The contribution of local factors to the elevated venous tone of congestive heart failure.

Since the concept of an elevated venous tone in congestive heart failure (CHF) has been recently questioned, the venous volume of the elevated calf at a venous pressure of 30 mm Hg (VV[30]) was determined in 18 normal volunteers (N) and 10 CHF patients with a mercury-in-rubber strain gauge plethysmograph. CHF patients had a significantly lower VV[30] at rest and after intra-arterial phentolamine (2 mg) than normal subjects, suggesting that in these patients a state of peripheral venoconstriction existed (rest-N: 4.63+/-0.17, CHF: 1.7+/-0.23 ml/100 ml, P < 0.01; pre- and postphentolamine-N: 4.85+/-0.21 to 4.95+/-0.31, CHF: 2.26+/-0.29 to 2.68+/-0.38 ml/100 ml, P < 0.01). Of note is that alpha adrenergic blockade failed to increase VV[30] significantly in N, but did increase it in CHF (P < 0.05), suggesting that part of the decreased VV[30] in CHF in due to an augmented sympathoadrenal discharge. When sodium nitrite (30 mg) was given as a single intra-arterial injection before or after phentolamine or when given in four successive doses at 3-min intervals, the VV[30] of CHF patients was never increased to more than 3.62+/-0.42 ml/100 ml and was always less than N (P < 0.01). Importantly, VV[30] in CHF after these interventions was even significantly less than that of N before intervention (P < 0.05), suggesting that factors other than local active smooth muscle venoconstriction were operative in CHF to lower VV[30]. It is suggested that perhaps clinically undetectable edema and an elevated tissue pressure may account for these differences.

A comparison of the effects of vasodilator stimuli on peripheral resistance vessels in normal subjects and in patients with congestive heart failure.

The objective of this investigation was to characterize the mechanism of peripheral vasoconstriction observed in heart failure and to determine whether it can be attributed to the augmented sympathetic nervous activity, characteristic of this state. The response of the resistance bed in the forearm after release of inflow occlusion (reactive hyperemia), to hand exercise, and to local heating and the response of the calf resistance vessels to arterial occlusion and intra-arterial sodium nitrite and phentolamine were studied in 23 patients with congestive heart failure and 21 normal subjects. In the normal subjects, reactive hyperemia blood flow after varying periods of arterial occlusion greatly exceeded the values observed in patients with heart failure. Local anesthetic blockade and intra-arterial phentolamine did not significantly alter the reactive hyperemia response in heart failure patients, militating against the possibility that increased sympathetic vasoconstrictor activity is responsible for the reduction of this response. Following compensation, the reactive hyperemia response returned toward normal. The striking elevations of the forearm blood flow observed after hand exercise and heating of the forearm in normal subjects were also markedly attenuated in patients with heart failure. Following intra-arterial phentolamine and/or sodium nitrite, peak calf blood flow was still significantly reduced in heart failure. These observations indicate that (1) heart failure is characterized by a striking reduction in the response to a variety of endogenous and exogenous vasodilator stimuli; (2) circulating catecholamines and sympathetic vasoconstrictor activity are not solely responsible for the elevation of peripheral vascular resistance and the reduced response to vasodilator stimuli in heart failure; and (3) heart failure may increase systemic vascular resistance directly by altering the mechanical properties and reducing the dilating ability of the resistance vessels.

Comparison of the reflex reactivity of skin and muscle veins in the human forearm.

To determine the relative participation of skin and muscle capacitance beds of the forearm in venomotor reflexes, epinephrine iontophoresis was combined with forearm plethysmography so that the volume of muscle veins could be estimated simultaneously with the volume of cutaneous veins, at a constant venous pressure. With this technique not only are the cutaneous veins markedly constricted but they also are prevented from filling since skin blood flow is abolished. In 10 normal subjects, the venous volume in the elevated control forearm at a congesting pressure of 30 mm Hg (VV[30]) was 3.16 +/-0.30 SEM cc/100 cc, while in the iontophoresed arm it was 2.54 +/-0.31 cc/100 cc. Thus the forearm cutaneous VV[30] was 1.62 cc/100 cc. With a deep breath, ice to the forehead, and leg exercise, and cutaneous VV[30] decreased 19.8% (P < 0.01), 36.6% (P < 0.01), and 32.6% (P < 0.02), respectively, whereas the muscle VV[30] was not altered significantly. Similar results were observed using the isolated forearm technique and a deep muscle vein. The infusion of epinephrine intra-arterially did not decrease reflex venomotor reactivity until cutaneous blood flow was completely suppressed, indicating that the inability of the veins to react in the iontophoresed arm was not the result of epinephrine diffusion into the muscle bed. Thus, these results indicate that, in the forearm, only cutaneous veins participate in venomotor reflexes. Further, since the forearm is principally composed of skeletal muscle and the hand skin, an explanation is provided for the observation that veins of the forearm, studied as a whole, appear less reactive to stimuli than veins of the hand. An explanation also is provided for fainting which occurs during motionless standing despite intense venoconstriction, thereby emphasizing the importance of the skeletal muscle pump in the legs in preventing postural syncope.

The cardiovascular effects of morphine. The peripheral capacitance and resistance vessels in human subjects.

To evaluate the effects of morphine on the peripheral venous and arterial beds, 69 normal subjects were evaluated before and after the intravenous administration of 15 mg morphine. Venous tone was determined by three independent techniques in 22 subjects. The venous pressure measured in a hand vein during temporary circulatory arrest (isolated hand vein technique) fell from 20.2+/-1.4 to 13.4+/-0.9 mm Hg (P < 0.01) 10 min after morphine, indicating that a significant venodilation had occurred. With the acute occlusion technique, morphine induced a reduction in forearm venous tone from 12.8+/-1.1 to 7.9+/-2.3 mm Hg/ml/100 ml (P < 0.01). Although forearm venous volume at a pressure of 30 mm Hg (VV[30]) was increased from 2.26+/-0.17 to 2.55+/-0.26 ml/100 ml, measured by the equilibration technique, the change was not significant (P > 0.1). Of note is that the initial reaction to morphine was a pronounced venoconstriction, demonstrated during the first 1-2 min after the drug. (Isolated hand vein pressure increased to 37.2+/-5.4 mm Hg, P < 0.01). This rapidly subsided, and by 5 min a venodilation was evident. Morphine did not attenuate the venoconstrictor response to a single deep breath, mental arithmetic, or the application of ice to the forehead when measured by either the isolated hand vein technique or the equilibration technique. To evaluate the effects of morphine on the peripheral resistance vessels in 47 normal subjects, forearm blood flow was measured plethysmographically before and 10-15 min after the intravenous administration of 15 mg of morphine. Although mean systemic arterial pressure was unchanged, forearm blood flow increased from 2.92+/-0.28 to 3.96+/-0.46 ml/min/100 ml (P < 0.01), and calculated vascular resistance fell from 42.4+/-5.2 to 31.6+/-3.2 mm Hg/ml/min/100 ml (P < 0.01). When subjects were tilted to the 45 degrees head-up position, morphine did not block the increase in total peripheral vascular resistance that occurs; however, it did significantly attenuate the forearm arteriolar constrictor response (before morphine, + 25.7+/-5.4; after morphine, + 13.7+/-5.3 mm Hg/ml/min/100 ml, P < 0.05). However, morphine did not block the post-Valsalva overshoot of blood pressure, nor did it block the increase in forearm vascular resistance produced by the application of ice to the forehead. Similarly, morphine did not block the arteriolar or venoconstrictor effects of intra-arterially administered norepinephrine. Morphine infused into the brachial artery in doses up to 200 mug/min produced no changes in ipsilateral forearm VV[30], forearm blood flow, or calculated forearm resistance. Intra-arterial promethazine, atropine, and propranolol did not block the forearm arteriolar dilator response to intravenous morphine; however, intra-arterial phentolamine abolished the response. These data suggest that in human subjects, morphine induces a peripheral venous and arteriolar dilation by a reflex reduction in sympathetic alpha adrenergic tone. Morphine does not appear to act as a peripheral alpha adrenergic blocking agent but seems to attenuate the sympathetic efferent discharge at a central nervous system level.

Effects of hyperlipoproteinemias and their treatment on the peripheral circulation.

The purpose of this study was to determine the effect of familial hyperlipoproteinemia (HLP) on peripheral vascular disease (PVD) and the extent to which the vascular disease (PVD) and the extent to which the vascular disease is modified by treatment of the lipoprotein disorder. PVD was detected plethysmographically by observing a diminished peak reactive hyperemia blood (PRHBF) following ischemia. The value for PRHBF in the extremity demonstrating the lowest response in 32 normal subjects (age 19-50 yr) was 39.6+/-1.5 SEM, ml/min per 100 g. Patients with untreated HLP. who had PRHBF below the lower limit of normal, were 2 of 11 type II, 9 of 12 type III, 1 of 10 type IV. As a group, patients with type III HLP showed diminished PRHBF (26.6 +/-3.0 ml/min per 100 g, P <0.01). In view of the high incidence of PVD and the striking reduction in serum lipids and complete resorption of xanthomas observed in type III HLP with therapy, six patients were studied before and after 3-6 months of treatment with a therapeutic diet and clofibrate. PRHBF in the most severely affected extremity increased markedly, from 20.4 +/-1.6 to 31.9 +/-1.8 ml/min per 100 g (P<0.01), indicating a dramatic increase in maximum blood flow to this extremity. In two type III patients with PVD not treated, no change in PRHBF occurred over 5 months. In two other type III patients the PRHBF increased 17% during the first 25 days of therapy concomitant with a 30% reduction in whole blood viscosity. Over the next 120 days, blood viscosity decreased only an additional 4.6% whereas the PRHBF increased 57%, indicating that the observed changes seen in the PRHBF with therapy of type III patients can be only minimally accounted for by changes in the viscosity of the blood. Thus, patients with type III HLP are particularly susceptible to the development of PVD and objective improvement of PVD can occur with medical treatment of this lipid transport disorder.

The role of skin and muscle resistance vessels in reflexes mediated by the baroreceptor system.

The role of skin and muscle vascular beds in baroreceptor-mediated alterations of peripheral vascular resistance was evaluated in six normal subjects in whom the skin circulation in one forearm was temporarily suppressed by epinephrine iontophoresis. Baroreceptor activity was enhanced by application of negative pressure to the neck (neck suction) and inhibited by application of lower body negative pressure. Forearm blood flow was measured simultaneously in both arms with strain gauge plethysmographs. Since blood flow in the treated arm consisted entirely of muscle flow, skin flow was calculated from the difference between total forearm flow in the intact arm and muscle flow in the treated arm. Vascular resistances were calculated as the ratio of mean arterial pressure to the blood flow of each vascular bed. During neck suction, mean arterial pressure decreased from an average of 89 to 75 mm of Hg (P < 0.005), heart rate decreased from an average of 60 to 55 beats/min (P < 0.005), and total skin and muscle flows remained essentially unchanged. Cutaneous vascular resistance decreased from an average of 75 to 49 mm of Hg/ml per 100 g per min (P < 0.05), muscle vascular resistance from 68 to 51 (P < 0.005), and total forearm vascular resistance from 36 to 24 (P < 0.025). During lower body negative pressure, heart rate increased from an average of 59 to 69 beats/min (P < 0.005), mean arterial pressure did not change significantly, and significant decreases occurred in forearm blood flow from 5.4 to 2.7 ml/100 g per min, in skin blood flow from 3.1 to 1.4, and in muscle blood flow from 2.3 to 1.3. Cutaneous vascular resistance increased from an average of 47 to 110 mm of Hg/ml per 100 g per min (P < 0.05), muscle vascular resistance from 43 to 72 (P < 0.005), and total forearm vascular resistance from 20 to 38 (P < 0.001). These results demonstrate that both the skin and muscle resistance vessels participate in reflex changes initiated by alterations in baroreceptor activity.

Prejunctional angiotensin II receptors. Facilitation of norepinephrine release in the human forearm.

To determine if peripheral angiotensin II (Ang II) prejunctional receptors facilitating NE release exist in humans, we used [3H]NE kinetic methodology to measure forearm NE spillover during intrabrachial arterial Ang II infusions in eight normal male subjects. We used the following protocol to optimize conditions for demonstrating these receptors: (a) lower body negative pressure (-15 mmHg) to increase sympathetic nerve activity to skeletal muscle; and (b) intraarterial nitroprusside to maintain a high constant forearm blood flow (approximately 10 ml/min.100 ml) to maximize the proportion of neuronally released NE that spills over into the circulation. During lower body negative pressure, the following were infused intraarterially for three consecutive 20-min periods: saline, Ang II (4 ng/min), and Ang II (16 ng/min). During the Ang II infusions, forearm venous NE increased significantly from 173 to 189 and 224 pg/ml (P < 0.01), and forearm NE spillover increased from 384 to 439 and 560 ng/min.100 ml (P < 0.05 for high Ang II). Forearm NE clearance was unchanged. During low and high dose Ang II, the plasma venous Ang II concentrations were 25 and 97 pM, respectively. Since normal subjects increase plasma Ang II from 4 to 20-22 pM with exercise, standing, or diuretic administration, and patients with severe congestive heart failure can have a plasma Ang II of approximately 25 pM at rest, we suggest that Ang II might facilitate NE release in severe congestive heart failure, especially under conditions of stress.

Effect of baseline or changes in adrenergic activity on clinical outcomes in the beta-blocker evaluation of survival trial.

BACKGROUND: Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. METHODS AND RESULTS: Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the beta-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the beta-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (P<0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. CONCLUSIONS: In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation beta-blocker.

Regional vascular adjustments during recovery from myocardial infarction in rats.

Left ventricular function and systemic regional blood flow (radioactive microspheres, 15 +/- 5 mu) were studied 1, 3, 10 or 42 days after left coronary occlusion in conscious rats. One day after coronary occlusion, vascular resistance in the skeletal muscle and cutaneous beds increased while stroke work and left ventricular systolic pressure were depressed. Regional blood flow and hemodynamic data were similar for sham and infarction groups at 3 and 10 days after surgery, except for left ventricular end-diastolic pressure, which was significantly increased in rats with infarction (sham versus infarct: 11.5 +/- 1.0 versus 18.4 +/- 3.2 at day 3 and 12.2 +/- 1.4 versus 19.9 +/- 3.2 at day 10) (p less than 0.05). At 42 days after myocardial infarction, manifest heart failure occurred as documented by decreased cardiac output and left ventricular systolic pressure and elevated left ventricular end-diastolic pressure and vascular resistance in the cutaneous, skeletal muscle and renal beds. In a separate group of animals with moderate (33.2 +/- 2% of left ventricle) and large infarctions (45 +/- 1.3% of left ventricle), regional blood flow was compared with the sham group. Rats with a large infarct demonstrated significant (p less than 0.05) reduction in flow to kidney, gut and liver. In rats with a medium sized infarct, only renal blood flow was significantly reduced. It is concluded that in this model of myocardial infarction, early cardiocirculatory depression is followed by a partially compensated state with increased left ventricular end-diastolic pressure and subsequent systemic and regional vasoconstriction which, in turn, may contribute to late deterioration of heart failure.

Regulation of tissue noradrenaline in the rat myocardial infarction model of chronic heart failure.

OBJECTIVE: The aim was to evaluate mechanisms regulating tissue noradrenaline in congestive heart failure. METHODS: Tissue noradrenaline was measured in the conscious post myocardial infarction rat model of congestive heart failure and in sham operated rats (1) under control conditions, (2) 6 h after inhibition of tyrosine hydroxylase by the intraperitoneal administration of alpha-methyl-para-tyrosine (AMPT) (100 mg.kg-1 every 2 h), (3) 6 h after AMPT with desipramine pretreatment (0.3 mg.kg-1), and (4) following exhaustive exercise after AMPT. Tissue noradrenaline was extracted with perchloric acid and measured by high performance liquid chromatography with electrochemical detection. RESULTS: In control animals without drug, tissue noradrenaline concentration was lower in the following tissues in the rats with myocardial infarction compared with the sham operated group: left and right ventricles, spleen, soleus and white gastrocnemius muscles, kidney cortex, and tail artery. After AMPT, tissue noradrenaline concentration in the sham operated group was significantly lower than control; in the myocardial infarction group the fall in noradrenaline was only significant in the kidney, and group differences were no longer present. In the sham operated animals, coadministration of desipramine with AMPT attenuated the fall in tissue noradrenaline caused by AMPT in the heart and spleen. With exercise to exhaustion, cardiac noradrenaline was lower in rats with myocardial infarction than in sham operated rats, but higher in the soleus muscle. CONCLUSIONS: These data suggest that tissue noradrenaline depletion in congestive heart failure is not isolated to the heart, and it occurs despite activation of mechanisms that might be operating to conserve neuronal noradrenaline. One mechanism may be reduced organ blood flow to retard diffusion of noradrenaline into the circulation. If this increases interstitial noradrenaline concentration, it would facilitate prejunctional alpha 2 receptor restraint on noradrenaline release. Metabolic coronary vasodilatation during exercise reverses this process, and makes the heart most susceptible to noradrenaline depletion in congestive heart failure.

Effects of nitric oxide synthase inhibition on the muscle blood flow response to exercise in rats with heart failure.

OBJECTIVE: The aim of this study was to investigate whether the role of nitric oxide (NO) in regulating blood flow (BF) to working skeletal muscle is impaired in chronic heart failure (CHF). METHODS: The effect of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, was studied in conscious rats with and without CHF due to myocardial infarction (MI). BF to the hindquarter musculature was measured with radiolabelled microspheres during exercise after 4 min of treadmill running (10% grade, 20 m/min) before and after L-NAME (20 mg/kg i.a.) administration. RESULTS: Before L-NAME administration, BF measured in the total hindquarter musculature was less (P < 0.05) during exercise in rats with a large MI (MI size; 44 +/- 2% of the left ventricular endocardial circumference; n = 8) when compared with sham-operated rats (SHAM; n = 10) and rats with a small MI (MI size; 25 +/- 4%; n = 5). The BF measured during exercise following L-NAME administration was similar between the 3 groups. Of the 28 individual hindquarter muscles, BF was reduced in 23 and 19 muscles following the administration of L-NAME for the SHAM rats and rats with a small MI, respectively. In comparison, BF was reduced to only 4 of 28 muscles in rats with a large MI. CONCLUSIONS: These results suggest that the contribution of the NO pathway to the hyperaemic BF responses found in the hindquarter muscles during exercise could be attenuated in rats with CHF. This attenuation of the NO pathway may be associated with the impairment of skeletal muscle BF distribution during exercise in CHF.

Beneficial effect of dexamethasone on the "no reflow" phenomenon in canine myocardium.

The purpose of the present study was to determine if pretreatment with dexamethasone 6 mg.kg-1 would preserve coronary artery blood flow during reperfusion, thus preventing the no reflow phenomenon. Blood flow to small segments of the left ventricle was measured by the use of 15 micrometer tracer microspheres in intact dog hearts. During 2 hours of occlusion of the anterior descending coronary artery by balloon catheter, dexamethasone produced a small increase of the blood flow to perfused myocardium, when compared with untreated animals; this effect was not seen in underperfused segments of the myocardium. In nontreated animals, reperfusion of the underperfused portion of the left ventricle did not lead to a restoration of flow to normal when measured 1 hour later. In fact, the "no reflow" phenomenon resulted in a post reperfusion left ventricular segment which was similar to that measured during coronary arterial occlusion. However in the dexamethasone treated animals there was a decrease in the extent of left ventricular underperfusion from 19 to 6%. It is concluded that dexamethasone protects the border zone of canine myocardium during occlusion, and prevents the no reflow phenomenon in underperfused regions during reperfusion

Effects of isolated right and left ventricular stretch on regional arteriolar resistance.

In order to evaluate right and left ventricular stretch receptors without concomitantly stimulating those of the contralateral ventricle, 12 dogs were placed on total cardiopulmonary bypass. Balloons connected to compliant reservoirs were introduced into the right and left ventricles. Changes in systemic, gracilis muscle, and paw perfusion pressure at a constant flow were used as indices of systemic, muscle, and cutaneous vascular resistance. To induce left ventricular stretch, the balloon in that chanber was rapidly inflated from a mean pressure of 1.33 kPa (10 mmHg) to a mean pressure of 7.32 kPa (55 mmHg) for 15s (6.00 kPa [45mmHg] increment). For right ventricular stretch, the pressure was increased from 0.67 to 4.00 kPa (5 to 30 mmHg) for 30 s (3.34 kPa [25 mmHg] increment). Both left and right ventricular stretch produced a significant fall in systemic (-4.92 kPa [-37 mmHg], -36%) and gracilis muscle (-5.59 kPa [-42 mmHg], -30%) perfusion pressure, with only minimal changes in cutaneous vascular resistance (-0.80 kPa [-6 mmHg], -4%). This reflex was found to be vagally mediated, to have a low threshold for stimulation (left ventricle, 0.67 kPa [5 mmHg] increment; right ventricle, 1.33 kPa [10 mmHg] increment), and to have a neurogenic sympathetic alpha-adrenergic efferent limb. The low threshold for stimulation suggests that these reflexes may play a physiological role with changes in body position and may be important in such pathological conditions as semilunar valvular stenosis and myocardial infarction.

Linear dose response and quantitative attenuation by potassium of the inotropic action of acetylstrophanthidin.

To evaluate the nature of the inotropic dose response of digitalis and to determine the effects of potassium on this response, isometrically contracting isolated supported right ventricular cat papillary muscles were studied relative to their peak tension and peak dT/dt increases to physiologic cumulative doses of acetylstrophanthidin (ACS) in different extracellular potassium concentrations in the muscle bath. The inotropic dose response to ACS was observed to be linear in cumulative glycoside concentrations ranging from 0.40 to 4.23 X 10(-7) M ACS in 3.5 mM K+ medium and from 1.22 to 7.47 X 10(-7) M ACS in 7.0 mM K+ medium. The influence of potassium alterations in the muscle bath from the low to the high K+ concentrations prior to ACS resulted in marked attenuation of the positive inotropic property of ACS. From these data, it is concluded that the dose inotropic response of digitalis is linear, with small doses producing proportionally the same effects as larger doses, and that extracellular potassium markedly influences this linear dose response such that higher K+ concentrations considerably attenuate the positive inotropic response of digitalis.

Probucol: a new cholesterol-lowering drug effective in patients with type II hyperlipoproteinemia.

Type II hyperlipoproteinemia or hyperbetalipoproteinemia (B-HLP), a condition with considerable atherogenic potential, is one of the most difficult lipid disorders requiring treatment. Since this abnormality responds minimally to dietary therapy alone, supplemental drug therapy is usually essential. Although the available bile-sequestering resins are effective in B-HLP, these substances are unpalatable and constipating. Since lifelong drug therapy is necessary as an adjunct to diet in the treatment of B-HLP, the ideal drug should be both effective and well tolerated. Probucol, a new cholesterol-lowering drug in tablet form without serious adverse effects, was evaluated in a 12-wk double-blind crossover trial in 11 patients with B-HLP whose serum cholesterol levels were in excess of 275 mg/dl. Probucol, in a dosage of 500 mg twice daily, produced a 10% or greater reduction in serum cholesterol levels in all 11 patients. Serum cholesterol was lowered (p less than 0.01) from 353 to 291 mg/dl in the entire group receiving probucol. There was no significant change (p greater than 0.1) in serum cholesterol (352 mg/dl) during placebo administration. These were no untoward drug effects during the study, and all patients maintained excellent complicance to the schedule of medication. These results indicate that probucol possesses considerable cholesterol-lowering activity and may be a promising new nontoxic therapeutic agent in type II hyperlipoproteinemia.

Plasma lipid changes in young adult couples consuming polyunsaturated meats and dairy products.

Twenty-five young couples consumed either a saturated or polyunsaturated fat diet for a 20-week period. The polyunsaturated beef, lamb and dairy products, high in linoleic acid, were produced by feeding ruminant animals "protected lipid" feeds which prevent hydrogenation of fats in the rumen. The experimental design provided for four dietary groups: A) saturated diet for 20 weeks; B) polyunsaturated diet for 20 weeks; C) saturated diet for 10 weeks then polyunsaturated diet for 10 weeks; and D) polyunsaturated for 10 weeks then saturated diet for 10 weeks. Polyunsaturated-to-saturated ratios (linoleic: total saturated fatty acids) for the diets were: prestudy, 0.43-0.56; saturated 0.11-0.14; polyunsaturated, 0.56-0.62. Factors other than diet that appeared to affect cholesterol responses were carefully considered. During the initial 3 weeks (regimentation period) plasma cholesterol concentration decreased in all groups irrespective of diet. This was followed by two experimental periods in which the effects of the prescribed diets were readily apparent (response periods I and II). The final 4 weeks of the study were characterized by diminishing compliance with the dietary discipline (abatement period). Subjects in each group (A,B,C,D) were subdivided into high and low on a basis of each group's initial median cholesterol level. Those in the high subgroups were very responsive to dietary changes whereas those in the low subgroups were not. Combined responses of high subjects were: polyunsaturated diet, -10.7 mg/dl (P less than 0.025), saturated diet, d8 mg/dl (P less than 0.05). Combined difference between saturated and polyunsaturated diets was 18.5 mg/dl or approximately a 10% cholesterol difference between the experimental polyunsaturated and saturated diets.

Thallium-scan myocardial defects and echocardiographic abnormalities in patients with sarcoidosis without clinical cardiac dysfunction. An analysis of 44 patients.

Sarcoidosis of the myocardium, an illness occurring predominantly in young adults, frequently becomes clinically apparent when the disease is far advanced. Since the thallium myocardial perfusion scan (TMPS) is known to be capable of detecting granulomas, it seemed to be promising as a noninvasive means of screening for this complication of sarcoidosis. We, therefore, examined 44 consecutive patients with sarcoidosis, none of whom had clinical evidence of heart disease, utilizing TMPS, echocardiography, electrocardiography, systolic time interval ratios (PEP-LVET) and 24-hour Holter monitoring. TMPS disclosed left ventricular defects in 14 patients (32 per cent) and abnormalities of the right ventricle in an additional four patients. Left ventricular abnormalities on the TMPS were associated with echocardiographic evidence of left ventricular dysfunction (widened mitral E point septal separation) but not with abnormalities on Holter monitoring or electrocardiograms. Systolic time interval ratios were insensitive but highly specific for the presence of abnormalities on the TMPS. We conclude that the TMPS frequently discloses abnormalities in sarcoidosis, which may be a reflection of its sensitivity in this setting.

The pharmacokinetics of diltiazem in healthy American men.

Plasma diltiazem concentration was determined for 24 hours after oral administration of 30, 60, 90 and 120 mg (sustained release tablets) in healthy adult white men. The plasma concentration was too low after the 30 mg dose to calculate pharmacokinetic variables. After administration of 60 mg (n = 12), 90 mg (n = 10), and 120 mg (n = 4), peak plasma concentrations were 72, 117, and 152 ng/cm3 and time to peak concentrations were 3.9, 3.3, and 4.0 hours, respectively. Half-lives for clearance from the plasma were 4.1, 5.1, and 5.6 hours and areas under the concentration-time curve were 514, 984, and 1258 ng/hour per cc, respectively. There was wide variability among patients after the administration of a single dose. The area under the curve also tended to increase more than the multiple of the dose administered. If the plasma diltiazem concentration is quantitatively related to efficacy and toxicity, then these data suggest that dosage requirements may vary considerably from patient to patient. Therefore, if a patient fails to respond sufficiently, the plasma drug concentration should be determined to see if adequate concentration has been attained. Alternatively, if the drug should prove to have a high therapeutic index, one might simply administer more than the usually required dose of diltiazem.

Vascular sympathetic nerve function in congestive heart failure.

To determine if intrinsic abnormalities of sympathetic nerve function might contribute to enhanced vascular tone in congestive heart failure, chronic myocardial infarction (infarct) was produced in rats by coronary artery ligation 9 to 10 months previously for comparison with animals subjected to sham operation (sham). The excised pulmonary artery, preincubated with 3H-norepinephrine (NE) was superfused, and stimulated electrically at 2, 4, 8 and 16 Hz. The nonnormalized data at each frequency for electrically evoked 3H overflow in excess of basal outflow was similar in sham and infarct vessels (difference not significant); however, the shape of the frequency-response curves was different. The 3H overflow/pulse from sham vessels was constant between 2 and 16 Hz; however, for the infarct vessels there was a significant reduction (p less than 0.05) at the highest frequency (16 Hz). Because of an 18.4% lower peak 3H overflow at 16 Hz (difference not significant), the infarct frequency-response curve shifted significantly (4 and 8 Hz, p less than 0.025 and p less than 0.01) to the left when data were expressed as a percent of peak percent 3H overflow, suggesting an increased sensitivity of the system. These data suggest that an intrinsic vascular sympathetic nerve abnormality is not a major cause of the increased plasma NE in congestive heart failure; increased nerve activity or decreased clearance of NE may be more important.

Aging reduces venous distensibility and the venodilatory response to nitroglycerin in normal subjects.

To determine if aging alters venous tone, venous distensibility was measured during control conditions and after the administration of nitroglycerin (0.8-mg spray) to 50 subjects ranging in age from 21 to 78 years. The mean arterial pressure decreased and the heart rate increased significantly after nitroglycerin. Control venous distensibility, measured after the inflation of an upper arm cuff to 30 mm Hg above cuff zero (VV[30]) was 2.69 +/- 1.26 (standard deviation) cc/100 cc arm. The VV[30] increased to 3.06 +/- 1.43 cc/100 cc arm after the administration of nitroglycerin. There was a significant relation between age and baseline venous distensibility (r = 0.53, p less than 0.001) and between age and the change in venous distensibility after nitroglycerin (r = 0.56, p less than 0.001). Both baseline venous distensibility and the venodilatory response to nitroglycerin decreased with age. There was no significant relation between systemic arterial pressure and baseline venous distensibility or between arterial pressure and the venodilatory response to nitroglycerin. Aging appears to diminish baseline venous distensibility and attenuate the venodilatory response to nitroglycerin.