Cardiovascular adaptation to orthostatic stress during vasodilator therapy.

BACKGROUND: Orthostatic hypotension is a dangerous problem in elderly patients, often exacerbated by vasodilator medications. Age- and disease-related impairments in cardioacceleration and diastolic ventricular function may make older patients particularly vulnerable to the hypotensive effects of these drugs. Therefore we aimed to determine mechanisms of postural blood pressure regulation in elderly patients with coronary artery disease and to compare the effects of isosorbide dinitrate and nicardipine hydrochloride on postural blood pressure homeostasis in these patients. METHODS: Twenty elderly subjects with stable coronary artery disease (age, 76 +/- 4 [SD] years) underwent a baseline evaluation followed by a double-blind, randomized crossover comparison of nicardipine (20 mg by mouth t.i.d.) versus isosorbide (20 mg by mouth t.i.d.). Doppler echocardiography and a 15-minute 60-degree head-up tilt test were conducted on no study medications and then after successive 3-week treatment periods with nicardipine or isosorbide. Blood pressure, heart rate, vascular resistance, cardiac output, and spectral characteristics of heart rate and blood pressure variability were measured before and during each tilt. RESULTS: Isosorbide treatment was associated with a higher prevalence of symptoms of cerebral hypoperfusion and a failure to increase systemic vascular resistance during tilt. While taking isosorbide subjects were able to preserve cardiac output and maintain upright blood pressure through enhanced cardioacceleration. During nicardipine treatment systemic vascular resistance and low-frequency blood pressure variability were reduced, but the ability to increase systemic vascular resistance during tilt was preserved. CONCLUSIONS: Although nicardipine may decrease vascular responsiveness to sympathetic activation, the baroreflex-mediated vasoconstrictor response to upright tilt remains intact. In contrast, isosorbide impairs the systemic vascular response to orthostatic stress in elderly patients with stable coronary artery disease.

Effects of chronic estrogen replacement therapy on beat-to-beat blood pressure dynamics in healthy postmenopausal women.

Recent data showing gender differences in autonomic control of heart rate and acute estrogen effects on vasodilatation suggest that estrogen may influence autonomic regulation of heart rate and blood pressure. We aimed to determine the effect of postmenopausal estrogen replacement therapy on autonomic control of beat-to-beat heart rate and blood pressure dynamics. Subjects included 20 healthy postmenopausal women aged 60 to 75 years with normal exercise tolerance tests, 10 of whom were taking oral estrogen for 13 +/- 3 (+/- SEM) years. Six healthy premenopausal women were also studied. Continuous electrocardiographic and noninvasive radial artery blood pressure measurements and intermittent forearm blood flow recordings (by venous-occlusion plethysmography) were obtained before and after a 20-minute, 60 degrees head-up tilt and a 420-kcal meal during periods of spontaneous and metronomic breathing (at 0.25 Hz). Low-frequency (0.01- to 0.15-Hz) and high-frequency (0.15- to 0.50-Hz) heart rate and blood pressure spectral powers were compared with a fast Fourier transform. Cardiovascular and heart rate spectral power responses to upright tilt and meal digestion were the same in postmenopausal estrogen users and nonusers. However, during spontaneous breathing the blood pressure spectral power responses to upright tilt and meal ingestion were significantly different between the two groups of women. The low-frequency systolic pressure power response to upright tilt was smaller in estrogen users than nonusers (P = .01). After meal ingestion nonusers had an early postprandial fall (20 to 30 minutes after the meal) and late rise (50 to 60 minutes) in low-frequency systolic and diastolic pressure powers, which were significantly attenuated in estrogen users (P < .02).(ABSTRACT TRUNCATED AT 250 WORDS)

Postprandial hypotension in elderly patients with unexplained syncope.

BACKGROUND: Syncope in older patients may be caused by a variety of disorders, including hypotension, but frequently remains unexplained. Postprandial hypotension is a common disorder of blood pressure regulation in the elderly. OBJECTIVE: To determine the pathogenic mechanisms and potential role of postprandial hypotension in elderly patients with otherwise unexplained syncope. METHODS: We studied 16 elderly patients with unexplained syncope and nine elderly controls. Blood pressure, heart rate, forearm vascular resistance, plasma norepinephrine level, and cardiac and splanchnic blood volumes were measured before and after a 1680-kJ meal. RESULTS: Eight elderly patients with syncope had postprandial hypotension, with a decline in supine mean arterial blood pressure of 17 +/- 2 mm Hg after a meal (P < .001). The blood pressure remained unchanged after the meal in the other patients with syncope and the controls. In patients with postprandial hypotension, systemic vascular resistance fell after the meal, while it remained unchanged in the other groups. Heart rate and plasma norepinephrine level increased to a similar extent in all three groups. Forearm vascular resistance increased only in the control subjects. Splanchnic blood volume increased by 26% (P < .01) in patients with syncope who had postprandial hypotension and by 22% (P < .01) in control subjects. Splanchnic blood volume remained unchanged in the patients with syncope without postprandial hypotension. CONCLUSIONS: Postprandial hypotension may be an important causative factor in elderly patients with unexplained syncope. The evaluation of syncope in elderly patients should therefore include blood pressure measurements surrounding a meal. Elderly patients with syncope who have postprandial hypotension fail to maintain systemic vascular resistance, probably because of splanchnic blood pooling without a compensatory increase in peripheral vascular resistance.

Muscle strength and fall rates among residents of Japanese and American nursing homes: an International Cross-Cultural Study.

OBJECTIVE: In Western society, aging if often associated with adoption of a sedentary lifestyle and associated disuse muscle atrophy and weakness. Recent studies suggest a relationship between quadriceps muscle weakness and falls in elderly residents of US nursing homes (NHs). We hypothesized that fall rates would be lower in Japanese NHs, where lifestyle differences such as squatting to toilet or sleeping on the floor may maintain quadriceps strength and result in fewer falls. Therefore, we examined the relationships between falls, muscle strength, lifestyle, and other clinical characteristics in residents of a Japanese and an American NH. DESIGN: Cross-culture, prospective, cohort study. MEASUREMENTS: We evaluated disease histories and current medications, quadriceps strength, and mobility of ambulatory American (n = 76) and Japanese (n = 89) NH residents, then followed these residents prospectively for the development of falls. Project staff from both sites trained together to assure uniform data ascertainment. MAIN RESULTS: During a 6-month follow-up period, fall rates were nearly 4-fold higher in the American than in the Japanese residents (49% vs 13%, respectively; P < 0.0001). In the American sample, fall rates declined with increasing muscle strength, while in Japan there was no relationship between fall rates and quadriceps strength. Residents also differed in number of medical diagnoses and use of medications, which were greater among American residents. The Japanese had slower gait speeds. Very few Japanese residents practiced squatting behaviors while living in the NH. CONCLUSIONS: The relationship between muscle weakness and falls is probably modified by multiple characteristics of the individual, their culture, and their environment. Information from cross-cultural studies may provide new insights into effective fall prevention strategies for nursing home residents.

Haemodynamic and neurohumoral effects of caffeine in elderly patients with symptomatic postprandial hypotension: a double-blind, randomized, placebo-controlled study.

1. The aim of this study was to determine the effects of caffeine on haemodynamic and neurohumoral responses to meal ingestion in elderly patients with a history of symptomatic postprandial hypotension. 2. Postprandial hypotension is a common disorder of blood pressure regulation in the elderly, associated with falls and syncope. The pathophysiological mechanism is thought to be related to impaired vascular compensation for splanchnic blood pooling after a meal. Since caffeine inhibits vasodilatory adenosine receptors in the splanchnic circulation, we postulated that caffeine would reduce splanchnic blood pooling and prevent the development of postprandial hypotension. 3. We conducted a randomized, double-blind, placebo-controlled, cross-over study in nine elderly patients [age 76 +/- 9 (SD) years] with histories of symptomatic postprandial hypotension. Standardized 1674kJ liquid meals with 250 mg of caffeine or placebo were given on two occasions, at least 1 week apart. Blood pressure, heart rate, forearm vascular resistance (by venous occlusion plethysmography), and plasma caffeine and catecholamine levels were measured. Cardiac and splanchnic blood volume were determined by radionuclide scans. 4. By 30 min after both caffeine and placebo meal studies, supine mean arterial blood pressure fell significantly (P = 0.006) by 31 +/- 7 and 19 +/- 6 mmHg, respectively (mean +/- SEM, between group difference was not significant). Heart rate, cardiac output and splanchnic blood volume increased significantly, but to a similar extent, after caffeine and placebo. Forearm vascular resistance was unchanged after both meals. 5. Oral caffeine given with a meal does not reduce splanchnic blood pooling nor prevent postprandial hypotension in symptomatic elderly patients.

Biomechanical properties of reperfused transmural myocardial infarcts in rabbits during the first week after infarction. Implications for left ventricular rupture.

Left ventricular (LV) rupture potential was studied after transmural myocardial infarction (MI) in rabbits by measuring 1) the tensile strength of infarcted tissue strips, 2) the force required to initiate a tear (tear threshold) in the central infarcted region, and 3) the intracavitary pressure required to rupture the infarcted ventricle. During the first week after MI, infarcts resulting from a permanent coronary occlusion were compared with infarcts reperfused "late" (i.e., 3 hours) after coronary occlusion with a resultant hemorrhagic transmural infarct but no reduction in infarct size. The reperfused hemorrhagic infarcted strips had less tensile strength than strips from permanently occluded infarcts in the initial 24 hours after MI (16 +/- 1 versus 24 +/- 3 g/mm2, p less than 0.05), but the tear threshold and response to increased LV pressure were not influenced by infarct reperfusion at this time. By 3 days after MI, reperfused infarcts had equal tensile strength, had greater resistance to infarct tearing, and could withstand a greater LV distending pressure compared with permanently occluded infarcts. By 5 days after MI, reperfused infarcts maintained a greater tear threshold but had less tensile strength than permanently occluded infarcts, although all infarct values were equivalent or greater than normal LV values. By 7 days after MI, reperfused and permanently occluded infarcts were equally strong by all measurements. Thus, late reperfusion of transmural infarcts increased resistance to infarct tearing and LV rupture above that of nonreperfused permanently occluded infarcts by 3 days after MI and enhanced tissue strength after an initial 24-hour vulnerable period. These findings suggest that late reperfusion may accelerate myocardial healing after MI.

Rapid expression of fibronectin in the rabbit heart after myocardial infarction with and without reperfusion.

The expression of fibronectin in the repair process after myocardial infarction was studied using two protocols of coronary occlusion in the rabbit: a permanent occlusion or 3 h of occlusion followed by reperfusion (too late for salvage). We found a rapid and progressive increase in cardiac fibronectin expression in the infarcted region of the ventricle. Steady-state mRNA levels for fibronectin increased 13- and 16-fold, respectively, in the permanent and reperfused infarcts 1 d postinfarction. Immunological detection of the protein with a polyclonal antibody against plasma fibronectin showed significant increases of the protein fibronectin in the infarcted myocardium by day 3 in the reperfused group and by day 5 in the permanent coronary occlusion group. Ribonuclease protection assays established the induction of EIIIB containing fibronectin mRNA in both models by day 1 and use of a monoclonal antibody showed an increase in the EIIIA isoform 2 d postinfarction. Increases in steady-state mRNA levels for several collagen types were found in both groups, but these changes occurred after those noted for fibronectin. Thus fibronectin mRNA and protein expression increased rapidly postinfarction suggesting a functional role in the repair process.

Reversible and irreversible elongation of ischemic, infarcted, and healed myocardium in response to increases in preload and afterload.

BACKGROUND: Left ventricular aneurysm formation after myocardial infarction (MI) has been associated with elongation of infarcted tissue in response to wall stress. Such elongation most commonly occurs in acutely infarcted or partially healed regions during the early post-MI period; however, recent reports have indicated that mature (15-week-old) healed infarct regions also undergo elongation after stress. METHODS AND RESULTS: To assess factors contributing to post-MI left ventricular aneurysm formation, we subjected isolated strips (n = 50) of rabbit myocardial tissue from acutely ischemic (noninfarcted left ventricular), acutely infarcted (24 hours after MI), and healed infarct (3 and 15 weeks after MI) regions to a range of loading conditions and measured the reversible and irreversible length changes that occurred. The isolated strips were repetitively stretched for 1 hour at 4 Hz to impose cyclical physiological peak and resting stresses of 2.0 and 0.2 g/mm2. During a second hour, either peak stress ("afterload") or resting stress ("preload") was tripled, and the increase in strip length (strain) was measured. During a third hour, peak and resting stresses were returned to the initial values to assess the reversibility of length changes occurring during increased load. Elongation was expressed as the increase in natural strain from the first hour. Increasing afterload caused similar irreversible length increases of 4-5%/hr in acutely infarcted and 3- and 15-week-old healed infarct strips; acutely ischemic tissue length increased by 7.4%/hr (p less than 0.05 versus acutely infarcted tissue and scars). Increasing preload in acutely ischemic and acutely infarcted tissue caused a reversible length increase of less than 1%/hr. (Scar strips were not tested for the effect of preload.) CONCLUSIONS: Since an irreversible length increase may represent an early event in aneurysm formation, our results suggest that 1) afterload increases are more likely to lead to aneurysm development than preload increases, 2) acutely ischemic tissue is the most vulnerable to increased afterload, and 3) for a given wall stress level, healing scar tissue is as susceptible to irreversible length changes as is acutely infarcted tissue. The observation that even mature post-MI scar elongated in response to increases in afterload implies that long-term pharmacological management of afterload in post-MI patients may be beneficial in preventing tissue elongation and aneurysm formation and that factors that increase wall stress (e.g., hypertension and exercise stress) have the potential to promote aneurysm formation in healed infarct scars.

Effect of coronary occlusion and reperfusion on myocardial blood flow during infarct healing.

Coronary occlusion (CO) of 1 h or longer causes transmural myocardial infarction (MI) in the rabbit. We studied how reperfusion of an infarct affected myocardial blood flow (MBF) acutely and after 3 wk of healing. CO was performed in rabbits for 60 or 180 min (n = 22) followed by reperfusion, and MBF to normal and infarcted zones was determined by radioactive microspheres. In a separate series (n = 23), MBF was measured at 21-25 days post-CO in three groups that had either permanent CO or reperfusion after 60 or 180 min of CO. MBF to the infarct was approximately 8 +/- 3% (+/-SE) of normal MBF (3.8 +/- 0.5 ml.min-1.g-1) during 60-180 min of CO but 3 wk later had increased to 33 +/- 6% of normal MBF (P less than 0.005). Reperfusion after 60 or 180 min of CO resulted in 74 +/- 6% and 41 +/- 5% return of normal MBF, respectively, but 3 wk later, MBF had decreased to 25 +/- 5% (P less than 0.001) and 24 +/- 4% (P less than 0.025) of normal MBF, respectively. Thus after 3 wk of postinfarction healing, MBF to the permanently occluded infarcts increased fourfold, whereas MBF decreased by 50% in the reperfused infarcts so that MBF to the scar tissue was comparable among the three groups and was not influenced by acute post-MI reperfusion.

Effect of myocyte necrosis on strength, strain, and stiffness of isolated myocardial strips.

Cardiac rupture accounts for 8% to 10% of patient deaths after acute myocardial infarction, suggesting that myocyte necrosis weakens the ventricular wall in the initial days after occlusion. To test this theory, permanent occlusion of the left anterior descending coronary artery was performed in dogs. Twenty-four hours after occlusion, the tensile strength, strain at rupture, and stiffness of necrotic epicardium, midmyocardium, endocardium, subepicardium, and the visceral pericardium (VP) were quantified and compared with those of noninfarcted cardiac tissue. The relationship between tensile strength, stiffness, and collagen content was also examined. These material properties did not differ between necrotic and normal myocardium in any of the layers, indicating that myocyte necrosis, per se, does not weaken the myocardium. In both necrotic and normal tissue, marked transmural heterogeneity was observed; tensile strength of the endo- and epicardium (21.3 +/- 3.3 and 21.3 +/- 3.2 gm/mm2) was significantly greater (p less than 0.01) than that of the midmyocardium (4.0 +/- 0.3 gm/mm2) and subepicardium (5.0 +/- 0.5 gm/mm2), whereas the VP was substantially stronger (greater than 100 gm/mm2) than any myocardial layer. Similar results were obtained for stiffness. In contrast, strain at rupture did not vary significantly among myocardial layers and ranged from 0.40 +/- 0.03 (VP) to 0.53 +/- 0.03 (endocardium). Both tensile strength and stiffness of the myocardial layers were found to correlate directly with their collagen content: the higher the hydroxyproline concentration, the greater the tensile strength (r = 0.83). These results support the concept that the collagen fibroskeleton is an important determinant of the material properties of the myocardium. As myocyte necrosis, per se, did not affect tensile strength, we tentatively conclude that cardiac rupture may be a consequence of a defect or weakness in the collagenous framework of the heart.

Effects of reperfusion after coronary artery occlusion on post-infarction scar tissue.

Early reperfusion after a coronary occlusion may reduce myocardial infarct size, but late reperfusion into necrotic myocardium may alter post-infarction healing. In rabbits, we compared 1- or 3-week-old scars resulting from permanent coronary occlusion to those resulting from a 1- or 3-hour occlusion followed by reperfusion. Reperfusion at 1 hour post-occlusion did not affect scar mechanical properties assessed at 1 week post-infarction, but at 3 weeks post-infarction, these scars had a tensile strength significantly lower than those not reperfused (78 +/- 11 vs. 158 +/- 15 g/mm2, P less than 0.001). They also were composed of a mixture of fibrous tissue (58 +/- 8%) and myocytes (43 +/- 8%) with a hydroxyproline content of 23 +/- 2.5 mg/g dry weight. The nonreperfused scars had a higher proportion of fibrous tissue (73 +/- 3%) by histological evaluation and a 35% higher hydroxyproline content (31 +/- 2 mg/g dry weight, P less than 0.001) than the scars reperfused after 1 hour. In contrast, 3-week-old scars resulting from "late" reperfusion at 3 hours post-occlusion were similar to nonreperfused scars in fibrous tissue composition and hydroxyproline content. Nonetheless, the tensile strength of these scars reperfused 3 hours post-occlusion was significantly less than that of the nonreperfused scars (72 +/- 5 vs. 158 +/- 15 g/mm2, P less than 0.001). The lower tensile strength was associated with a lower collagen cross-link density in this reperfused group of scars. At physiological stress levels (approximately 3 g/mm2), all groups of reperfused and nonreperfused scars had similar mechanical properties in terms of natural strain, stiffness, creep, and stress relaxation. Thus, although the reperfused scars ruptured more easily at high stresses, when assessed at physiological stresses their mechanical properties were not significantly different from those of nonreperfused scars.

Myocardial healing and repair after experimental infarction in the rabbit.

Adequacy of healing after acute myocardial infarction may determine the incidence of postmyocardial infarction rupture and ventricular aneurysm. Accordingly, in 36 rabbits, from 1 to 8 days after coronary ligation, and in 18 shams, we measured collagen formation and mechanical resistance of the infarcted left ventricle to stretch and rupture. Prolyl hydroxylase, an intracellular enzyme of collagen synthesis, increased from control activity of 3970 +/- 431 to 9224 +/- 643 counts/min per mg (cpm/mg) extractable protein (P less than 0.01) at 48 hours and was nearly maximal at 3 days postmyocardial infarction (14,518 +/- 2,030 cpm/mg, P less than 0.01). Lysyl oxidase, an extracellular collagen cross-linkage enzyme, increased from control activity of 29.6 +/- 4.8 to 74.7 +/- 18.8 cpm/mg extractable protein (P less than 0.01) at 72 hours and peaked at 121.5 +/- 7.3 (P less than 0.01) 4-6 days postmyocardial infarction. Hydroxyproline, a measure of collagen content, increased from control of 2.8 +/- 0.2 to 5.3 +/- 0.6 mg/g dry weight (P less than 0.05) at 72 hours and continued to increase at 8 days postmyocardial infarction (14.5 +/- 1.7 mg/g dry weight; P less than 0.01). When enzyme activities and hydroxyproline content were expressed relative to other reference bases, including DNA, tissue protein, dry weight, and total left ventricle, similar results were obtained. The mechanical properties of the infarcted left ventricle were determined by filling a balloon in the excised left ventricle until rupture. The rupture threshold in the normal left ventricle, [664 +/- 43 mm Hg (n = 16)], was not significantly different from that of the infarcted left ventricle on days 1-8 postmyocardial infarction. However, left ventricular rupture occurred more often through the myocardial infarction on days 1-4 postmyocardial infarction (59%) than on days 6 and 8 (18%; P = 0.03) when collagen content had significantly increased. Wall stress at the point of rupture in left ventricles from shams and normals was 30 +/- 2 g/mm2; tensile strength in isolated left ventricle muscle strips was 25 +/- 4 g/mm2 and in isolated scar strips at 7 days postmyocardial infarction was 59 +/- 7 g/mm2. The passive stiffness of the infarcted left ventricle increased from control of 61 +/- 5 to 94 +/- 6 mm Hg/100 microliters (P less than 0.05) at 4 days and 100 +/- 7 mm Hg/100 microliters (P less than 0.01) at 6 days postmyocardial infarction. Stiffness correlated with hydroxyproline content over the 8 days postmyocardial infarction (r = 0.599; P less than 0.001). Thus, the acutely infarcted ventricle was highly resistant to rupture during the initial 48 hours postmyocardial infarction, before any increase in collagen occurred. This result suggests that the preinfarction collagen content has an important role in preventing rupture. After 72 hours postmyocardial infarction, collagen synthesis appeared to be a determinant of infarct stiffness and resistance of the infarcted ventricle to rupture.

Increased collateral arterial and venous endothelial cell turnover after renal artery stenosis in the dog.

Renal artery stenosis was induced in dogs and collateral arterial formation assessed by serial angiography and histology. Endothelial cell turnover was estimated by radioautography in five normal and five collateral-forming kidneys 18-39 days following stenosis with tritiated thymidine. Normal arterial endothelial labeling was 0.1% with a highly significant (p less than 0.0005), 55-fold increase in endothelial labeling in arterial collateral vessels. A smaller but statistically significant increase in the labeling index was also found in endothelial cells of the renal vein, from a normal of 0.065% to 0.4% (p less than 0.005). An excellent correlation was found between endothelial cell labeling in small arteries and the renal veins (r = 0.97; p less than 0.01). A marked increase in epithelial cell labeling of the ureters draining the stenotic kidneys was also evident (p less than 0.005). Thus, collateral vessel development is characterized by active DNA synthesis in cellular elements, and a humoral factor is implicated in the vascular response.

Some properties of the external activation site of the sodium pump in crab nerve.

1. Methods are described for using the changes in respiration of intact Libinia nerve to follow the rate of energy utilization by the sodium pump in this tissue.2. Short tetani in 10 K(Na)ASW (artificial sea water in which Na is the major cation and the potassium concentration is 10 mM) increased the oxygen uptake which then declined exponentially. From the net influx of Na during the tetanus and the associated oxygen uptake, values between 1.9 and 3.4 were calculated for the Na: approximately P ratio. After longer tetani, the recovery curve was S-shaped.3. The pump was activated by potassium ions in the external medium and this activation was competitively inhibited by external sodium ions. The data are consistent with a Michaelis constant (K(m)) for external potassium of 1 mM and an inhibitor constant (K(i)) for external sodium of 60 mM.4. In activating the pump, K could be replaced by Tl(+), Rb, NH(4) and Cs ions; but, of the monovalent ions tested, sodium seemed to be unique in its inhibitory action.5. In sea waters containing 460 mM-Na, ouabain behaved like a mixed inhibitor of the pump, reducing both the maximum velocity and the apparent affinity for external potassium. At a given ouabain concentration, reducing the sodium content of the medium was without effect on the maximum rate of pumping; but the apparent affinity for potassium increased more steeply than in a ouabain-free solution.6. The rate of energy utilization associated with pumping was unaffected by inclusion of quite high concentrations of sulphydryl-blocking agents in the external medium.