Cardiopulmonary Receptor and Arterial Baroreceptor Reflexes After Acute Myocardial Infarction Guido Grassi, MD, Cristina Giannattasio, MD, Gino Seravalle, MD, Giuseppe Osculati, MD, Franc0 Valagussa, MD, Albert0 Zanchetti, MD, and Giuseppe Mancia, MD
The baroreceptor-heart rate reflex in human is impaired 2 days after a myocardiai infarction but it improves 10 days after the acute coronary event. This study investigated whether (1) the baroreceptor-heart rate reflex improvement takes the reflex back to normal, and (2) the cardiopulmonary reflex is affected by myocardial infarction. In subjects studied 8 to 11 days after a transmurai anterior or inferior myocardiai infarction the baroreceptor-heart rate reflex sensitivity (slope of the linear regression between negative neck chamber pressures and lengthenings in RR interval) was similar to that seen in control subjects (-6.2 f 0.8 vs -6.0 f 0.6 ms/mm Hg, mean f SEM) and did not change when reassessed 10 days later. In contrast, the cardiopulmonary reflex sensitivity (changes in forearm vascular resistance induced by changing central venous pressure through nonhypotensive lower body suction and leg raising) was markedly less in subjects studied 8 to 11 days after myocardiai infarction than in control subjects; the reduction amounted to 58.1 f 8% (p 1 hour) chest pain and by standard electrocardiographic and laboratory criteria. No patient had evidenceof a previous myocardial infarction, and none had a history of high blood pressure,diabetes,autonomic neuropathy, renal damage or other major cardiovascular diseases.The presenceof heart failure was excluded by the absenceof breathlessness,pulmonary rales, third heart sound and signs of pulmonary hypertension and cardiac enlargement on chest radiography. Left ventricular end-diastolic diameter measuredby echocardiography was always 65 mm. When admitted to the coronary care unit, patients with myocardial infarction received morphine sulphate, intravenous nitroglycerin, streptokinaseor heparin, or a combination of these.Calcium antagonists,/3 blockers and nitrates were given accordingly to the clinical needsbut, with the exception of aspirin, drugs with major cardiovascular action were withdrawn during the 48 hours preceding the first or From the Clinica Medica Generale and Cattedra di Medicina Intema, second baroreflex and cardiopulmonary reflex study Universita di Milano, Milano; CkpedaleMa&ore, Milano; CkpedaleS. (see later). Gerardo, Monza; and Centro Auxologico Italiano, Milano, Italy. ManThirty-four hospitalized patients of either sex were uscript received March 8, 1991; revised manuscript received and actaken as control subjects.The subjects were selectedif cepted December 2,199 1. Address for reprints: Giuseppe Mancia, MD, Centro Fisiologia there were no major systemic and cardiovascular disClinica e Ipertensione,Via F. Sforza 35, 20122 Milano, Italy.
eases and if there was none of the aforementioned con-
CARDIOVASCULAR REFLEXES AND MYOCARDIAL INFARCTION
873
ditions affecting autonomic cardiovascular control. All subjects gave their informed consent to the study and the protocol was approved by the ethical committee of our institution. Evaluation of the carotid baroreflex: The carotid baroreceptor control of heart rate was studied by the neck chamber technique that allows one to produce a negative pressure around the neck, increasing carotid transmural pressure and selectively stimulating carotid baroreceptors.I2913The study was performed in 30 patients with a myocardial infarction (age 52 f 1 year, range 41 to 64) and in 24 control subjects (age 50 f 1 year, range 39 to 64) 8 to 11 days after the coronary event and the hospitalization (mean 10 f 1 and 10 f 1 days), respectively, and after 1 week of mobilization in the semi-intensive care ward. In 24 patients with myocardial infarction, the baroreflex was reassessed18 to 22 days (mean 21 f 1) after the coronary event and following discharge from the hospital without any physical rehabilitation program. In each experimental session the negative pressure was applied in 6 separate stepsof lo-second duration, ranging in magnitude from -7 to -40 mm Hg. Each step was repeated3 times and the stepswere applied in a random order and separated from each other by 2 minutes. Baroreceptor deactivation by positive neck chamber pressurewas not pursued becausethe procedure was disturbing to the patients. During the experimental session,the pressurewithin the collar was measured by a Statham transducer (model P23 ID, Gould Statham, Hato Rey, Puerto Rico). Blood pressurewas measuredby a sphygmomanometer using the first and fifth Korotkoff sounds to identify systolic and diastolic blood pressure,respectively. Heart rate was measured by a cardiotachometer triggered by the R wave of an electrocardiographiclead. The neck pressureand heart rate signals were recorded on a Grass Polygraph (Grass Instruments, Quincy, Massachusetts),which also displayed the electrocardiographic signal to allow precisemeasurementsof the RR interval. Evaluation of the cardiopulmonary reffex: Cardiopulmonary receptors were (1) stimulated by increasing central venouspressurethrough passiveelevation of legs to 60°2; and (2) deactivated by reducing central venous pressure through application, with a lower body negative device, of a negative pressureso mild (approximately -15 mm Hg) as to have little effect on blood pressure and heart rate and thus modify arterial baroreceptor activity to only a minor degree.2A more marked lower body negative pressurewas also applied (approximately -35 mm Hg) to cause a reduction in blood pressure,deactivate both cardiopulmonary and arterial baroreceptors and thus simulate the concomitant engagement of these homeostatic mechanismsin physiological conditions (e.g., orthostatic stress). The study was performed in 12 patients with myocardial infarction (aged 52 f 2 years, range 34 to 63) and in 12 control subjects (aged 50 f 2 years, range 39 to 65) 9 to 13 days after the acute coronary event and hospitalization (mean 11 f 1 and 10 f 1 days), respectively,and after 1 week of mobilization in the semintensivecare ward. In 874
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
7 patients with myocardial infarction, the cardiopulmonary reflex was reassessed28 to 45 days (mean 37 f 10) after the coronary event and following discharge from the hospital without any physical rehabilitation program. In each experimental sessionthe stimuli were applied randomly and maintained for 5 minutes. Each stimulus was separatedfrom the preceding one by a lominute interval. Sevenpatients with myocardial infarction and 7 control patients also participated in the baroreflex study. During the experimental sessionarterial blood pressure and heart rate were measuredas describedfor the baroreflex study. The pressurewithin the box was measured by a Statham transducer (P23 ID, Gould Statham, Hato Rey, Puerto Rico). Central venous pressure was measuredby a catheter placed in or near the right atrium from an antecubital vein of the arm used for blood pressure measurementsand also connected to a Statham transducer. Forearm blood flow was measured by venous occlusion plethysmography (Hokanson EC4, Issaqua, Washington), using the forearm other than that measured for blood pressure. The measurements were performed as described in previous studies.4Jv7J Forearm vascular resistancewas derived from the ratio betweenmean arterial pressure(diastolic blood pressure plus % third of pulse pressure)and forearm blood blow. Blood pressure,heart rate, forearm blood flow and forearm vascular resistancewere measuredalso before and during l-minute immersion of 1 hand in ice water (4OC) to determine the hemodynamic responsesto a neurogenic stimulus different from that originating from cardiopulmonary receptors. Data were calculated by an investigator unaware of the experimental design. Baseline values were obtained by averaging the measurementsbefore the various stimuli. The responseto neck pressureapplication was calculated by taking the maximal lengthening of RR interval over the 3 beats following the onset of the stimulus, i.e. over a time interval still devoid of blood pressure effects.14Data from the 3 stimuli of similar magnitude were averagedand the slope of the linear regressionof RR interval on neck pressurechangeswas taken as the carotid baroreflex sensitivity. The response to lower body negative pressure,leg raising and cold pressortest was calculated by taking the values of the last minute of the stimulus. Forearm blood flow (and vascular resistance) was always derived from the averageof 3 consecutive values. Individual data were averagedseparatelyfor the patients with myocardial infarction and control subjectsto obtain the means (& SE) for the 2 groups. The differencesbetweenmean data were analyzed by the t test for unpaired (myocardial infarction vs control patients) or paired (first vs second study) observations. Relationships betweenvariables were assessedby linear regression analysis. A p value
The baroreceptor-heart rate reflex in human is impaired 2 days after a myocardiai infarction but it improves 10 days after the acute coronary event. This study investigated whether (1) the baroreceptor-heart rate reflex improvement takes the reflex back to normal, and (2) the cardiopulmonary reflex is affected by myocardial infarction. In subjects studied 8 to 11 days after a transmurai anterior or inferior myocardiai infarction the baroreceptor-heart rate reflex sensitivity (slope of the linear regression between negative neck chamber pressures and lengthenings in RR interval) was similar to that seen in control subjects (-6.2 f 0.8 vs -6.0 f 0.6 ms/mm Hg, mean f SEM) and did not change when reassessed 10 days later. In contrast, the cardiopulmonary reflex sensitivity (changes in forearm vascular resistance induced by changing central venous pressure through nonhypotensive lower body suction and leg raising) was markedly less in subjects studied 8 to 11 days after myocardiai infarction than in control subjects; the reduction amounted to 58.1 f 8% (p 1 hour) chest pain and by standard electrocardiographic and laboratory criteria. No patient had evidenceof a previous myocardial infarction, and none had a history of high blood pressure,diabetes,autonomic neuropathy, renal damage or other major cardiovascular diseases.The presenceof heart failure was excluded by the absenceof breathlessness,pulmonary rales, third heart sound and signs of pulmonary hypertension and cardiac enlargement on chest radiography. Left ventricular end-diastolic diameter measuredby echocardiography was always 65 mm. When admitted to the coronary care unit, patients with myocardial infarction received morphine sulphate, intravenous nitroglycerin, streptokinaseor heparin, or a combination of these.Calcium antagonists,/3 blockers and nitrates were given accordingly to the clinical needsbut, with the exception of aspirin, drugs with major cardiovascular action were withdrawn during the 48 hours preceding the first or From the Clinica Medica Generale and Cattedra di Medicina Intema, second baroreflex and cardiopulmonary reflex study Universita di Milano, Milano; CkpedaleMa&ore, Milano; CkpedaleS. (see later). Gerardo, Monza; and Centro Auxologico Italiano, Milano, Italy. ManThirty-four hospitalized patients of either sex were uscript received March 8, 1991; revised manuscript received and actaken as control subjects.The subjects were selectedif cepted December 2,199 1. Address for reprints: Giuseppe Mancia, MD, Centro Fisiologia there were no major systemic and cardiovascular disClinica e Ipertensione,Via F. Sforza 35, 20122 Milano, Italy.
eases and if there was none of the aforementioned con-
CARDIOVASCULAR REFLEXES AND MYOCARDIAL INFARCTION
873
ditions affecting autonomic cardiovascular control. All subjects gave their informed consent to the study and the protocol was approved by the ethical committee of our institution. Evaluation of the carotid baroreflex: The carotid baroreceptor control of heart rate was studied by the neck chamber technique that allows one to produce a negative pressure around the neck, increasing carotid transmural pressure and selectively stimulating carotid baroreceptors.I2913The study was performed in 30 patients with a myocardial infarction (age 52 f 1 year, range 41 to 64) and in 24 control subjects (age 50 f 1 year, range 39 to 64) 8 to 11 days after the coronary event and the hospitalization (mean 10 f 1 and 10 f 1 days), respectively, and after 1 week of mobilization in the semi-intensive care ward. In 24 patients with myocardial infarction, the baroreflex was reassessed18 to 22 days (mean 21 f 1) after the coronary event and following discharge from the hospital without any physical rehabilitation program. In each experimental session the negative pressure was applied in 6 separate stepsof lo-second duration, ranging in magnitude from -7 to -40 mm Hg. Each step was repeated3 times and the stepswere applied in a random order and separated from each other by 2 minutes. Baroreceptor deactivation by positive neck chamber pressurewas not pursued becausethe procedure was disturbing to the patients. During the experimental session,the pressurewithin the collar was measured by a Statham transducer (model P23 ID, Gould Statham, Hato Rey, Puerto Rico). Blood pressurewas measuredby a sphygmomanometer using the first and fifth Korotkoff sounds to identify systolic and diastolic blood pressure,respectively. Heart rate was measured by a cardiotachometer triggered by the R wave of an electrocardiographiclead. The neck pressureand heart rate signals were recorded on a Grass Polygraph (Grass Instruments, Quincy, Massachusetts),which also displayed the electrocardiographic signal to allow precisemeasurementsof the RR interval. Evaluation of the cardiopulmonary reffex: Cardiopulmonary receptors were (1) stimulated by increasing central venouspressurethrough passiveelevation of legs to 60°2; and (2) deactivated by reducing central venous pressure through application, with a lower body negative device, of a negative pressureso mild (approximately -15 mm Hg) as to have little effect on blood pressure and heart rate and thus modify arterial baroreceptor activity to only a minor degree.2A more marked lower body negative pressurewas also applied (approximately -35 mm Hg) to cause a reduction in blood pressure,deactivate both cardiopulmonary and arterial baroreceptors and thus simulate the concomitant engagement of these homeostatic mechanismsin physiological conditions (e.g., orthostatic stress). The study was performed in 12 patients with myocardial infarction (aged 52 f 2 years, range 34 to 63) and in 12 control subjects (aged 50 f 2 years, range 39 to 65) 9 to 13 days after the acute coronary event and hospitalization (mean 11 f 1 and 10 f 1 days), respectively,and after 1 week of mobilization in the semintensivecare ward. In 874
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
7 patients with myocardial infarction, the cardiopulmonary reflex was reassessed28 to 45 days (mean 37 f 10) after the coronary event and following discharge from the hospital without any physical rehabilitation program. In each experimental sessionthe stimuli were applied randomly and maintained for 5 minutes. Each stimulus was separatedfrom the preceding one by a lominute interval. Sevenpatients with myocardial infarction and 7 control patients also participated in the baroreflex study. During the experimental sessionarterial blood pressure and heart rate were measuredas describedfor the baroreflex study. The pressurewithin the box was measured by a Statham transducer (P23 ID, Gould Statham, Hato Rey, Puerto Rico). Central venous pressure was measuredby a catheter placed in or near the right atrium from an antecubital vein of the arm used for blood pressure measurementsand also connected to a Statham transducer. Forearm blood flow was measured by venous occlusion plethysmography (Hokanson EC4, Issaqua, Washington), using the forearm other than that measured for blood pressure. The measurements were performed as described in previous studies.4Jv7J Forearm vascular resistancewas derived from the ratio betweenmean arterial pressure(diastolic blood pressure plus % third of pulse pressure)and forearm blood blow. Blood pressure,heart rate, forearm blood flow and forearm vascular resistancewere measuredalso before and during l-minute immersion of 1 hand in ice water (4OC) to determine the hemodynamic responsesto a neurogenic stimulus different from that originating from cardiopulmonary receptors. Data were calculated by an investigator unaware of the experimental design. Baseline values were obtained by averaging the measurementsbefore the various stimuli. The responseto neck pressureapplication was calculated by taking the maximal lengthening of RR interval over the 3 beats following the onset of the stimulus, i.e. over a time interval still devoid of blood pressure effects.14Data from the 3 stimuli of similar magnitude were averagedand the slope of the linear regressionof RR interval on neck pressurechangeswas taken as the carotid baroreflex sensitivity. The response to lower body negative pressure,leg raising and cold pressortest was calculated by taking the values of the last minute of the stimulus. Forearm blood flow (and vascular resistance) was always derived from the averageof 3 consecutive values. Individual data were averagedseparatelyfor the patients with myocardial infarction and control subjectsto obtain the means (& SE) for the 2 groups. The differencesbetweenmean data were analyzed by the t test for unpaired (myocardial infarction vs control patients) or paired (first vs second study) observations. Relationships betweenvariables were assessedby linear regression analysis. A p value
