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Abrupt propranolol withdrawal: Effects on the determinants of myocardial oxygen consumption (MV̇O2) in man
ABSTRACTS
ABRUPT •PROPRANOLOL WITHDRAWAL: EFFECTS ON THE DETERMINANTS OF MYOCARDIAL OXYGEN CONSUMPTION (MVO 2) IN MAN JoAnnLindenfeldo MD; Michael Crawford, MD, FACC; Lawrence Horwitz, MD, FACC and Robert O'Rourke, MD, FACC. University of Texas Health Science Center and Veterans AdminiStratiOn Hospital, San Antonio, Texas. Controversy exists regarding the mechanism for the observed increase in clinical symptoms following the abrupt withdrawal of propranolol (P) in some patients (pts) with ischemic heart disease. Therefore, we performed serial studies in I0 normal subjects before, during and after the oral administration of 160 mg ~f P daily for two weeks. The table below details the basal heart rate (HR); the peak HR and HR-systolic blood pressure (SBP) product during maximum supine bicycle exercise; and t h e p e a k plasma free fatty acids (FFA)after intravenous epinephrine (0.I mg/kg/min x 5 min) before, during and after P (mean ± SE): Basal HR Peak HR HRxSBP FFA (beats/min) (beats/min) (xl03) (uEg/l) Pre P 59±4 150±5 27.3±1.4 800±70 During P 50±2+ 112±4" 17.0±1.0" 522±43" 48 hr post P 58i2 147±6 26.1±1.7 702±68 96 hr post P 60±2 153±5 27.8±1.5 791±68 * = p< 0.001 and + = p<0.01 for paired comparison to the pre P value Echocardiography at rest and during exercise showed an increase in LV end-diastolic dimension on P and a decrease in percent dimensional shortening during systole. These measures returned to their control values post P and no further increase in percent shortening was observed. Thus, in the 96 hrs after P withdrawal there was no augmentation in the metabolic response to epinephrine nor the determinants of MVO 2 at rest or during exercise, which strongly suggests that adverse clinical reactions to abrupt P withdrawal are not due to a physiologic "rebound" mechanism.
EFFECT OF VERAPAMIL ON MYOCARDIAL PERFORMANCE IN CORONARY DISEASE Jack Ferlinz.MD, FACC; John L. Easthope,MD;Wilbert S. Aronow,MD, FACC; Long Beach Veterans Administration Hospital and University of California,Irvine A new experimental drug,verapamil (V),has been shown to have potent antiarrhythmicproperties. Because V acts by blocking calcium transport through the slow channel,it has been feared that it will simultaneously depress myocardial performance in cardiac patients (pts). To investigate this possibility,20 pts with coronary artery disease (CAD) but no heart failure weregiven intra-
~e~o~ v (0.I ~/kg bolu~,fono~d by 0.00~ ~g/~g/ minute infusion),and studied with a combined hemodynamicangiographic approach. V markedly lowered mean aortic pressure (94 2 17 to 82 f 13 mm Hg, P < 0.0005) and systemic vascular resistance (i,413 ~ 429 to 1,069 235 dynes sec cm-5, P < 0.0005). Simultaneously,all• indices of left ventricular (LV) performance greatly improved: cardiac index rose from 2.8 2 0.6 to 3.1 2 0.7 1/min/m 2 (P
•HEMODYNAMIC EFFECTS OF NIFEDIPINE AFTER AN•ACUTE MYOCARDIAL INFARCTION Jean-Claude Debaisieux~ MD; Pierre Th@roux, MD, FACC; David D. Waters, MD, FACC; Henry F. Mizgala, MD, FACC, Montreal Heart Institute, Montreal, Quebec
NITROGLYCERIN EFFECTS ON INTRACRANIALPRESSURE Mark C. Rogers, M.D. ; Richard J. Traystman, Ph. D. and Mel H. E p s t e i n , M,D., Johns Hopkins Medical I n s t i t u t i o n s Baltimore, Maryland
Calcium antagonist drugs are increasingly used for the treatment of coronary artery disease, yet their hemodynamic effects in man have not yet been completely defined. Therefore, after obtaining informed consent, the effect of a single 20 mg oral dose of nifedipine was studied in 21 patients in stable clinical condition three days after an acute myocardial infarction before withdrawal of SwanGanz and intra-arterial catheters. Hemodynamic effects were detectable between 15 min and 2 hours after ingestion. Peak effect occurred at 30 min and consisted in a fall in mean arterial blood pressure from 81±12 (SD) to 71±i0 mmHg (p<0.02) and in peripheral vascular resistance from 1471±387 to 1175±278 dynes/sec/cm -5 (p<0.01)' Cardiac index (CI) rose from 2.7±0.6 L/mi~/m 2 to 3±0.6 (NS) and heart rate from 77±15 to 82±15 (NS). Pulmonary diastolic pressure was unchanged from 12±3 mmHg. CI increased by a mean of 20% (p<0.05) in 8 of the 9 pts with a control CI less than 2.5 L/min/m 2 but in 8 of the 12 pts with a control CI above 2.5 L/min/m 2 CI was unchanged No untoward side effects were noted except for facial flush in 2 pts and mild gastrointestinal complaints in 2 others We conclude that the predominanthemodynamic effect of oral nifedipine is an arteriolar vasodilatat•ion without detectable primary effect on heart rate, left ventricular filling pressure or the inotropic state of the left ventricle. Beneficial effects were found in patients with impaired left ventricular function.
Alterations in intracranial pressure (ICP) associated with nitrogylcerin (NTG) are unknown. The ability .•to dilate cranial vessels and produce increased ICP in the face of systemic hypotension is a potential property of NTG which needs to be documented. In 48 observations in 8 cats •, intravenous NTG produced a significant increase in ICP. All animals were ventilated and maintained at a pC02 of 40~3 torr, a pH of 7.42±.04, and a pO2 of greater than 90 torr. Temperature was kept at 37+0.5"C. In 17 observations, lowering mean systemic blood,pressure (BP)from control (90.4~6.3 torr) by a total of 30.3+7.4 torr resulted in a significant increase in ICP from control (9.8~2.9 torr) to 19.9 + 4.6 t orr (p<.01). In 14 observations smaller decreases in BP of 21.4+6.8 torr also resulted in dramatic increases in ICP from control (8.0+_3.2 torr) to 18.3~4.•2 torr (p<.01). Even a mild drop in B P of only 12.4 ~ 3.6 torr from control resulted in a significant increase in ICP from control (7.4 + 2.1 torr) to 12.3 £ 2.1 torr (p<.05). T h e elevations in ICP remained 1-3 minutes after BP returned to control. Observations in the dog confirm these ICP results and show marked increases in carotid blood flow •and little change in cerebral blood flow with NTG administration. These changes also occur with sublingual NTG and document the potential for pathologic ICP elevation (>30 torr) with NTG. Increased ICP appears to be a complication of NTG administration which must be considered in its use.
342
February 1979
The American journal of CARDIOLOGY
Volume 43
ABRUPT •PROPRANOLOL WITHDRAWAL: EFFECTS ON THE DETERMINANTS OF MYOCARDIAL OXYGEN CONSUMPTION (MVO 2) IN MAN JoAnnLindenfeldo MD; Michael Crawford, MD, FACC; Lawrence Horwitz, MD, FACC and Robert O'Rourke, MD, FACC. University of Texas Health Science Center and Veterans AdminiStratiOn Hospital, San Antonio, Texas. Controversy exists regarding the mechanism for the observed increase in clinical symptoms following the abrupt withdrawal of propranolol (P) in some patients (pts) with ischemic heart disease. Therefore, we performed serial studies in I0 normal subjects before, during and after the oral administration of 160 mg ~f P daily for two weeks. The table below details the basal heart rate (HR); the peak HR and HR-systolic blood pressure (SBP) product during maximum supine bicycle exercise; and t h e p e a k plasma free fatty acids (FFA)after intravenous epinephrine (0.I mg/kg/min x 5 min) before, during and after P (mean ± SE): Basal HR Peak HR HRxSBP FFA (beats/min) (beats/min) (xl03) (uEg/l) Pre P 59±4 150±5 27.3±1.4 800±70 During P 50±2+ 112±4" 17.0±1.0" 522±43" 48 hr post P 58i2 147±6 26.1±1.7 702±68 96 hr post P 60±2 153±5 27.8±1.5 791±68 * = p< 0.001 and + = p<0.01 for paired comparison to the pre P value Echocardiography at rest and during exercise showed an increase in LV end-diastolic dimension on P and a decrease in percent dimensional shortening during systole. These measures returned to their control values post P and no further increase in percent shortening was observed. Thus, in the 96 hrs after P withdrawal there was no augmentation in the metabolic response to epinephrine nor the determinants of MVO 2 at rest or during exercise, which strongly suggests that adverse clinical reactions to abrupt P withdrawal are not due to a physiologic "rebound" mechanism.
EFFECT OF VERAPAMIL ON MYOCARDIAL PERFORMANCE IN CORONARY DISEASE Jack Ferlinz.MD, FACC; John L. Easthope,MD;Wilbert S. Aronow,MD, FACC; Long Beach Veterans Administration Hospital and University of California,Irvine A new experimental drug,verapamil (V),has been shown to have potent antiarrhythmicproperties. Because V acts by blocking calcium transport through the slow channel,it has been feared that it will simultaneously depress myocardial performance in cardiac patients (pts). To investigate this possibility,20 pts with coronary artery disease (CAD) but no heart failure weregiven intra-
~e~o~ v (0.I ~/kg bolu~,fono~d by 0.00~ ~g/~g/ minute infusion),and studied with a combined hemodynamicangiographic approach. V markedly lowered mean aortic pressure (94 2 17 to 82 f 13 mm Hg, P < 0.0005) and systemic vascular resistance (i,413 ~ 429 to 1,069 235 dynes sec cm-5, P < 0.0005). Simultaneously,all• indices of left ventricular (LV) performance greatly improved: cardiac index rose from 2.8 2 0.6 to 3.1 2 0.7 1/min/m 2 (P
•HEMODYNAMIC EFFECTS OF NIFEDIPINE AFTER AN•ACUTE MYOCARDIAL INFARCTION Jean-Claude Debaisieux~ MD; Pierre Th@roux, MD, FACC; David D. Waters, MD, FACC; Henry F. Mizgala, MD, FACC, Montreal Heart Institute, Montreal, Quebec
NITROGLYCERIN EFFECTS ON INTRACRANIALPRESSURE Mark C. Rogers, M.D. ; Richard J. Traystman, Ph. D. and Mel H. E p s t e i n , M,D., Johns Hopkins Medical I n s t i t u t i o n s Baltimore, Maryland
Calcium antagonist drugs are increasingly used for the treatment of coronary artery disease, yet their hemodynamic effects in man have not yet been completely defined. Therefore, after obtaining informed consent, the effect of a single 20 mg oral dose of nifedipine was studied in 21 patients in stable clinical condition three days after an acute myocardial infarction before withdrawal of SwanGanz and intra-arterial catheters. Hemodynamic effects were detectable between 15 min and 2 hours after ingestion. Peak effect occurred at 30 min and consisted in a fall in mean arterial blood pressure from 81±12 (SD) to 71±i0 mmHg (p<0.02) and in peripheral vascular resistance from 1471±387 to 1175±278 dynes/sec/cm -5 (p<0.01)' Cardiac index (CI) rose from 2.7±0.6 L/mi~/m 2 to 3±0.6 (NS) and heart rate from 77±15 to 82±15 (NS). Pulmonary diastolic pressure was unchanged from 12±3 mmHg. CI increased by a mean of 20% (p<0.05) in 8 of the 9 pts with a control CI less than 2.5 L/min/m 2 but in 8 of the 12 pts with a control CI above 2.5 L/min/m 2 CI was unchanged No untoward side effects were noted except for facial flush in 2 pts and mild gastrointestinal complaints in 2 others We conclude that the predominanthemodynamic effect of oral nifedipine is an arteriolar vasodilatat•ion without detectable primary effect on heart rate, left ventricular filling pressure or the inotropic state of the left ventricle. Beneficial effects were found in patients with impaired left ventricular function.
Alterations in intracranial pressure (ICP) associated with nitrogylcerin (NTG) are unknown. The ability .•to dilate cranial vessels and produce increased ICP in the face of systemic hypotension is a potential property of NTG which needs to be documented. In 48 observations in 8 cats •, intravenous NTG produced a significant increase in ICP. All animals were ventilated and maintained at a pC02 of 40~3 torr, a pH of 7.42±.04, and a pO2 of greater than 90 torr. Temperature was kept at 37+0.5"C. In 17 observations, lowering mean systemic blood,pressure (BP)from control (90.4~6.3 torr) by a total of 30.3+7.4 torr resulted in a significant increase in ICP from control (9.8~2.9 torr) to 19.9 + 4.6 t orr (p<.01). In 14 observations smaller decreases in BP of 21.4+6.8 torr also resulted in dramatic increases in ICP from control (8.0+_3.2 torr) to 18.3~4.•2 torr (p<.01). Even a mild drop in B P of only 12.4 ~ 3.6 torr from control resulted in a significant increase in ICP from control (7.4 + 2.1 torr) to 12.3 £ 2.1 torr (p<.05). T h e elevations in ICP remained 1-3 minutes after BP returned to control. Observations in the dog confirm these ICP results and show marked increases in carotid blood flow •and little change in cerebral blood flow with NTG administration. These changes also occur with sublingual NTG and document the potential for pathologic ICP elevation (>30 torr) with NTG. Increased ICP appears to be a complication of NTG administration which must be considered in its use.
342
February 1979
The American journal of CARDIOLOGY
Volume 43