Heart failure in diabetes mellitus: causal and treatment considerations.

The metabolic abnormalities associated with diabetes mellitus result in macrovascular and microvascular complications in multiple organ systems; it is the cardiovascular impact that accounts for the greatest morbidity and mortality associated with this disease. Heart failure, both with reduced and preserved systolic function, is a major complication, arising from the frequent associations with coronary atherosclerosis, hypertension, and a specific heart muscle dysfunction (cardiomyopathy) that occurs independently of coronary artery disease. Hyperglycemia, insulin resistance, and hypertension, together with activation of both circulating and tissue renin-angiotensin-aldosterone systems, contribute to structural fibrosis and autonomic neuropathy. Thus it becomes imperative to identify cardiac abnormalities early in the course of both type 1 and type 2 diabetes in order to allow early and aggressive intervention to control glucose and blood pressure and to normalize blood lipid profiles. Patients with diabetes should be treated to secondary prevention targets, including blood pressure less than 130/80 mm Hg and LDL less than 100 mg/dL. Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, certain calcium channel blockers, statins, and aspirin have all been demonstrated to significantly reduce cardiovascular morbidity and mortality in patients with diabetes.

High blood pressure in the geriatric population: treatment considerations.

Increases in blood pressure (BP), particularly systolic BP, have traditionally been considered to be a normal or "physiologic" component of the aging process. However, it is now clear that elevated BP, particularly systolic BP, represents a pathophysiologic manifestation of altered cardiovascular physiology and structure, ultimately manifesting as increased cardiovascular morbidity and mortality (myocardial infarction, stroke, and total cardiovascular death rates). More than one half of the population aged 65 or older have hypertension, defined as BP > or = 140/90 mm Hg. Framingham data indicate that the risk of coronary heart disease increases with lower diastolic BP at any level of systolic BP > or = 120 mm Hg, thus further stressing the importance of pressure-induced arterial vascular compliance changes and introducing pulse pressure as an important predictor of cardiovascular risk. Geriatric hypertension is generally of a salt-sensitive nature and often associated with impaired baroreflex function. Reduction in sodium intake is important and effective in older patients, and should be initiated before or together with drug therapy. Encouraging data from clinical trials now strongly support the aggressive anti-hypertensive treatment of elderly patients. A recent meta-analysis of eight outcome trials evaluating the risks of treated and untreated isolated systolic hypertension has demonstrated a 30% reduction in combined fatal and nonfatal stroke, a 26% reduction in fatal and nonfatal cardiovascular events, and a 13% reduction in total mortality. Those drugs effective in younger patients also appear effective in the elderly; low-dose thiazides (alone or in combination with potassium sparing agents), beta blockers, long-acting dihydropyridine calcium antagonists, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers all have demonstrated efficacy. In selecting an agent, it is important to consider comorbid disease states, and to recognize the potential of all nonsteroidal anti-inflammatory drugs, whether conventional or cyclooxygenase-2 specific, to increase BP or interfere with other antihypertensive agents. In general, the elderly should be treated to target BP levels identical to those suggested for younger patients, although a more gradual reduction to target, perhaps with an intermediate BP goal of < 160 mm Hg, may be advisable.

Beyond the usual strategies for blood pressure reduction: therapeutic considerations and combination therapies.

Rapidly accumulating clinical data have repeatedly demonstrated not only the critical importance of even small increases in blood pressure as a pathophysiologic factor in the development of cardiovascular disease, particularly in individuals with diabetes mellitus, but also the therapeutic necessity of more aggressive blood pressure reduction and the achievement of progressively lower blood pressure targets in reducing cardiovascular event rates. JNC VI has defined optimal blood pressure as or=140/80 mm Hg. Target blood pressures are now 1 gm/24 hours. Achieving such target pressures is increasingly difficult, particularly in diabetic patients with chronic renal disease, who require complex multidrug antihypertensive regimens. This review attempts to provide some suggestions for constructing such antihypertensive regimens, and provides considerations for the appropriate use of diuretics and the most effective drug combinations. Factors potentially contributing to drug resistant hypertension include such problems as failure to maximize drug dosing, suboptimal diuretic use, noncompliance, and possible confounding effects of such concomitant medications as nonsteroidal and anti-inflammatory drugs or decongestants. The issues underlying drug-resistant hypertension are listed, together with strategies for overcoming this problem.

Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of heart failure caused by left ventricular systolic dysfunction.

Activation of the renin-angiotensin-aldosterone system (RAAS) in left ventricular systolic dysfunction is a critically important determinant in the pathophysiologic processes that lead to progression of heart failure and sudden death. Angiotensin II, acting at the specific angiotensin receptor (AT1-R), activates a series of intracellular signaling sequences which are ultimately expressed within the cardiovascular system as vasoconstriction and associated vascular hypertrophy and remodeling. Angiotensin converting enzyme (ACE) inhibition leads to increases in the vasodilatory peptides bradykinin and substance P and at least an initial reduction in angiotensin II concentrations. AT1-R blocking drugs prevent access of angiotensin II to the AT1-R and thus prevent cellular activation. ACE inhibitors have clearly been demonstrated through a large number of clinical trials to increase survival in congestive heart failure, primarily by reducing the rate of progression of left ventricular dilatation and decompensation. However, this beneficial effect diminishes over time. Preliminary short-term clinical studies evaluating the efficacy of AT1-R blocking drugs in the treatment of heart failure have suggested that they elicit similar hemodynamic and neuroendocrine effects as do the ACE inhibitors. The combination ACE inhibitors and AT1-R blocking drugs offer the theoretical advantage of increasing bradykinin while blocking the actions of angiotensin II, and thus possibly show a synergistic effect. Again, preliminary studies have yielded encouraging results that are difficult to interpret because neither ACE inhibitor nor the AT1-R blocking drug doses were titrated to tolerance. Pharmacological manipulation of the RAAS has led to better understanding of its role in heart failure and improved clinical outcomes.

Relationship between resting metabolic rate and the composition of the fat-free mass.

Although a low resting metabolic rate (RMR) has been shown to be a risk factor for future weight gain, little is known about the mechanisms determining its level. We tested the hypothesis that the composition of the fat-free mass (FFM) is a main determinant of RMR. If this hypothesis is true, a regression model including internal organ masses as independent variables should explain a larger fraction of the variance in RMR than is explained using only FFM as a predictor. We measured fat mass by hydrodensitometry, liver and kidney volumes by computed tomography (CT), heart mass by echocardiography, muscle mass by dual-energy x-ray absorptiometry (DEXA), and RMR by calorimetry in 40 subjects. FFM and fat mass explained 83% of the variability in RMR (standard error of the estimate [SEE], 420 kJ/d) in a multiple regression analysis. Combinations of organ and muscle masses performed as well as but not better than stepwise multiple regression models. The fact that the composition of the lean mass could not improve the prediction of RMR in comparison to the traditional FFM-fat mass model suggests that the weight of internal organs is not a main determinant of RMR. This may indicate that the variability in RMR is associated with variation in energy expenditure per kilogram of tissue of the individual organs.

Preservation of left ventricular function and coronary flow by angiotensin I-converting enzyme inhibition in the hypertensive-diabetic Dahl rat.

The effect of the angiotensin I-converting enzyme (ACE) inhibitor benazepril (55 mg/kg orally) on the preservation of cardiac performance in diabetic-hypertensive Dahl S rats was investigated. Diabetes mellitus was produced by streptozotocin. Fasting (4-h) blood glucose levels were 279 +/- 50 mg/dL in diabetic Dahl salt-sensitive v 79 +/- 5 mg/dL in nondiabetic Dahl salt-sensitive rats. Cardiac performance was determined at the end of 8 weeks in an isolated perfused working heart apparatus. Peak left ventricular pressure (LVPmax), left ventricular peak negative dP/dt, and coronary flow were depressed in diabetic Dahl S rats (P < or = .05 v control). These deficits in cardiac function were not observed in diabetic Dahl S rats chronically treated with benazepril. The beneficial effects of benazepril apparently were independent of systolic blood pressure reduction. Although plasma ACE activity was increased in diabetic Dahl S rats, plasma renin activity was reduced. This suggests that the beneficial effects of ACE inhibition may be due to an effect upon the kinin system rather than the renin-angiotensin system. The benazepril-associated preservation of cardiac function in this study suggests that ACE inhibitors may be beneficial in the treatment of diabetic heart disease.

Acute hypotension alters hemodynamic response to methionine-enkephalin in conscious dogs.

In the conscious dog, intravenous administration of methionine-enkephalin produces simultaneous increases in both heart rate (HR) and mean arterial blood pressure (MAP). This report describes both depressor and cardioaccelerator responses to methionine-enkephalin (10 micrograms/kg IV) in conscious dogs following acute hypotension induced by either bolus injection of isoproterenol (0.1-5.0 micrograms/kg IV) or infusion of sodium nitroprusside (SNP, 3-8 micrograms/kg/min). Cardiovascular responses to methionine-enkephalin were blocked by naloxone. Pretreatment of the dogs with the beta-adrenergic receptor antagonist propranolol failed to prevent the hypotensive response to methionine-enkephalin following SNP infusion. The results indicate that the hemodynamic responses to methionine-enkephalin can be altered by acute manipulation of blood pressure. These results may have implications relative to the role of endogenous opiates in regulation of blood pressure, especially in acute hypotensive states.

Comparative effects of nitrendipine and hydrochlorothiazide on calciotropic hormones and bone density in hypertensive patients.

The effects of the calcium antagonist nitrendipine and the diuretic hydrochlorothiazide on plasma calciotropic hormone concentrations and lumbar bone density were compared during the treatment of hypertension in a randomized, double-blind, 8 week parallel study, followed by a 52 week open label study. There were 32 subjects with stable essential hypertension (sitting diastolic blood pressure > or = 95 mm Hg and < or = 115 mm Hg without medication) without evidence of renal insufficiency or active heart disease. They were randomly assigned to receive either 10 mg nitrendipine twice daily or 50 mg hydrochlorothiazide daily. In order to reach and maintain target blood pressure (diastolic blood pressure < or = 95 mm Hg) during the open label period, the nitrendipine dose was titrated up to 30 mg twice daily, and additional antihypertensive drugs, of differing classes, were added as necessary. Blood samples were analyzed for concentrations of calcium, parathyroid hormone, and calcitonin, and lumbar bone density was determined by dual photon absorptiometry, at the baseline and at 24 and 52 weeks of antihypertensive drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of interleukin-2 to alter systolic blood pressure in Dahl salt-sensitive rats.

The effect of interleukin-2 (IL-2) on systolic blood pressure in Dahl salt-sensitive rats was investigated. The treatment group received human IL-2 injections (5000 units/kg). Control animals received subcutaneous saline injections. Both groups of animals were placed on a diet containing 1.5% sodium the day of the first injection and maintained on that diet for the duration of the study. Systolic blood pressure increased in both the IL-2 treated and the control groups (P = .0001) over 7 weeks. The increase in SBP was the same for both groups (P = .8823 for between group differences). At the end of 7 weeks, when SBP in both groups was elevated to a similar degree, the IL-2 group and the control group were each administered 5000 units/kg of IL-2. SBP in both groups remained elevated, showing no decrease over the next two weeks. These results indicate that perhaps unlike in SHR, IL-2 does not alter systolic blood pressure in Dahl salt-sensitive rats.

Prolonged hemodynamic benefits from a high-dose bolus injection of human atrial natriuretic factor in congestive heart failure.

The physiologic and potential pharmacologic roles of atrial natriuretic factor in congestive heart failure have remained confusing. We have evaluated the hemodynamic responses to human atrial natriuretic factor [ANF (102-126)] given as bolus intravenous doses of 2.0 or 4.5 micrograms/kg to 12 patients with congestive heart failure. Responses were monitored with pulmonary and systemic arterial catheters in place. By 30 minutes after 4.5 micrograms/kg ANF (n = 6), heart rate decreased from 97 +/- 16 to 91 +/- 15 beats/min, right atrial pressure from 14 +/- 4 to 12 +/- 3 mm Hg, and pulmonary capillary wedge pressure from 33 +/- 3 to 23 +/- 2 mm Hg (all p less than 0.05); responses persisted for 120 minutes. Mean arterial pressure, cardiac index, stroke volume index, and pulmonic and systemic vascular resistances did not change significantly. The 2.0 micrograms/kg ANF dose produced similar responses, but only heart rate and right atrial pressure decreased significantly. No clinically important side effects were noted. High-dose ANF bolus doses can be administered simply and safely and improve hemodynamic parameters in chronic heart failure. Therefore ANF does have pharmacologic activity in heart failure and may have therapeutic potential.

Intravenous captopril in congestive heart failure.

Hemodynamic and neurohumoral effects of intravenous captopril were studied in ten patients with severe chronic congestive heart failure (NYHA Functional Class III and IV). Incremental bolus doses of captopril, titrated to a maximum cumulative dose of 15 mg, were given at 10-minute intervals. Systemic arterial pressure, mean pulmonary capillary wedge pressure, systemic vascular resistance, mean pulmonary artery pressure, and heart rate decreased (P less than .05). Cardiac index and stroke volume index increased (P less than .05). Maximum hemodynamic effects occurred after cumulative doses of 7 mg and were seen within 30 minutes after initiation of therapy; responses persisted for 30-90 minutes after the last dose. Plasma renin activity increased, and plasma atrial natriuretic factor concentration decreased. No adverse effects were observed with the use of intravenous captopril. Thus, intravenous captopril produces rapid and favorable hemodynamic improvement in advanced heart failure patients.

Efficacy of nicardipine in angina pectoris.

The dose-related efficacy and safety of nicardipine, a new calcium antagonist of the dihydropyridine class, was assessed by exercise tolerance testing in a randomized, double-blinded, placebo-controlled study in 19 patients with chronic, stable effort angina pectoris. Four patients were assigned to each of four treatment sequences receiving nicardipine three times daily in an extended Latin-Square study design. An increase in total exercise capacity, time to onset of angina and time to 1 mm ST segment depression was observed with nicardipine 90 mg/day compared to placebo (P less than .05). Gradual upward dose titration in 30 mg/day increments starting from 30 mg/day appeared to produce maximal increase in exercise capacity. Two patients developed adverse side effects attributable to the drug when administered nicardipine 90 mg/day directly from placebo.

Myocardial disease in hypertensive-diabetic patients.

Experimental and clinical evidence points to the existence of a cardiomyopathy associated with diabetes mellitus that is not due to coronary atherosclerosis. The condition is characterized by distinct clinical presentations and physiologic and biochemical abnormalities. Potential mechanisms for the development of diabetic cardiomyopathy are complex but are probably associated, in part, with hyperglycemia and hyperlipidemia. Primary hypertension is also associated with the development of myocardial abnormalities. Many of these changes are similar to those seen in diabetic cardiomyopathy. It is now clear that the co-existence of hypertension and diabetes mellitus produces a more severe cardiomyopathy than that produced by hypertension or diabetes alone. Potential mechanisms for interaction are numerous. Treatment of hypertension in diabetic patients must be targeted to more specific needs. Antihypertensive drugs should not worsen cardiac risk factors or glucose control and should have favorable effects on left ventricular function. The calcium antagonists and angiotensin-converting enzyme inhibitors have pharmacologic profiles that make them attractive as monotherapy for diabetic patients.

Endothelin produces systemic vasodilation independent of the state of consciousness.

The effects of endothelin, ET-1, on pulmonary and systemic hemodynamics were studied in the open chest dog and changes in systemic arterial pressure in dogs under conscious and anesthetized states were compared. Rapid intravenous (IV) bolus injections of ET-1, 100-1,000 nanograms/kg, significantly decreased systemic arterial pressure, and significantly decreased systemic vascular resistance whereas left atrial pressure and pulmonary vascular resistance were not altered. Reductions in systemic arterial pressure in response to bolus injection of ET-1, 100 and 300 nanograms/kg IV, during conscious state and during anesthesia were similar, respectively. The present data suggest that ET-1 dilates the systemic vascular bed independent of the animal's state of consciousness. The present data also suggest that when compared to the systemic vascular bed, the pulmonary vascular bed is less responsive to bolus administration of ET-1.

Interactions between circulating peptides and the central nervous system in hemodynamic regulation.

Enkephalins and endothelins are endogenous peptides, which, at least at pharmacologic doses, produce complex hemodynamic responses after intravenous administration. The enkephalins, when injected into conscious animal models and humans, increase blood pressure, heart rate and minute ventilation. This response occurs by activation of specific opiate receptors located outside the bloodbrain barrier; the actual mechanism involves an increase in adrenergic autonomic nervous system tone and a decrease in cholinergic tone. These opiate receptors may activate afferent fibers, perhaps nicotinic cholinoceptors; in many ways their properties are suggestive of chemoreceptors. Furthermore, enkephalin responses appear to be modulated by gamma-aminobutyric acid complexes, in that the reversal of the excitatory hemodynamic responses seen in the conscious state to vasodepressor responses after barbiturate anesthesia may result from alteration of the state of activation of the gamma-aminobutyric acid complex. The enkephalin receptors are localized to the vertebral artery vascular distribution; the specific site may be the area postrema, a blood-brain barrier-deficient circum-ventricular organ demonstrated to modulate heart rate and blood pressure and to represent a target site for circulating angiotensin II. Endothelin increases heart rate and blood pressure when infused slowly into conscious or anesthetized dogs, although barbiturates do blunt the increase in heart rate. The mechanism appears to involve modification of autonomic tone, but also some element of direct vasoconstrictor activity. Interestingly, rapid bolus doses of endothelin produce only vasodepressor responses, suggesting that the rate and concentration at which circulating endothelin reaches afferent receptors or vasoconstrictor sites on vascular smooth muscle may determine the net hemodynamic response observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic actions of endothelin in conscious and anesthetized dogs.

The newly described endogenous peptide, endothelin, was administered to five chronically instrumented conditioned dogs. Endothelin produced significant and simultaneous increases in both heart rate (HR) and mean arterial pressure (MAP) in conscious dogs. Endothelin also produced significant increases in MAP in anesthetized animals. Ganglionic suppression induced by hexamethonium (10 mg/kg) and atropine (0.1 mg/kg) blocked HR responses and markedly inhibited the pressor responses to endothelin in conscious animals. These results suggest that endothelin in part acts to elevate blood pressure and heart rate through modification of autonomic nervous system tone. When endothelin and angiotensin II were administered in mole equivalent doses, angiotensin II produced a pressor response of greater magnitude than did endothelin in conscious animals.