Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol.

Quinidine pharmacokinetics (half-life, volume of distribution, and clearance) as well as protein binding were evaluated following a single 200 mg. oral dose of quinidine sulfate in eight control patients, in eight patients with moderate to severe cirrhosis, and in seven patients receiving 40 to 400 mg./day of propranolol. Patients with cirrhosis had a significantly longer quinidine half-life (9 +/- 1 hr; p less than .01) when compared to control patients (6 +/- 0.5h). This was not related to a reduced quinidine clearance rate but rather to an increase in quinidine volume of distribution (4.1 +/- .4 L./Kg. in cirrhotic patients vs 2.6 +/- 1 L./Kg. in control patients; p less than .01). Abnormal quinidine binding (greater than 25 per cent unbound fraction) was noted in seven of the eight cirrhotic patients. In contrast, patients receiving propranolol had a normal quinidine half-life of 6 +/- 0.5 hr. However, these patients had a significantly reduced quinidine clearance (3.3 +/- .7 ml./min./Kg. vs. 5.3 +/- .5 ml./min./Kg. in controls; p less than .05) and higher peak concentrations (1.25 +/- .20 micrograms/ml. vs. .80 +/- .5 micrograms/ml. in controls; p less than .05). Therefore in patients receiving propranolol, quinidine levels may be higher than expected shortly after dosage, and therefore a potential for transient toxicity exists in these patients. Maintenance quinidine dosage may have to be reduced in patients with moderate to severe hepatic cirrhosis, but not in patients receiving propranolol. Total quinidine concentration measurement underestimate free quinidine concentrations in most cirrhotic patients.     

Blood pressure during sleep is associated with arterial stiffness and urine microalbumin to creatinine ratio in youth with type 1 diabetes

AimsTo determine whether sleep blood pressure (BP) is associated with increased cardiovascular disease (CVD) risk in youth with type 1 diabetes (T1DM).MethodsWe enrolled youth with T1DM, 12–21 years old. Carotid-femoral Pulse Wave Velocity (PWV_cf) assessed arterial stiffness, a CVD marker. Sleep systolic and diastolic BP variables were obtained from 24-hour BP Monitoring. Linear regression models analyzed the relationship of each BP variable with PWV_cf, adjusted for HbA1c. Correlation of sleep BP with urine microalbumin-to-creatinine ratio (UAC) was examined.ResultsNocturnal hypertension was found in 36% and abnormal dipping in 48% of the 25 participants, aged 17.7 ± 2.2 years old. Sleep systolic BP [beta = 0.039, 95% Confidence Interval (CI; 0.006–0.073)], diastolic BP [beta = 0.058, 95% CI (0.003–0.114)], Mean Arterial Pressure (MAP) [beta = 0.075, 95% CI (0.018–0.131)] and MAP index [beta = 3.547, 95% CI (0.867–6.227)] were significantly associated with PWV_cf. Sleep diastolic BP, load, MAP correlated with UAC.ConclusionsBlood pressure alterations during sleep are common in youth with T1DM and they are associated with arterial stiffness and UAC. Larger studies are needed to confirm our results and examine whether interventions that target sleep and night-time BP could decrease CVD risk.     

Dose-independent pharmacokinetics of digoxin in humans.

Nine healthy male volunteers received single 0.5, 1.0, and 1.5 mg. doses of intravenous digoxin in a randomized three-way crossover study. Multiple venous blood samples were drawn during 35 hours after each dose, and all urine was collected for 6 consecutive days. Concentrations of digoxin in serum and urine were determined by radioimmunoassay. Over-all mean values for kinetic variables were: distribution half-life, 0.35 hours; elimination half-life, 27.9 hours; volume of distribution, 5.46 liters/Kg; total clearance, 2.51 ml./min./Kg. The mean projected cumulative urinary excretion of digoxin was 70.1% of the dose; mean renal clearance of digoxin was 1.71 ml./min./Kg., not significantly different from creatinine clearance (1.50 ml./min./Kg.). None of the identifiable pharmacokinetic variables was significantly influenced by dose, suggesting that digoxin disposition is dose-independent in healthy individuals.     

Acute Intravenous Infusion of an Adenosine Regulating Agent Improves Left Ventricular Function in Dogs with Advanced Heart Failure

Purpose

GP531 is a second generation adenosine regulating agent (ARA) that increases concentrations of endogenous adenosine, a natural cardioprotective agent, in ischemic/hypoxic tissue. This study examined the effects of acute intravenous infusions of GP531 on left ventricular (LV) systolic and diastolic function in dogs with advanced chronic heart failure (HF) (LV ejection fraction, EF <30 %).

Methods

Six dogs with intracoronary microembolization-induced HF received a constant intravenous infusion of GP531 (10 μg/kg/min) or vehicle (normal saline) for 6 h in random order 1 week apart. Hemodynamic measurements were made at baseline and at 1, 2, 3, 4, 5 and 6 h after initiating drug infusion. Myocardial oxygen consumption (MVO₂) was measured at baseline and 4 and 6 h. LV pressure-volume relationship (PVR) was measured at baseline and 6 h.

Results

Vehicle infusions had no effect on indexes of LV systolic and diastolic function. GP531 infusion had no effect on heart rate or mean aortic pressure but significantly decreased LV end-diastolic pressure, end-diastolic volume, end-systolic volume and end-diastolic wall stress. GP531 significantly increased LV EF (27?±?1 at baseline to 34?±?1 after 6 h of drug infusion, p?<?0.05), deceleration time of early mitral inflow velocity and the slope of end-systolic PVR without increasing MVO₂.

Conclusions

Results of the study indicate that approaches which increase the local release of adenosine in failing LV myocardium, such as ARAs, have a favorable impact on LV performance. These observations support the continued development of ARA’s for the treatment of acute HF syndromes.     

Phasic changes in human right coronary blood flow before and after repair of aortic insufficiency

We have shown previously that acute aortic insufficiency in chronically instrumented dogs reverses the normally high ratio of diastolic to systolic coronary blood flow.Phasic blood flow in the dominant right coronary artery was measured directly with an electromagnetic flow meter during surgery in eight patients with severe aortic insufficiency before and after replacement of the aortic valve. Before the insufficiency was eliminated, right coronary flow averaged 116 ± 37 ml./minute and the diastolic to systolic flow ratio was 0.88 ± 17. Mean arterial blood pressure averaged 106 ± 17 mm. Hg, heart rate 84 ± 19 beats/minute, and mean diastolic pressure averaged 67 ± 10 mm. Hg. After the aortic valve was replaced with an average heart rate of 90 ± 15 and mean blood pressure of 103 ± 13 mm. Hg, the average right coronary blood flow increased to 180 ± 40 ml./minute with a $\text{D}\text{S}$ ratio of 2.18 ± 0.8. In all cases the right coronary blood flow increased after the aortic insufficiency was eliminated surgically. Right coronary flow probably increased because of the improved diastolic perfusion pressure and the change from predominantly systolic to diastolic coronary flow.     

Impaired left ventricular filling rate induced by treatment with recombinant interleukin 2 for advanced cancer.

BACKGROUND--Immunotherapy with recombinant interleukin 2 (rIL 2) has been extensively used to treat cancer but its use has been hampered by serious side effects including severe hypotension, arrhythmias, and myocardial infarction. OBJECTIVE--To assess the effects of rIL 2 on human left ventricular function. METHODS--Left ventricular (LV) function was monitored in 22 patients (9 women, 13 men) (mean (SD) age 53 (10) years) undergoing a 120 h continuous intravenous infusion of rIL 2 (18 x 10(6) IU/m2/day) for melanoma (4), renal cell (16), ovarian (1), and colon cancer (1). Radionuclide ventriculography was performed before and 1 h after the end of treatment. Ejection fraction (EF), peak emptying rate (PER), peak filling rate (PFR), and regional left ventricular wall motion were analysed. Heart rate (HR), central venous pressure (CVP), systolic (SBP) and diastolic blood pressures (DBP), the electrocardiogram, and myocardial enzyme concentrations were monitored throughout the study. RESULTS--All variables (mean (SD)) were normal before rIL 2 was given. After rIL 2 administration HR increased significantly from 84 (11) to 125 (18) beats/min (p < 0.0001), SBP fell from 128 (11) to 100 (9) mmHg (p < 0.001) and DBP from 76 (9) to 65 (7) mmHg (p < 0.0001). CVP decreased from 3.70 (3.2) to 1.30 (0.45) cm H2O (p < 0.001). EF (65 (7) to 64 (8%) and PER (3.56 (0.60) to 3.86 (0.83) EDV/s) did not change significantly. PFR decreased significantly at the end of the rIL 2 infusion from 2.68 (0.46) to 2.37 (0.43) EDV/s (p < 0.01). Left ventricular segmental hypokinesia developed in 6 patients. Myocardial enzyme concentrations remained normal throughout the study. CONCLUSIONS--The results of this study confirmed that rIL 2 produces important haemodynamic changes, predominantly related to decreased systemic resistance. However, the observed reduction in PFR in most patients suggested that rIL 2 might exert its action at the level of the heart muscle itself. The localised systolic dysfunction in some patients suggested that rIL 2 might also adversely affect myocardial perfusion.     

Insulin Infusion Normalizes Cardiovascular Responses and Plasma Noradrenaline after Oral Glucose in Type 1 (Insulin-dependent) Diabetes

ABSTRACT. We examined whether the abnormal regulation of the cardiovascular system and plasma noradrenaline observed after oral glucose in insulin-dependent diabetic patients could be normalized by intravenous infusion of insulin. Eight patients with type 1 (insulin-dependent) diabetes were examined after an oral glucose load with and without simultaneous infusion of insulin. Insulin infusion increased plasma insulin from 0.07 to 0.31 nmol/1. In the control experiment (glucose only), mean heart rate and mean arterial systolic blood pressure remained unchanged and plasma noradrenaline (NA) decreased (p < 0.05). After oral glucose plus intravenous insulin, mean heart rate increased by 11 % and mean systolic blood pressure by 5 % (p < 0.05, p < 0.01), whereas plasma NA did not change significantly. The present study indicates that physiologic increments in plasma insulin concentration are of importance in the regulation of the cardiovascular system and plasma NA following an oral glucose load.     

Angiotensin II stimulates respiration in awake dogs and antagonizes baroreceptor inhibition

The effects of intravenous infusions of physiologic doses of angiotensin II (AII) on expired ventilation (V̇E) and acid-base balance were examined in awake dogs. A control infusion of saline was followed by AII infusion, initially with mean arterial pressure (MAP) raised 15%, and then with MAP at control levels of concurrent infusion of sodium nitroprusside (SNP). To control for SNP, the protocol was repeated using arginine vasopressin (AVP). Ventilatory responses of CO₂ (VRC) were measured at the end of these protocols and separately with MAP elevated during infusion of AII. With AVP, increased MAP inhibitedV̇E, heart rate (HR) and metabolism. However, with MAP elevated during AII infusion, stimulation by AII opposed baroreceptor reflexes and these variables, as well as plasma AVP, did not change. When MAP was lowered to control during AII infusion all variables increased. With AII, Pa_CO2 followedV̇E changes, decreasing 3 Torr with MAP at control levels; however, [H⁺] remained constant due to a decrease in arterial strong ion difference. The stimulatory effects of AII were not due to SNP; SNP did not stimulateV̇E during AVP infusion. The slope of the VRC was unaltered by AII infusion or MAP; however, AVP reduced the VRC slope. Physiological increases in AII stimulateV̇E and other systems at normal MAP and maintain several regulatory systems at control levels during baroreceptor inhibition.     

Effect of glucose--insulin--potassium solution on the exercise performance of patients with coronary artery disease.

Treadmill exercise testing was performed in double blind fashion on nine untrained nondiabetic subjects with angiographically proven coronary artery disease and stable exercise tolerance. They were exercised on three different days in randomized sequence as follows: With infusion of 30 per cent solution of glucose in water containing 50 units of regular insulin and 80 mM. of KCl per liter, 50 ml. bolus followed by 1 ml./Kg./hr. (GIK); with infusion of normal saline, (NSS), 50 ml. bolus followed by 1 ml./Kg./hr. and without infusion (control). There were no significant differences between control and saline experiments.A decrease in work capacity (9.9 ± 3.4 to 7.0 ± 2.1 METS p < 0.005) and the product of the heart rate and systolic blood pressure (20318 ± 6068 to 17597 ± 5788 mm. Hg min.^?1, p < 0.05) at the end of exercise was observed in GIK experiments. Angina occurred at lower exercise levels in GIK studies (6.4 ± 1.4 METS) than in NSS studies (9.9 ± 3.4 METS p < 0.01). When compared at the same exercise level (5 METS), more pronounced ST depression (0.21 ± 0.11 mV.) was seen in GIK than in NSS studies (0.1 ± 0.18 mV., p < .025). In two patients, the exercise test was negative in NSS and became positive in GIK.In GIK, a decrease in serum FFA compared to resting level was noted at the end of exercise (197 ± 246 μEq/L.) and during exercise at 5 METS (272 ± 400 μEq/L.) as opposed to an increase (566 ± 853 μEq/L., p < 0.025 at 5 METS and 650 ± 996 μEq/L., p < 0.05 at the end of exercise) in NSS. An increase in blood glucose (73 ± 74 mg./100 ml., p < 0.01) at the end of exercise and (116 ± 75 mg./100 ml., p < 0.005) at 5 METS was noted in GIK but not in NSS studies. A small decrease in serum potassium (by 0.11 ± 0.23 mEq./L. at 5 METS and by 0.15 ± 0.24 mEq./L. at the end of exercise) was seen in GIK but an increase in the saline group (by 0.21 ± 0.39 mEq./L., p < 0.05 at 5 METS and by 0.43 ± 0.38 mEq./L., p < 0.001 at the end of exercise). No significant differences in serum lactate were noted.The data indicate that GIK diminishes the exercise performance and hastens the onset of angina in patients with coronary artery disease. It appears that increased availability of glucose and potassium does not have a beneficial effect in the presence of depressed FFA levels during exercise.     

Posterior wall velocity: an unreliable index of total left ventricular performance in patients with coronary artery disease

Posterior wall velocity determined by use of echocardiography has been proposed as an index of total left ventricular performance in patients with ischemic heart disease. Accordingly, in 9 normal subjects and 39 patients with angiographically documented coronary artery disease, we compared mean endocardial posterior wall velocity determined by echocardiography with echocardiographic and biplane cineangiographic calculations of ejection fraction and the mean rate of circumferential fiber shortening (mean V_CF), and with externally recorded systolic time intervals. All studies were performed on the same day in each patient. Mean endocardial posterior wall velocity averaged 4.6 cm/sec (range 2.9 to 8.7) and correlated poorly with echocardiographic ejection fraction (r = 0.47), cineanglographic ejection fraction (r = 0.26), cineangiographic mean V_CF (r = 0.47), the ratio of preejection period to left ventricular ejection time (r = ?0.35) and the preejection period corrected for heart rate (r = ?0.30). Substitution of maximal for mean endocardial posterior wall velocity did not improve the separation of normal from depressed left ventricular performance. Epicardial posterior wall velocity, a measurement more easily obtainable than endocardial posterior wall velocity, also did not correlate well with systolic time intervals or with ejection fraction or mean v_cf derived from the echocardiogram and cineangiogram. Both endocardial and epicardial posterior wall velocity values were poorly reproducible on a day to day or a beat to beat basis. We conclude that neither endocardial nor epicardial posterior wall velocity, whether derived as a mean or a maximum, provides an accurate measure of total left ventricular performance in patients with coronary artery disease.     

Intravenous quinidine: relations among concentration, tachyarrhythmia suppression and electrophysiologic actions with inducible sustained ventricular tachycardia

A computer simulation was used to devise quinidine sulfate infusions to produce pseudo-steady-state concentrations in the low (8 microM/liter) and high (14 microM/liter) therapeutic ranges, avoiding high peak concentrations. Using this infusion, efficacy and electrophysiologic actions of quinidine sulfate were assessed in 21 patients with sustained inducible ventricular tachycardia (VT) when concentrations were 12.6 +/- 11 microM/liter (mean +/- standard deviation) and 18 +/- 9 microM/liter. Although mean concentrations approximated target levels, there was substantial individual variation. A reciprocal linear relation (r = 0.8, p less than 0.01) was noted between resultant serum concentrations and drug-free ejection fraction (EF). Transient hypotension occurred early in 3 patients, 2 of whom had a normal left ventricular (LV) EF. No hemodynamic compromise was seen in patients with LVEFs of less than 30%. Induced VT was suppressed in 5 patients at low concentrations and in an additional 4 at high concentrations (total 9 of 21, 42%). Concentration-dependent changes in the ventricular effective refractory period of the beat induced by S3 paralleled antiarrhythmic efficacy. Independent of response or lack of response to intravenous quinidine, 17 patients received gradually increasing oral quinidine dosages adjusted to reproduce plasma levels that had been effective during intravenous administration, or to maximal well-tolerated dosage (if side effects occurred). VT was still inducible during oral treatment in 4 of 5 patients in whom VT had been suppressed during the intravenous infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Doppler and echocardiographic assessments of effects of disopyramide on non-obstructive hypertrophic cardiomyopathy

We assessed the effects and therapeutic implications of disopyramide on left ventricular systolic and diastolic functions in 19 patients with non-obstructive hypertrophic cardiomyopathy by Doppler echocardiography. All patients were in sinus rhythm. Parameters measured were fractional shortening (FS (%)), mean velocity of circumferential fiber shortening (mean Vcf (circ/sec)), ejection fraction (EF (%)), peak left ventricular outflow velocity (peak-LVOT (cm/sec)), peak rapid filling inflow velocity (peak-R (cm/sec)), peak late filling inflow velocity (peak-A (cm/sec)) and peak-A/peak-R ratio (A/R ratio). These values were compared before and after infusion of disopyramide (2 mg/kg). There was no significant difference in heart rate, systolic and diastolic blood pressures before and after infusion of disopyramide. Following the intravenous drip infusion of disopyramide, FS decreased from 38.1 +/- 5.4 to 33.2 +/- 4.9 (p less than 0.05) and the mean Vcf decreased from 1.285 +/- 0.181 to 1.141 +/- 0.188 (NS). EF and peak-LVOT also decreased from 67.7 +/- 6.3 to 61.9 +/- 7.0 (p less than 0.05), and from 107.6 +/- 29.5 to 92.4 +/- 25.2 (p less than 0.01), respectively. The infusion of disopyramide increased the peak-R from 47.3 +/- 18.2 to 55.5 +/- 19.2 (p less than 0.05), and decreased peak-A from 52.0 +/- 13.6 to 40.2 +/- 12.6 (p less than 0.01), resulting in a decrease of A/R ratio from 1.277 +/- 0.537 to 0.818 +/- 0.475 (p less than 0.01). These results suggest that disopyramide improved left ventricular diastolic function, although systolic function decreased slightly. In conclusion, disopyramide can be also used beneficially in non-obstructive hypertrophic cardiomyopathy without arrhythmias.     

Left ventricular filling in sickle cell anemia

M-mode echocardiography was performed on 11 normal black subjects and 38 patients with sickle cell anemia while they were at rest to evaluate their left ventricular (LV) systolic and diastolic function. The patients with sickle cell anemia were also evaluated by radionuclide exercise tests and, based on their ejection fraction (EF) response, were separated into 2 groups: a group with a normal EF response to exercise (73 +/- 9%, mean +/- standard deviation) and a group with an abnormal EF response to exercise (53 +/- 9%). Computer-assisted analysis of the M-mode echocardiograms identified abnormalities of diastolic function (impaired left ventricular filling) in patients with sickle cell anemia compared with the normal subjects. The abnormal EF response group had significantly more impaired diastolic function and did less exercise than the normal EF response group. Both groups of patients had a decrease in left ventricular end-diastolic volume during exercise. The patients with sickle cell anemia had abnormalities of systolic and diastolic function on echocardiographic and radionuclide testing. The abnormalities in diastolic and systolic function assumed greater significance at the increased heart rates associated with exercise, accounting for the decrease in left ventricular end-diastolic volume and the abnormal EF response, and contributed to exercise intolerance in patients with sickle cell anemia.     

Effects of chronic oral quinidine on left ventricular performance

We studied the effects of 10 to 14 days of oral quinidine administration (200 mg every 8 hrs) on left ventricular (LV) $\text{dP}\text{dt}$ max and shortening fraction (%ΔD) in seve preinstrumented consclous dogs in the resting state, during atrial pacing at 120 bpm, and during an acute pressure load produced by intravenous phenylephrine. Dogs were studied before, during, and after oral quinidine administration with control measurements varying by < 10%. In the resting state, heart rate (85 ± 6 SEM vs 88 ± 7 bpm), LV end-diastolic pressure (7.2 ± 1.4 vs 6.7 ± 1.1 mm Hg), LV end-diastolic diameter (39.6 ± 3.2 vs 38.9 ± 2.7) did not differ (p > 0.05) before or during quinidine, respectively. During atrial pacing LV $\text{dP}\text{dt}$ increased similarly during the control and quinidine periods (+ 13 and + 11%), and %ΔD decreased equally (?26% and ?21%) during phenylephrine infusion off and on quinidine. Thus chronic oral quinidine administration in clinically therapeutic doses (serum quinidine levels 2.3 to 7.5 μg/ml) produced no depression in LV performance at rest or during an acute pressure load.     

Effects of cerivastatin on forearm vascular responses, blood pressure responsiveness and ambulatory blood pressure in type 2 diabetic men

OBJECTIVE: The objective of the study was to investigate the effects of cerivastatin therapy on forearm endothelial dependent acetylcholine (ACH) and independent (nitroprusside) vasodilator responses, blood pressure (BP) responses to intravenous infusions of angiotensin II (AII) and noradrenaline (NA) and on 24-h ambulatory BP recordings in type 2 diabetic men. DESIGN: Eleven type 2 diabetic men aged 59 +/- 9 years with total cholesterol levels of 5.0 +/- 1.26 mmol/l, triglycerides of 2.23 mmol/l and high-density lipoprotein cholesterol levels of 1.24 mmol/l completed a double-blind, randomized, crossover trial comparing 8 weeks of cerivastatin therapy (800 microg of nocte) with placebo. Forearm vascular resistance (FVR) responses to intrabrachial-arterial infusions of ACH (3-24 microg/min), nitroprusside (2-16 microg/min), the nitric oxide(NO) synthase inhibitor l-nitro-mono-methyl arginine (l-nmma) (8 micromol/min), ACH during l-NMMA infusion and BP responses to intravenous infusions of AII (12.5-50 ng/min) and NA (20-400 ng/min) were measured at the end of each treatment period. Twenty-four-hour ambulatory BP recordings were also performed. RESULTS: FVR responses to ACH during l-NMMA infusion were significantly (p = 0.026) greater during cerivastatin than during placebo therapy. In contrast, FVR responses to ACH in the absence of NO synthase inhibition did not differ significantly between cerivastatin and placebo therapies (p = 0.81). FVR increased by 31.4 +/- 57.3% in response to l-NMMA infusion during cerivastatin therapy compared with 6.1 +/- 41.2% during placebo therapy (p = 0.20). FVR responses to nitroprusside did not differ between cerivastatin and placebo therapies (p = 0.28), nor did BP responses to AII (systolic BP, p = 0.99; diastolic BP, p = 0.98) or NA (systolic BP, p = 0.21; diastolic BP, p = 0.48). Mean 24-h BP was similar during cerivastatin (123 +/- 10 or 70 +/- 7 mmHg) and placebo therapies (129 +/- 11 or 74 +/- 7 mmHg) (systolic BP, p = 0.26; diastolic BP, p = 0.41). CONCLUSION: Cerivastatin increases FVR responses to ACH in type 2 diabetic men with mild dyslipidaemia but only following NO synthase inhibition. This may indicate an improvement in endothelium-derived hyperpolarizing factor-mediated responses.     

Reduced quinidine clearance in elderly persons.

The influence of age on quinidine pharmacokinetics was assessed in 22 healthy male and female volunteers; 14 of the subjects were young (aged 23 to 34 years) and 8 elderly (aged 60 to 69 years). All subjects received 180 to 300 mg of quinidine base by constant rate intravenous infusion over 10 to 15 minutes. The concentration of total and unbound quinidine in multiple serum samples and in urine collected within 48 hours after the administration of quinidine qas determined with spectrophotofluorometric assay. Mean kinetic values for total quinidine in the young subjects were: elimination half-life (t 1/2 beta), 7.3 hours; total volume of distribution (Vd), 2.39 liters/kg; total clearance, 4.04 ml/min per kg; renal clearance 1.43 ml/min per kg; and percent unbound, 24.6 In the elderly subjects, the values for Vd (2.18 liters/kg) and percent unbound (28.2) did not differ significantly from these values in the young subjects. However, in the elderly subjects t 1/2 beta was significantly longer (9.7 hours, P less than 0.05) and total quinidine clearance significantly less (2.64 ml/min per kg, P less than 0.005) than in the young subjects. Renal clearance of quinidine in the elderly was also significantly less (0.99 ml/min per kg, P less than 0.05) than in the young and was associated with lower rates of creatinine clearance in the elderly (r = 0.66). Reduced clearance of quinidine and prolongation of its elimination half-life could predispose to toxicity in the elderly unless the dose were appropriately adjusted.     

Abnormal left ventricular filling in patients with sustained myocardial relaxation: Assessment of diastolic parameters using radionuclide angiography and echocardiography

Parameters of left ventricular filling obtained from time-activity curves of radionuclide angiograms were compared with parameters of myocardial relaxation from digitized M-mode curves of the free wall endocardium in 25 consecutive patients. Eight patients had normal left ventricular systolic and diastolic function. Five patients with low ejection fraction (EF < 50%) also had abnormal values of peak filling rate (PFR), time to peak filling rate (T_r), and/or time constant of endocardial retraction (T_e). Twelve patients with normal EF had three (40%), two (40%), or one (20%) of the diastolic parameters within the pathological range. T_r correlated significantly with T_e (r=0.88, p<0.001), and patients with T_e prolongation always had high values of T_r. One of the diastolic parameters (PFR) correlated significantly with EF (r=0.60, p<0.01). Parameters of left ventricular filling and myocardial relaxation are thus abnormal in many patients with normal systolic function, indicating that diastolic parameters may be more sensitive to myocardial deterioration.     

Course of ejection fraction, regurgitation fraction and ventricular volumes during exertion in chronic aortic insufficiency. Study using technetium 99m gamma-cineangiography

Previous studies have shown that variations of the ejection fraction (EF) during exercise were representative of the contractile state of the left ventricle: an increased EF on effort is considered to be physiological, whilst a decrease would indicate latent LV dysfunction unmasked during exercise. This hypothesis was tested by performing Technetium 99 gamma cineangiography at equilibrium under basal conditions and at maximal effort in 8 healthy subjects and 44 patients with pure, severe aortic regurgitation to measure the ejection and regurgitant fractions and the variations in end systolic and end diastolic LV volume. In the control group the EF increased and end systolic volume decreased significantly on effort whilst the regurgitant fraction and end diastolic volume were unchanged. In the 44 patients with aortic regurgitation no significant variations in EF, end systolic and end diastolic volumes were observed because the individual values were very dispersed. Variations of the EF and end systolic volume were inversely correlated. The regurgitant fraction decreased significantly on effort. Based on the variations of the EF and end systolic volume three different types of response to effort could be identified: in 7 patients, the EF increased on effort and end systolic volume decreased without any significant variation in the end diastolic volume, as in the group of normal control subjects; in 22 patients, a reduction in EF was observed on effort, associated with an increased end systolic volume. These changes indicated latent IV dysfunction inapparent at rest and unmasked by exercise; in a third group of 15 patients, the EF decreased on effort despite a physiological decrease in end systolic volume due to a greater decrease in end diastolic volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Acute Intravenous Infusion of Apelin on Left Ventricular Function in Dogs With Advanced Heart Failure

BackgroundApelin-13 (APLN) through apelin receptor (APJ) exerts peripheral vasodilatory and potent positive inotropic effects. We examined the effects of exogenous intravenous infusion of APLN on left ventricular (LV) systolic function in dogs with heart failure (HF, LV ejection fraction, EF～30%).Methods and ResultsStudies were performed in 7 dogs with microembolization-induced HF. Each dog received an intravenous infusion of low dose and high dose APLN followed by washout period. LV end-diastolic volume (EDV), end-systolic volume (ESV) and LV EF were measured at specified time points. APLN protein level was determined in plasma at all time points. mRNA and protein levels of APLN and APJ in LV tissue were also measured in 7 normal (NL) and 7 heart failure (HF) dogs. APLN reduced EDV only at the high dose, significantly reduced ESV and increased EF with both doses. In plasma of HF dogs, APLN levels were reduced significantly compared to NL dogs. APLN treatment in HF dogs significantly increased the plasma APLN levels at both low and high doses. Expression of APLN, but not of APJ, was reduced in LV tissue of HF dogs compared to NL.ConclusionsExogenous administration of APLN improved LV systolic function in dogs with advanced HF.     

Comparative influence of ouabain,norepinephrine and heart rate on myocardial oxygen consumption and inotropic state in dogs

The purpose of this study was to compare the myocardial oxygen cost of augmented inotropic state produced by ouabain, norepinephrine, or increased heart rate. This problem was examined in dogs using an isovolumically contracting left ventricular preparation. Inotropic state was measured as the maximum observed contractile element velocity at the lowest common level of wall stress (MAX V). Peak left ventricular wall stress was maintained constant in each dog so that it would not influence changes in myocardial oxygen consumption (MVO₂). Ouabain (4 × 10² μmoles/Kg.) and norepinephrine (2 × 10³ μmoles/Kg./minute) always augmented inotropic state (MAX V) and increased MVO₂. The positive slopes of the regression of MVO₂ on MAX V for ouabain (45.4 ± 12.5 μl/beat/100 Gm./muscle length/sec; mean ± SEM) and norepinephrine (34.5 ± 5.6 μl/beat/100 Gm./muscle length/sec; mean ± SEM) were not significantly different, indicating that for an equal augmentation of inotropic state, ouabain increases myocardial oxygen demands to the same extent as does norepinephrine. When the results with ouabain or norepinephrine were compared to results obtained by altering heart rate, it was found that increasing inotropic state by these pharmacologic agents is more costly in terms of myocardial energy demands than when inotropic state is enhanced by increasing heart rate.