, and sepsis by a normal relationship between LVEDP and RAP. In all three groups a significant positive correlation was noted between RAP and LVEDP, with the regression line in cor pulmonale deviated significantly toward the RAP axis and the regression line in myocardial infarction exhibiting a zero RAP intercept at an elevated LVEDP.Low cardiac outputs with elevated LVEDP in myocardial infarction indicated severe left ventricular failure. Low outputs with elevated RAP in cor pulmonale were consistent with right ventricular overload. Although cardiac outputs often were normal in sepsis, low outputs with elevated cardiac filling pressures in some patients were consistent with a hemodynamic or humoral-induced generalized depression of cardiac performance.Vasoconstrictor and inotropic drugs often produced a functional disparity between the two ventricles, with the gradient between LVEDP and RAP increasing, apparently because of an increase in left ventricular work or an inadequacy of left ventricular oxygen delivery. Acute plasma volume expansion with dextran in patients with pulmonary vascular disease resulted in a somewhat more rapid rise in RAP than in LVEDP. In septic and myocardial infarction shock, however, LVEDP and RAP usually rose proportionally, with the absolute rise of LVEDP surpassing that of RAP. Although the absolute level of the central venous pressure thus may not be a reliable indicator of left ventricular function in shock, changes in venous pressure during acute plasma volume expansion should serve as a fairly safe guide to changes in LVEDP.

Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin receptor blocker added to angiotensin converting enzyme inhibitor therapy in patients with heart failure. Vasodilator Heart Failure Trial (V-HeFT) Study Group.

BACKGROUND: ACE inhibitors may not adequately suppress deleterious levels of angiotensin II in patients with heart failure. An angiotensin receptor blocker added to an ACE inhibitor may exert additional beneficial effects. METHODS AND RESULTS: Eighty-three symptomatic stable patients with chronic heart failure receiving long-term ACE inhibitor therapy were randomly assigned to double-blind treatment with valsartan 80 mg BID, valsartan 160 mg BID, or placebo while receiving their usual ACE inhibitor therapy. Studies were performed before and after the first dose of the test drug and again after 4 weeks of therapy. A single dose of lisinopril was administered during study days to ensure sustained ACE inhibition. Compared with placebo, the first dose of valsartan 160 mg resulted in a significantly greater reduction in pulmonary capillary wedge pressure at 3, 4, and 8 hours and during the prespecified 4- to 8-hour interval after the dose and in systolic blood pressure at 2, 3, 6, 8, and 12 hours and 4 to 8 hours after the dose. A pressure reduction from valsartan 80 mg did not achieve statistical significance. After 4 weeks of therapy, net reductions in 0-hour trough pulmonary capillary wedge pressure (-4.3 mm Hg; P=0. 16), pulmonary artery diastolic pressure (-4.7 mm Hg; P=0.013), and systolic blood pressure (-6.8 mm Hg; P=0.013) were observed in the valsartan 160 mg group compared with placebo. After 4 weeks of therapy, plasma aldosterone was reduced by valsartan 80 mg BID (-52. 1 pg/mL; P=0.001) and 160 mg BID (-47.8 pg/mL; P<0.001) compared with placebo, and there was a trend for a reduction in plasma norepinephrine (-97 pg/mL; P=0.10). Seventy-four of the 83 patients completed the trial. CONCLUSIONS: Physiologically active levels of angiotensin II persist during standard long-term ACE inhibitor therapy.

Efficacy of vasodilators in the treatment of heart failure.

Vasodilator drugs have been undergoing evaluation as therapy for heart failure for > 20 years. It has become clear that hemodynamic benefits, short-term improvement in exercise tolerance and long-term alteration in mortality are independent end points for efficacy of these drugs. Differing hemodynamic responses, variable effects on exercise capacity and differential effect on mortality of various vasodilator compounds raise the likelihood that vascular smooth muscle relaxation is not the sole mechanism of action of these drugs. Neurohormonal and antiproliferative effects of these agents may play a key role in the long-term response. Data from trials indicate that the vasodilator combination of hydralazine and isosorbide dinitrate as well as converting enzyme inhibitors can favorably affect all end points. The global efficacy of other vasodilators, such as calcium antagonists, has not yet been fully evaluated.

Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling.

Cardiac remodeling is generally accepted as a determinant of the clinical course of heart failure (HF). Defined as genome expression resulting in molecular, cellular and interstitial changes and manifested clinically as changes in size, shape and function of the heart resulting from cardiac load or injury, cardiac remodeling is influenced by hemodynamic load, neurohormonal activation and other factors still under investigation. Although patients with major remodeling demonstrate progressive worsening of cardiac function, slowing or reversing remodeling has only recently become a goal of HF therapy. Mechanisms other than remodeling can also influence the course of heart disease, and disease progression may occur in other ways in the absence of cardiac remodeling. Left ventricular end-diastolic and end-systolic volume and ejection fraction data provide support for the beneficial effects of therapeutic agents such as angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking agents on the remodeling process. These agents also provide benefits in terms of morbidity and mortality. Although measurement of ejection fraction can reliably guide initiation of treatment in HF, opinions differ regarding the value of ejection fraction data in guiding ongoing therapy. The role of echocardiography or radionuclide imaging in the management and monitoring of HF is as yet unclear. To fully appreciate the potential benefits of HF therapies, clinicians should understand the relationship between remodeling and HF progression. Their patients may then, in turn, acquire an improved understanding of their disease and the treatments they are given.

Hemodynamic effects of a new inotropic agent, piroximone (MDL 19205), in patients with chronic heart failure.

The hemodynamic and neurohumoral effects of cummulative intravenous doses of piroximone (MDL 19205), a noncatecholamine, nonglycoside, imidazole derivative with positive inotropic and vasodilating properties, were studied in eight patients with severe congestive heart failure. A dose of 1.25 mg/kg in seven patients and 1.75 mg/kg in one patient increased cardiac index by 75% from 1.96 to 3.41 liters/min per m2 and decreased systemic vascular resistance (-41%), right atrial (-66%) and pulmonary wedge pressure (-35%) (all p less than 0.005). Mean arterial pressure was slightly reduced from 78 to 71 mm Hg (p less than 0.05) and forearm blood flow increased by 42%. Plasma norepinephrine decreased from 830 to 542 pg/ml (p less than 0.05) and plasma renin activity tended to increase. In four patients, dobutamine (15 micrograms/kg per min) produced a comparable increase in cardiac index (+100%), but less decrease in pulmonary wedge pressure (-21 versus -41%, p less than 0.05 versus piroximone) and, unlike piroximone, significantly increased heart rate (+22%, p less than 0.05 versus piroximone) and heart rate-blood pressure product (+30%, p less than 0.01 versus piroximone). In four other patients, a single intravenous dose of piroximone (1 mg/kg) resulted in a 35% increase in the first derivative of left ventricular pressure (dP/dt) from 796 to 1,068 mm Hg/s (p less than 0.01). Thus, piroximone is a potent inotropic agent with an acute hemodynamic profile that may be more favorable than that of dobutamine. Because the drug is orally absorbed, clinical trials of chronic efficacy are indicated.

Hemodynamic and hormonal response to transdermal nitroglycerin in normal subjects and in patients with congestive heart failure.

The hemodynamic and hormonal responses to nitroglycerin administered transdermally in a gel-like matrix were evaluated in nine patients with severe congestive heart failure and in nine normal subjects. In normal subjects, peripheral vasodilation was accompanied by reflex sympathetic stimulation as reflected by an increase in heart rate and plasma norepinephrine. In patients with heart failure, nitroglycerin produced sustained hemodynamic effects that began 30 minutes after the application and fully persisted for at least 6 hours. A significant decrease in right and left ventricular filling pressures was associated with an increase in stroke index and a significant decrease in forearm and pulmonary vascular resistances. There was no change in heart rate and systemic arterial pressure or in plasma norepinephrine or plasma renin activity. After 24 hours, pressures had partially returned to control levels, but mean pulmonary artery pressure was still significantly lower than in the control period. After removal of the nitroglycerin, each patient exhibited a decrease in cardiac index and an increase, above the control values, in pulmonary and systemic arterial pressures and pulmonary, systemic and forearm vascular resistances. This transient rebound appeared to be unrelated to stimulation of the sympathetic or renin-angiotensin systems. Thus, transdermal absorption of this new form of nitroglycerin appears to provide a nitrate vascular effect that is sustained for 24 hours, but an endogenous vasoconstrictor effect may influence the hemodynamic response over the first 24 hours.

Abnormal neurohumoral response to nitroprusside infusion in congestive heart failure.

Vasodilator drugs produce tachycardia and an increase in circulating plasma norepinephrine in normal subjects. In contrast, heart rate does not change when the same drugs are given to patients with congestive heart failure. To assess if this difference could be related to a different reflex activation of the sympathetic nervous system, the response of plasma norepinephrine to nitroprusside infusion and to head-up tilt was studied in 5 normal subjects and in 46 patients with chronic congestive heart failure. Norepinephrine and heart rate increased significantly during both stimuli in normal subjects but were unchanged during nitroprusside infusion for the entire group of patients with heart failure, with considerable variability in individual responses. In 21 patients (Group I) norepinephrine increased during nitroprusside infusion, while in the remaining 25 (Group II) norepinephrine decreased. The hemodynamic response to nitroprusside was similar in the two groups, thus suggesting that the different changes in plasma norepinephrine could not be explained on the basis of a different hemodynamic response to the drug. Plasma norepinephrine also did not change significantly in Group II during tilt, although the decrease in intracardiac pressure and the increase in peripheral resistance were similar to those in Group I who increased norepinephrine normally by 56%. These data indicate that a subset of patients with severe ventricular dysfunction have an abnormal humoral, reflex sympathetic response to changes in arterial or intracardiac pressure, or both. The higher mortality in Group II suggests that this alteration in the sympathetic response may be a marker of the severity and prognosis of heart failure.

Regional blood flow response to orthostasis in patients with congestive heart failure.

To investigate the central and regional circulatory response to orthostasis in congestive heart failure, hemodynamic variables and forearm and hepatic blood flow were measured in 22 patients at supine rest and during a 65 degrees head-up tilt. Results were compared with those in nine normal subjects. Heart rate and mean arterial blood pressure increased during tilt in normal subjects, but not in patients with heart failure. Forearm blood flow decreased in normal subjects from 3.7 +/- 1.1 to 2.7 +/- 1.5 ml/min per 100 g (probability [p] less than 0.02), but did not change from a lower baseline (1.65 +/- 0.78 ml/min per 100 g) in patients. Forearm vascular resistance increased in normal subjects but not in patients. Hepatic blood flow did not change during tilt in either group, but hepatic vascular resistance increased in normal subjects from 0.37 +/- 0.13 to 0.47 +/- 0.15 U, (p less than 0.02). The increase was not seen in patients (1.2 +/- 1.1 to 1.4 +/- 1.0 U, p = not significant [NS] ). Total systemic resistance increased in patients from 1,848 +/- 560 to 2,132 +/- 731 dynes.s.cm-5 (p less than 0.005) indicating that resistance did increase in some vascular beds. Plasma norepinephrine also increased modestly in these patients from 665 +/- 377 to 761 +/- 379 pg/ml (p = 0.035), but individual changes in plasma norepinephrine did not correlate with changes in hepatic or forearm resistance. Thus, both the overall hemodynamic response and the regulation of regional blood flow and resistance differ in several respects in patients with congestive heart failure when compared with normal subjects. Changes in heart rate, blood pressure, forearm flow and forearm and hepatic vascular resistance are all blunted in patients. Reasons for the differences are not yet clear, but may be associated with abnormalities in reflex control of the circulation in patients with congestive heart failure.

ZK 36-374, a stable analog of prostacyclin, prevents acute hypoxic pulmonary hypertension in the dog.

Vasodilator therapy in pulmonary hypertension is limited by the lack of an agent selective for the pulmonary circulation. The effects of intravenous prostacyclin and two stable prostaglandin analogs, ZK 36-374 and CL 115,347, were assessed on the preconstricted pulmonary vasculature of the anesthetized dog. During hypoxic vasoconstriction ZK 36-374 (0.4 micrograms/kg per min) markedly reduced pulmonary artery pressure (26 +/- 3 to 13 +/- 1 mm Hg) (p less than 0.05) and pulmonary vascular resistance (6.2 +/- 1.1 to 2.8 +/- 0.2 mm Hg/liter per min) (p less than 0.01). There was no significant effect on cardiac output, aortic pressure or arterial blood gases. Pulmonary vasoconstriction induced by prostaglandin F2 alpha was similarly affected by ZK 36-374, and in this instance the aortic pressure was also reduced (158 +/- 11 to 129 +/- 11 mm Hg) (p less than 0.01). ZK 36-374 (0.2 micrograms/kg per min) was more effective in lowering hypoxic pulmonary vascular resistance (from 6.5 +/- 0.6 to 3.0 +/- 0.3 mm Hg/liter per min) than was prostacyclin (0.75 micrograms/kg per min) (from 6.3 +/- 0.6 to 4.2 +/- 0.4 mm Hg/liter per min) (p less than 0.05) and resulted in a smaller fall in aortic pressure (p less than 0.05). CL 115,347 (1.0 micrograms/kg per min) had no effect on the pulmonary vasculature during normoxia or when preconstricted by prostaglandin F2 alpha or hypoxia, but reduced aortic pressure and total systemic resistance (p less than 0.05). It appears to be a selective systemic vasodilator with no pulmonary vascular activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogen is associated with improved survival in aging women with congestive heart failure: analysis of the vesnarinone studies.

OBJECTIVES: This study sought to evaluate the effects of postmenopausal estrogen use on mortality in aging women with congestive heart failure (CHF). BACKGROUND: The age-related increase in CHF mortality in women may be related to a menopause-associated increased incidence of coronary artery disease. In addition to inhibiting coronary atherosclerosis, estrogen may also have protective effects on cardiac myocytes independent of the coronary vasculature. We hypothesized that estrogen use is associated with improved survival in elderly women with CHF. METHODS: Associations between survival, estrogen use and patient characteristics were assessed in 1,134 women who were at least 50 years of age, had CHF and left ventricular ejection fraction (EF) < or =30% and were enrolled in one of three clinical trials of vesnarinone. RESULTS: All-cause 12-month mortality was 15.0% among the 237 estrogen users versus 27.1% among the 897 estrogen nonusers (p = 0.004 for unadjusted comparison of survival). Similar results were observed for cardiac mortality. Regression analysis demonstrated that estrogen use was independently associated with improved survival (relative risk of mortality = 0.68, 95% confidence interval 0.48 to 0.96, p = 0.03). Advanced age, low EF, New York Heart Association class IV CHF, Caucasian race and abnormal serum creatinine, sodium, potassium and transaminase were independently associated with increased mortality. CONCLUSIONS: Estrogen use among older women with CHF is associated with decreased overall and cardiac mortality.

Myocardial bioenergetic abnormalities in a canine model of left ventricular dysfunction.

OBJECTIVES: The purpose of this study was to assess high energy phosphate compound metabolism in remodeled left ventricular myocardium. BACKGROUND: The development of heart failure several years after myocardial infarction is often unexplained. Certain abnormalities of remodeled myocardium suggest that structural changes occurring in viable myocardium after discrete myocardial damage may contribute to the later appearance of heart failure. Whether these abnormalities alter metabolism in the surviving muscle and thereby possibly contribute to ventricular dysfunction is unknown. METHODS: High energy phosphate compound metabolism was assessed using spatially localized phosphorus-31 nuclear magnetic resonance spectroscopy. Eleven dogs with documented left ventricular dysfunction, resulting from infarction produced by transmyocardial direct current shock, were compared with eight normal dogs. Analyses were performed at baseline and during coronary hyperperfusion induced by intravenous adenosine. Myocardial blood flow was measured with radioactive microspheres. RESULTS: The creatine phosphate/adenosine triphosphate (CP/ATP) ratio was significantly reduced in the left ventricular dysfunction group in both the subepicardium ([mean +/- SE] 1.94 +/- 0.08 vs. 2.32 +/- 0.13, p = 0.019) and the subendocardium (1.71 +/- 0.07 vs. 2.05 +/- 0.07, p = 0.004). Intravenous adenosine produced significant coronary hyperemia in both groups but was less marked in dogs with left ventricular dysfunction. The improvement in myocardial perfusion was accompanied by a significant increase in the subendocardial CP/ATP ratio (from 1.71 +/- 0.07 to 1.92 +/- 0.08, p = 0.01) in dogs with left ventricular dysfunction. CONCLUSIONS: An abnormal transmural distribution of high energy phosphate compounds is evident in remodeled myocardium. This abnormality may be related in part to mismatch of oxygen delivery and demand.

Hemodynamic effects of infused arginine vasopressin in congestive heart failure.

The hemodynamic effects of exogenously administered arginine vasopressin were assessed in 11 patients with chronic congestive heart failure. Infusion rates of 0.1 to 0.8 pmol/kg per min increased plasma arginine vasopressin from 6.5 +/- 2.7 (SD) pg/ml at control to 63 +/- 39 pg/ml at the highest infusion rate. There were progressive decreases in cardiac output and stroke volume, with increases in systemic vascular resistance and pulmonary capillary wedge pressure, but only minimal changes in heart rate and blood pressure. Changes in cardiac output, stroke volume and systemic resistance were evident from the first infusion rate, which increased plasma arginine vasopressin from 6.5 +/- 2.7 to 9.9 +/- 4.6 pg/ml. A paired analysis of baseline hemodynamic data with those measured during infusions producing an arginine vasopressin level averaging 15 +/- 2.6 pg/ml yielded the following changes: cardiac output decreased from 4.6 +/- 1.2 to 4.2 +/- 0.96 liters/min (p less than 0.01), stroke volume decreased from 60 +/- 19 to 54 +/- 16 ml (p less than 0.005) and systemic vascular resistance increased from 1,329 +/- 396 to 1,443 +/- 395 dynes X s X cm-5 (p = 0.01). Thus, small increases in circulating arginine vasopressin cause modest but significant adverse circulatory effects in patients with congestive heart failure. A fall in cardiac output, probably as a result of increased afterload, is seen at levels of arginine vasopressin within the basal range found in congestive heart failure. These data demonstrate that circulating arginine vasopressin in physiologic concentrations is capable of influencing hemodynamics in patients with congestive heart failure and suggest that therapy for this condition directed at inhibition of the vascular effect of arginine vasopressin may be potentially useful.

Long-term oral nitrate therapy prevents chronic ventricular remodeling in the dog.

OBJECTIVES: The purpose of this experiment was to assess the long-term effects of oral nitrate therapy on ventricular remodeling in a canine model of discrete myocardial damage. BACKGROUND: A progressive increase in left ventricular mass and volume has been documented after experimental and clinical myocardial infarction. This ventricular remodeling has been associated with the development of congestive heart failure. Nitrate therapy, especially when combined with hydralazine, is effective in the management of clinical heart failure. Moreover, nitrates inhibit infarct expansion, one of the earliest manifestations of ventricular remodeling. Whether nitrates can attenuate chronic left ventricular remodeling is unknown. METHODS: Dogs with discrete myocardial necrosis produced 24 h earlier by transmyocardial direct current shock were randomized to receive isosorbide mononitrate, 30 mg twice daily (n = 10), or no treatment (n = 4); the latter group was augmented by 13 control dogs from a prior study in which an identical protocol was used. Ventricular structure was assessed with nuclear magnetic resonance imaging at baseline and at 1 and 16 weeks after myocardial damage. RESULTS: Left ventricular mass increased at 1 week in the control group (mean +/- SD 68.1 +/- 10.7 g to 80.1 +/- 12.1 g, p = 0.0001) but not in the nitrate-treated group (70.2 +/- 7.7 g to 69.6 +/- 7.3 g, p = NS). No change in left ventricular volume was observed in either group during the 1st week after myocardial damage. After 16 weeks of follow-up left ventricular mass had increased by 12.7 +/- 7.1 g (p = 0.001) in the control group and had decreased by 1.2 +/- 7.7 g in the nitrate group. Left ventricular volume was increased at 16 weeks by 14.2 +/- 10.3 ml in the control group but was decreased by 3.7 +/- 7.5 ml in the nitrate group. Isosorbide mononitrate produced transient hemodynamic effects with a return of most measured variables toward baseline within 2 h after administration of the drug. At 1 week there was no intergroup difference in rest hemodynamic variables assessed 12 h after drug administration. At 16 weeks, pulmonary capillary wedge pressure (15 +/- 4 vs. 8 +/- 3 mm Hg, p = 0.0001), pulmonary artery pressure (24 +/- 5 vs. 16 +/- 3 mm Hg, p = 0.0001) and right atrial pressure (10 +/- 3 vs. 6 +/- 3 mm Hg, p = 0.008) were all higher in the control group. CONCLUSIONS: Long-term oral nitrate therapy attenuates the early and late manifestations of ventricular remodeling after myocardial damage in the dog. Hemodynamic observations suggest the possibility that drug-induced preload or afterload reduction does not completely explain this effect.

Impaired response of plasma vasopressin to orthostatic stress in patients with congestive heart failure.

Arginine vasopressin, a potent vasoconstrictor and regulator of body water, is frequently increased in the plasma of patients with congestive heart failure. Other neurohumoral control networks, such as the sympathetic nervous system and the renin-angiotensin system, also demonstrate increased activity in congestive heart failure, but fail to respond normally to physiologic stress, such as orthostatic tilt. To assess the response of plasma vasopressin to orthostasis in heart failure, vasopressin was measured before and at 10 and 45 minutes during passive upright tilt in 15 patients with congestive heart failure and their response was compared with that in 9 normal control subjects. Arginine vasopressin was measured by radioimmunoassay. In the normal subjects, plasma arginine vasopressin was 5.3 +/- 2.3 pg/ml at control, was unchanged at 10 minutes, but significantly increased to 7.0 +/- 2.5 pg/ml at 45 minutes (p less than 0.05). In contrast, patients with congestive heart failure showed no significant changes in arginine vasopressin levels from the control levels of 11.6 +/- 5.5 pg/ml. Both plasma norepinephrine and renin activity increased in the normal subjects, but failed to increase from higher baselines in patients with congestive heart failure. Thus, plasma arginine vasopressin, like plasma norepinephrine and renin activity, does not increase in response to upright tilt in patients with congestive heart failure. The explanation is not evident but could involve either abnormalities in reflex control of plasma vasopressin in congestive heart failure or in clearance of the hormone during orthostasis.

Angiotensin-converting enzyme inhibition and beta-adrenoceptor blockade regress established ventricular remodeling in a canine model of discrete myocardial damage.

OBJECTIVES: This study was designed to assess the effect of angiotensin-converting enzyme inhibition and beta-adrenoreceptor blockade on established ventricular remodeling. BACKGROUND: Angiotensin-converting enzyme inhibitor therapy attenuates the development of ventricular remodeling when given shortly after myocardial infarction. However, regression of established ventricular remodeling after infarction has received little attention. METHODS: The relative effects of angiotensin-converting enzyme inhibitor therapy and beta-adrenoceptor blockade on established ventricular remodeling were assessed in a canine model characterized by increased left ventricular mass and chamber dilation as a result of localized myocardial necrosis produced by transmyocardial direct current shock. Dogs were randomly assigned to 3 months of therapy with captopril (25 mg twice daily, n = 7) or metoprolol (100 mg twice daily, n = 7) or to a control group with no intervention (n = 6), 11 +/- 4 (mean +/- SD) months after acute myocardial damage. RESULTS: Compared with the control group, dogs in both the captopril and metoprolol groups had reduced left ventricular mass as measured by magnetic resonance imaging (-8.1 +/- 3.8 vs. 1.7 +/- 2.8 g, p = 0.003 and -9.6 +/- 5.6 vs. 1.7 +/- 2.8 g, p = 0.001), respectively. Captopril and metoprolol also produced a reduction in left ventricular end-diastolic volume (-7.6 +/- 6.0 and -6.0 +/- 5.8 ml, respectively) compared with the control value (-1.6 +/- 3.8 ml) (p = 0.14 [NS]). Both agents reduced mean arterial pressure but had disparate effects on pulmonary wedge pressure and right atrial pressure. There was no significant correlation between change in ventricular mass or volume and change in any measured hemodynamic or neurohormonal variable. CONCLUSIONS: These data suggest that pharmacologic intervention with angiotensin-converting enzyme inhibition or beta-adrenoceptor blockade can result in regression of established ventricular remodeling. The mechanism of this response will require further study, but these data did not support a close association between regression of remodeling and hemodynamic unloading of the ventricle or systemic neuroendocrine factors.

Relative attenuation of sympathetic drive during exercise in patients with congestive heart failure.

Patients with congestive heart failure have been considered to have augmented sympathetic drive both at rest and during dynamic exercise. The augmentation observed during exercise may be related to the state of near exhaustion experienced by patients with heart failure at relatively low work loads. To compare the response of the sympathetic nervous system to exercise in normal subjects and patients with heart failure when they are working in a comparable physiologic frame of reference, the data for both groups can be expressed as percent peak oxygen consumption achieved (percent peak VO2) rather than as a function of absolute oxygen consumption (VO2). Ten healthy control subjects and 31 patients with chronic clinical class II and III heart failure were studied during upright maximal bicycle exercise. Eighteen of the 31 patients had primary cardiomyopathy and 13 had ischemic cardiomyopathy. The average ejection fraction at rest was 24 +/- 10% (+/- SD) in the group with heart failure. Heart rate, systolic blood pressure, VO2 and plasma norepinephrine levels were measured at rest and throughout exercise. When the data were expressed as a function of percent peak VO2 achieved, patients with heart failure demonstrated a flatter slope (p = 0.004) than normal in the response of plasma norepinephrine to exercise, indicating a relative blunting of sympathetic drive. This was accompanied by attenuated heart rate (p = 0.001) and blood pressure (p less than 0.001) responses. These differences were not apparent when the data are expressed as a function of absolute VO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid, accurate and simultaneous noninvasive assessment of right and left ventricular mass with nuclear magnetic resonance imaging using the snapshot gradient method.

Left ventricular, and possibly also right ventricular, mass is an important determinant of prognosis in cardiovascular disease. Consequently, noninvasive estimation of ventricular mass may be an important clinical investigation. The ideal technique for this purpose would be widely available and accurate, employ short study times and avoid exposure to contrast agents and radiation. Conventional nuclear magnetic resonance (NMR) imaging fulfills most of these criteria, but it is time-consuming and expensive. Moreover, its accuracy in estimating right ventricular mass has yet to be assessed. Accordingly, high speed NMR imaging using the snapshot gradient echo technique was used to assess right and left ventricular mass in 10 dogs and the results were compared with values obtained at autopsy, which ranged from 26.1 to 52.9 and 61 to 119.8 g, respectively. The mean absolute difference between the NMR imaging estimates and autopsy findings was 2 +/- 1.2 g (range 0.4 to 4.2) for right ventricular mass and 4.4 +/- 1.7 g (range 1.8 to 6.6) for left ventricular mass. Total NMR imaging time was less than or equal to 5 min. These data demonstrate that high speed NMR imaging can be used to accurately estimate right as well as left ventricular mass.