Showing papers in "Circulation in 1986"

Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.

Abstract: We have previously shown that a brief episode of ischemia slows the rate of ATP depletion during subsequent ischemic episodes. Additionally, intermittent reperfusion may be beneficial to the myocardium by washing out catabolites that have accumulated during ischemia. Thus, we proposed that multiple brief ischemic episodes might actually protect the heart from a subsequent sustained ischemic insult. To test this hypothesis, two sets of experiments were performed. In the first set, one group of dogs (n = 7) was preconditioned with four 5 min circumflex occlusions, each separated by 5 min of reperfusion, followed by a sustained 40 min occlusion. The control group (n = 5) received a single 40 min occlusion. In the second study, an identical preconditioning protocol was followed, and animals (n = 9) then received a sustained 3 hr occlusion. Control animals (n = 7) received a single 3 hr occlusion. Animals were allowed 4 days of reperfusion thereafter. Histologic infarct size then was measured and was related to the major baseline predictors of infarct size, including the anatomic area at risk and collateral blood flow. In the 40 min study, preconditioning with ischemia paradoxically limited infarct size to 25% of that seen in the control group (p less than .001). Collateral blood flows were not significantly different in the two groups. In the 3 hr study, there was no difference between infarct size in the preconditioned and control groups. The protective effect of preconditioning in the 40 min study may have been due to reduced ATP depletion and/or to reduced catabolite accumulation during the sustained occlusion. These results suggest that the multiple anginal episodes that often precede myocardial infarction in man may delay cell death after coronary occlusion, and thereby allow for greater salvage of myocardium through reperfusion therapy.

Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging.

Abstract: A study in vitro of specimens of human aortic and common carotid arteries was carried out to determine the feasibility of direct measurement (i.e., not from residual lumen) of arterial wall thickness with B mode real-time imaging. Measurements in vivo by the same technique were also obtained from common carotid arteries of 10 young normal male subjects. Aortic samples were classified as class A (relatively normal) or class B (with one or more atherosclerotic plaques). In all class A and 85% of class B arterial samples a characteristic B mode image composed of two parallel echogenic lines separated by a hypoechoic space was found. The distance between the two lines (B mode image of intimal + medial thickness) was measured and correlated with the thickness of different combinations of tunicae evaluated by gross and microscopic examination. On the basis of these findings and the results of dissection experiments on the intima and adventitia we concluded that results of B mode imaging of intimal + medial thickness did not differ significantly from the intimal + medial thickness measured on pathologic examination. With respect to the accuracy of measurements obtained by B mode imaging as compared with pathologic findings, we found an error of less than 20% for measurements in 77% of normal and pathologic aortic walls. In addition, no significant difference was found between B mode-determined intimal + medial thickness in the common carotid arteries evaluated in vitro and that determined by this method in vivo in young subjects, indicating that B mode imaging represents a useful approach for the measurement of intimal + medial thickness of human arteries in vivo.

Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity.

Abstract: The analysis of plasma kinetics of the sympathetic neurotransmitter norepinephrine can be used to estimate sympathetic nervous "activity" (integrated nerve firing rate) for the body as a whole and for individual organs. In 12 patients with cardiac failure (left ventricular ejection fraction 10% to 39%), the mean arterial plasma norepinephrine concentration was 557 +/- 68 pg/ml (mean +/- SE) compared with 211 +/- 21 pg/ml in 15 subjects without heart failure (p less than .002). The difference was due to both increased release of norepinephrine to plasma (indicating increased "total" sympathetic activity) and reduced clearance of norepinephrine from plasma. The increase in sympathetic activity did not involve all organs equally. Cardiac (32 +/- 9 vs 5 +/- 1 ng/min; p less than .002) and renal (202 +/- 45 vs 66 +/- 9 ng/min; p = .002) norepinephrine spillover were increased by 540% and 206%, respectively, but norepinephrine spillover from the lungs was normal. Adrenomedullary activity was also increased in the patients with heart failure, whose mean arterial plasma epinephrine concentration was 181 +/- 38 pg/ml compared with 71 +/- 12 pg/ml in control subjects (p less than .02). There is marked regional variation, inapparent from measurements of plasma norepinephrine concentration, in sympathetic nerve activity in patients with congestive heart failure. The finding of increased cardiorenal norepinephrine spillover has important pathophysiologic and therapeutic implications.

Association of levels of lipoprotein Lp(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography.

Abstract: In a study of 307 white patients who underwent coronary angiography, the relationship of coronary artery disease (CAD) to plasma levels of lipoprotein Lp(a) and other lipid-lipoprotein variables was examined. Lp(a) resembles low-density lipoprotein (LDL) in several ways, but can be distinguished and quantified by electroimmunoassay. CAD was rated as present or absent and was also represented by a quantitative lesion score derived from estimates of stenosis in four major coronary vessels. Coronary lesion scores significantly correlated with Lp(a), total cholesterol, triglycerides, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol levels by univariate statistical analysis. By multivariate analysis levels of Lp(a) were associated significantly and independently with the presence of CAD (p less than .02), and tended to correlate with lesion scores (p = .06). Among subgroups Lp(a) level was associated with CAD in women of all ages and in men 55 years old or younger. An apparent threshold for coronary risk occurred at Lp(a) lipoprotein mass concentrations of 30 to 40 mg/dl, corresponding to Lp(a) cholesterol concentrations of approximately 10 to 13 mg/dl. Plasma Lp(a) in white patients appears to be a major coronary risk factor with an importance approaching that of the level of LDL or HDL cholesterol.

Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure.

Abstract: Patients with heart failure have increased vascular resistance and evidence for increased neurohumoral drive. High levels of circulating norepinephrine are found in patients with heart failure, but it is not known whether they reflect increased sympathetic neural activity or result from altered synthesis, release, or metabolism of norepinephrine. We used microneurography (peroneal nerve) to directly record sympathetic nerve activity to muscle (mSNA) and also measured plasma norepinephrine levels in patients with heart failure and in normal control subjects. Our goal was to determine whether sympathetic nerve activity is increased in patients with heart failure and whether plasma norepinephrine levels correlate with levels of mSNA in heart failure. Resting muscle sympathetic nerve activity in 16 patients with moderate to severe heart failure (54 +/- 5 bursts/min, mean +/- SE) was significantly higher (p less than .01) than the levels of activity in either nine age-matched normal control subjects (25 +/- 4 bursts/min) or 19 "young" normal control subjects (24 +/- 2 bursts/min). We found a significant correlation between plasma norepinephrine levels and mSNA (r = .73, p less than .05). Neither mSNA nor plasma norepinephrine levels correlated with total systemic vascular resistance, cardiac index, left ventricular ejection fraction, or heart rate. However, both mSNA and plasma norepinephrine levels showed significant positive correlations (p less than .05) with left ventricular filling pressures (r = .80, mSNA vs filling pressures; r = .82, norepinephrine levels vs filling pressures) and mean right atrial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion.

Abstract: Dilatation of infarcted segments (infarct expansion) may occur during recovery from myocardial infarction, but the fate of noninfarcted segments is uncertain. Accordingly, left ventricular geometric changes were assessed by left ventricular angiography and M mode echocardiography on admission and 2 weeks later in 30 patients with their first acute transmural myocardial infarction. All patients demonstrated chest pain, ST segment elevation with subsequent development of Q waves (15 anterior, 15 inferior), and elevation of cardiac enzymes. Sequential left ventricular angiographic and hemodynamic findings were available in these patients by virtue of their participation in a study of thrombolysis in acute myocardial infarction. By that study design, all patients treated successfully with thrombolytic therapy and demonstrating improvement of flow in an occluded coronary artery underwent repeat cardiac catheterization. At 2 weeks there was a significant decrease in left ventricular and pulmonary capillary wedge pressures (p less than .01), whereas both left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volume indexes increased (p less than .01). The increase in LVEDV correlated directly with the percentage of the ventriculographic silhouette that was akinetic or dyskinetic at the initial catheterization (r = .71, p less than .001). To assess regional changes in both infarcted and noninfarcted segments, serial endocardial perimeter lengths of both the akinetic-dyskinetic segments (infarction zone) and of the remainder of the cardiac silhouette (noninfarction zone) were measured in all patients who demonstrated at least a 20% increase in their LVEDV at 2 weeks after myocardial infarction. Notably, there was a mean increase of 13% in the endocardial perimeter length of infarcted segments and a 19% increase in the endocardial perimeter length of noninfarcted segments. Serial M mode echocardiographic studies showed no significant change in the wall thickness of noninfarcted myocardial segments. Hemodynamic changes that occurred in this subgroup of patients included significant decreases in left ventricular end-diastolic and pulmonary capillary wedge pressures (p less than .05) and significant increases in angiographic cardiac index (p less than .01) and LVESV index (p less than .01). We conclude that in patients who manifest cardiac dilatation in the early convalescent period after myocardial infarction, there is remodeling of the entire left ventricle including infarct expansion of akinetic-dyskinetic segments and volume-overload hypertrophy of noninfarcted segments.(ABSTRACT TRUNCATED AT 400 WORDS)

Restenosis after successful coronary angioplasty in patients with single-vessel disease.

Abstract: To determine risk factors for restenosis, we studied 998 patients who underwent elective coronary angioplasty (PTCA) to native coronary arteries between July 1980 and July 1984. Restenosis, defined as a luminal narrowing of greater than 50% at follow-up, was present in 302 patients (30.2%). Univariate analysis of 29 factors revealed seven factors related to restenosis: vessel dilated (circumflex coronary artery 18%, right coronary artery 27%, left anterior descending artery 34%; p less than .01), final gradient of 15 mm Hg or less compared with greater than 15 mm Hg (27% vs 38%, p less than .01), duration of angina greater than 2 months compared with angina of shorter duration (27% vs 35%, p = .01), post-PTCA stenosis of 30% or less compared with 31% to 50% (28% vs 36%, p less than .025), stable vs unstable angina (26% vs 34%, p less than .05), presence vs absence of intimal dissection (26% vs 32%, p = .07), and female gender vs male gender (25% vs 32%, p = .08). Multivariate analysis revealed five factors independently related to increased risk of restenosis in the following order of importance: PTCA in the left anterior descending artery, absence of intimal dissection immediately after PTCA, final gradient greater than 15 mm Hg, a large residual stenosis after PTCA, and unstable angina. Restenosis after PTCA is a multifactorial problem. The hemodynamic and angiographic result at the time of PTCA significantly influences long-term outcome, but additional measures aimed at reducing the rate of recurrence of atherosclerotic plaque are required.

Advantages and applications of the centerline method for characterizing regional ventricular function

Abstract: We sought to identify theoretical advantages and applications of the centerline method for quantitative assessment of regional ventricular function. Motion was measured along 100 chords constructed perpendicular to a centerline drawn midway between the end-diastolic and end-systolic contours, and normalized for heart size. Abnormality was expressed in units of standard deviations from the mean motion in a normal reference population to indicate both the severity and significance of the wall motion abnormality. The mean abnormality averaged over 100 chords correlated highly with the area ejection fraction (r = .97). The centerline method uses a "sliding window" to measure motion where it is abnormal, because assessment of wall motion in predefined regions of the ventricular contour underestimates abnormality. From the 100 data points, the extent (% of contour) of regional abnormalities can also be determined. The severity of hypokinesis at the site of acute myocardial infarction correlated better with infarct size estimated from creatine kinase release (r = -.78) than did the ejection fraction or the circumferential extent of hypokinesis. Because the centerline method measures motion along locally determined vectors, and requires no apex, origin, coordinate system, or geometric reference figure, it can be applied to contours as dissimilar as the 60 degree left anterior oblique projection of the left ventricle and the 75 degree left anterior oblique projection of the right ventricle.

Left ventricular filling dynamics: influence of left ventricular relaxation and left atrial pressure.

Abstract: Peak rapid filling rate (PRFR) is often used clinically as an index of left ventricular relaxation, i.e., of early diastolic function. This study tests the hypothesis that early filling rate is a function of the atrioventricular pressure difference and hence is influenced by the left atrial pressure as well as by the rate of left ventricular relaxation. As indexes, we chose the left atrial pressure at the atrioventricular pressure crossover (PCO), and the time constant (T) of an assumed exponential decline in left ventricular pressure. We accurately determined the magnitude and timing of filling parameters in conscious dogs by direct measurement of phasic mitral flow (electromagnetically) and high-fidelity chamber pressures. To obtain a diverse hemodynamic data base, loading conditions were changed by infusions of volume and angiotensin II. The latter was administered to produce a change in left ventricular pressure of less than 35% (A-1) or a change in peak left ventricular pressure of greater than 35% (A-2). PRFR increased with volume loading, was unchanged with A-1, and was decreased with A-2; T and PCO increased in all three groups (p less than .005 for all changes). PRFR correlated strongly with the diastolic atrioventricular pressure difference at the time of PRFR (r = .899, p less than .001) and weakly with both T (r = .369, p less than .01) and PCO (r = .601, p less than .001). The correlation improved significantly when T and PCO were both included in the multivariate regression (r = .797, p less than .0001). PRFR is thus determined by both the left atrial pressure and the left ventricular relaxation rate and should be used with caution as an index of left ventricular diastolic function.

Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response.

Abstract: We developed methods for identifying beta-adrenergic receptors in human right ventricular endomyocardial biopsy tissue with the radioligand (-)[125I]iodocyanopindolol (ICYP). Specific ICYP binding in a crude, high-yield membrane preparation derived from endomyocardial biopsy tissue was high (specificity greater than 90%), of high affinity (KD around 20 pM), saturable and stereospecific for the (-) vs the (+) isomer of isoproterenol. Subjects with mild-moderate and severe biventricular dysfunction had respective decreases in beta-adrenergic receptor density of 38.2% and 57.7% when normalization methods were averaged, with no significant differences in ICYP dissociation constant. A subgroup of subjects was subdivided by left ventricular ejection fraction (LVEF) into those with mild cardiac dysfunction (LVEF less than 0.50 greater than 0.40) and severe heart failure (LVEF less than 0.20) and given graded sequential infusions of dobutamine and calcium gluconate. Those with severe cardiac dysfunction had marked impairment of the dobutamine dP/dt and stroke work index response, whereas these responses to calcium did not differ in the two groups. These data indicate that in the intact human heart endomyocardial biopsy may be used for direct analysis of beta-adrenergic receptors, heart failure-associated myocardial beta-adrenergic down-regulation begins with mild-moderate ventricular dysfunction, reduction in myocardial beta-receptor density is related to degree of heart failure, and beta-receptor down-regulation is associated with pharmacologically specific impairment of the beta-agonist-mediated contractile response.

Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death.

Abstract: A specific search for intramyocardial platelet aggregates was made in 90 patients who died suddenly of ischemic heart disease. Platelet aggregates in small intramyocardial vessels were found in 27 (30%). There was a significant difference (p less than .05) in the incidence of platelet aggregates in patients with chest pain of recent onset (unstable angina) before death (16/36, 44.4%) and that in those without it (11/54, 20.4%). Multifocal microscopic necrosis with involvement of the full thickness of the ventricular wall, including the subpericardial zone, was significantly more common (p = less than .005) in the patients with platelet emboli (55.6% vs 12.7%). With one exception, aggregates were confined to the segment of myocardium immediately downstream of a major epicardial coronary artery containing an atheromatous plaque that had undergone fissuring and on which mural thrombus had developed. The results support the view that platelet aggregates in the myocardium represent an embolic phenomenon and are a potential cause of unstable angina. The association of myocardial necrosis with such emboli could precipitate sudden death from ventricular fibrillation.

Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm.

Abstract: We injected acetylcholine (ACh), the neurotransmitter of the parasympathetic nervous system, into the coronary arteries of 28 patients with variant angina. Injection of 10 to 80 micrograms ACh into the coronary artery responsible for the attack induced spasm together with chest pain and ST segment elevation or depression on the electrocardiogram in 30 of the 32 arteries of the 25 of the 27 patients. The injection of 20 to 100 micrograms ACh into the coronary artery not responsible for the attack in 18 patients resulted in various degrees of constriction in most of them, but no spasm in any of them. After intravenous injection of 1.0 to 1.5 mg atropine sulfate, the injection of ACh into the coronary artery responsible for the attack did not induce spasm or attack in any of the nine coronary arteries injected in eight patients. We conclude that the intracoronary injection of ACh induces coronary spasm and attack in patients with variant angina and that the activity of the parasympathetic nervous system may play a role in the pathogenesis of coronary spasm. We also conclude that the intracoronary injection of ACh is a useful test for provocation of coronary spasm.

Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure.

Abstract: Although past reports have identified a variety of prognostic factors in patients with severe chronic heart failure, previous studies have not evaluated the interaction of prognostic variables and drug treatment. We analyzed the association of 30 clinical, hemodynamic, and biochemical variables with survival in 203 consecutive patients with severe heart failure; all variables were assessed just before initiation of treatment with a variety of vasodilator drugs, and all patients were subsequently followed for 6 to 94 months. By regression analysis, pretreatment serum sodium concentration was the most powerful predictor of cardiovascular mortality, with hyponatremic patients having a substantially shorter median survival than did patients with a normal serum sodium concentration (164 vs 373 days, p = .006). The unfavorable prognosis for hyponatremic patients appeared to be related to the marked elevation of plasma renin activity that we noted in these individuals (10.0 +/- 2.0 ng/ml/hr), since hyponatremic patients fared significantly better when treated with angiotensin converting-enzyme inhibitors than when treated with vasodilator drugs that did not interfere with angiotensin II biosynthesis (median survival 232 vs 108 days, p = .003). In contrast, there was no selective benefit of converting-enzyme inhibition on the survival of patients with a normal serum sodium concentration, in whom plasma renin activity was low (1.9 +/- 0.3 ng/ml/hr). This interaction between serum sodium concentration, drug treatment, and long-term outcome suggests that the renin-angiotensin system may exert a deleterious effect on the survival of some patients with chronic heart failure, which can be antagonized by converting enzyme inhibition, and provides a clinical counterpart for the similar prognostic role that has been postulated for angiotensin II in experimental preparations of heart failure.

Adenosine-sensitive ventricular tachycardia: evidence suggesting cyclic AMP-mediated triggered activity.

Abstract: Catecholamine-induced triggered activity is thought to be caused by intracellular calcium overload mediated by elevation of intracellular cyclic AMP (cAMP). Although shown to occur in isolated preparations, evidence supporting its clinical existence has been lacking. Electrophysiologic studies were performed in four patients with structurally normal hearts who had exertionally related sustained ventricular tachycardia (VT). Programmed stimulation reproducibly initiated and terminated VT in all patients. Induction of tachycardia was also facilitated by infusion of isoproterenol. Adenosine, an endogenous nucleoside, whose only known electrophysiologic effect on ventricular myocardium and Purkinje fibers is antagonism of catecholamine-induced stimulation of intracellular cAMP production, reproducibly terminated all episodes of VT. The tachycardia was also terminated by intravenous verapamil and by the Valsalva maneuver and/or carotid sinus massage. Beta-Adrenergic receptor blockade with propranolol either terminated or prevented induction of VT during programmed stimulation or catecholamine challenge. Adenosine was also administered during VT to 14 patients whose arrhythmias fulfilled standard criteria for reentry, two of whom also had exercise-induced VT. Adenosine, at a dose (112.5 to 225 micrograms/kg iv) sufficient to cause either sinus slowing/arrest or ventriculoatrial block during ventricular pacing, failed to slow or terminate any episode of VT in these patients. Verapamil and autonomic modulation were also ineffective in this group of patients. Adenosine, verapamil, vagal maneuvers (acetylcholine), and beta-adrenergic receptor blockade are all known to decrease the slow-inward calcium current either directly by modulating calcium channels or indirectly by inhibiting production of cellular cAMP. Therefore the observation in this study that interventions that lower intracellular cAMP either terminate or prevent induction of VT in patients with structurally normal hearts and exercise-induced VT suggests that the mechanism of tachycardia may be cAMP-mediated triggered activity.

Prognostic significance of ventricular tachycardia and fibrillation induced at programmed stimulation and delayed potentials detected on the signal-averaged electrocardiograms of survivors of acute myocardial infarction.

Abstract: The relative prognostic significance of ventricular tachycardia and ventricular fibrillation inducible at programmed stimulation within 1 month of acute myocardial infarction was compared in a prospective study of 403 clinically well survivors of transmural infarction who were 65 years old or younger. The prognostic significance of delayed potentials on the signal-averaged electrocardiogram was also examined in a subset of 306 patients without bundle branch block. Among the study patients, 20% had inducible ventricular tachycardia, 14% had inducible ventricular fibrillation, and 66% had no inducible arrhythmias. The 2 year probability of remaining free from cardiac death or nonfatal ventricular tachycardia or fibrillation was 0.73 for those with inducible ventricular tachycardia, 0.93 for those with inducible ventricular fibrillation, and 0.92 for those with no inducible arrhythmias. The cycle length of inducible ventricular tachycardia was 230 msec or more in 70% of the patients with inducible tachycardia who died. Of the patients studied by signal-averaged electrocardiography, 26% had delayed potentials. At 2 years, the probability of remaining free from cardiac death or nonfatal ventricular tachycardia or fibrillation was 0.73 for patients with delayed potentials and 0.95 for patients with no delayed potentials. There was a significant correlation (p less than .001) between the presence of delayed potentials and the ability to induce ventricular tachycardia. In conclusion, in survivors of recent infarction who have not had spontaneous ventricular tachycardia or fibrillation, inducible tachycardia (but not inducible fibrillation) at programmed stimulation predicts a significant risk of death or spontaneous tachycardia or fibrillation. A similar risk is found for patients with delayed potentials on the signal-averaged electrocardiogram.

Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries.

Abstract: We studied six patients who suffered from angina pectoris but had angiographically patent major coronary arteries. Two of the patients suffered also from congestive heart failure. Three patients had supraventricular tachyarrhythmias. Three patients had conduction disturbances. During coronary angiography the patients had significantly reduced flow velocity of angiographic contrast medium compared with that in a control group. Echocardiographic and Doppler flow studies showed a tendency for symmetrical thickening of the left ventricular wall, enlargement of the right ventricle, and reduced compliance of both ventricles. Right ventricular endomyocardial biopsy revealed pathologic small coronary arteries with fibromuscular hyperplasia, hypertrophy of the media, myointimal proliferation, and endothelial degeneration. Capillaries had swollen endothelial cells encroaching on the lumen. Myocardial hypertrophy, lipofuscin deposition, and patchy fibrosis were also observed. These cases show that small-vessel coronary artery disease can cause classic angina pectoris. The diagnosis can be suspected when the coronary angiogram shows large patent arteries with slow flow of the angiographic contrast medium and it can be confirmed by endomyocardial biopsy.

The coronary circulation in human septic shock.

Abstract: Reversible myocardial depression, manifested by ventricular dilatation and decreased ejection fraction, is common in human septic shock. A proposed mechanism, based on animal studies, is myocardial ischemia resulting from inadequate coronary blood flow. Coronary flow observations have not been reported for human septic shock. To determine whether myocardial depression in human septic shock is associated with reduced coronary flow, thermodilution coronary sinus catheters were placed in seven patients with septic shock for measurements of coronary flow and myocardial metabolism. Four of the seven patients developed myocardial depression. These patients had coronary flow similar to or higher than that of control subjects and similar to that of the other three patients, who did not develop myocardial depression. None of the patients had net myocardial lactate production. In general, compared with values in control subjects, the oxygen content difference (arterial minus coronary sinus) was narrowed, and the fractional extraction of arterial oxygen was diminished. This pattern of disordered coronary autoregulation is analogous to the pattern of arteriovenous shunting in other organs in patients with septic shock. The preservation of coronary flow, the net myocardial lactate extraction, and the increased availability of oxygen to the myocardium argue against global ischemia as the cause of myocardial depression in human septic shock.

Limitation of myocardial ischemia by collateral circulation during sudden controlled coronary artery occlusion in human subjects: a prospective study.

Abstract: We have shown improvement in collateral filling immediately after sudden controlled coronary occlusion in human subjects undergoing elective coronary angioplasty. It has been suggested but not proved that collateral circulation can limit myocardial ischemia. We prospectively studied 23 patients with isolated left anterior descending (n = 14) or right coronary (n = 9) disease and normal left ventriculograms during elective coronary angioplasty. A second arterial catheter was used for injection of the contralateral artery to assess collateral filling before balloon placement and during coronary occlusion by balloon inflation. Left ventriculography was performed during another inflation. Grading of collateral filling was as follows: 0 = none, 1 = filling of side branches only, 2 = partial filling of the epicardial segment, 3 = complete filling of the epicardial segment. Indexes of myocardial ischemia included percent of the left ventricular perimeter showing new hypocontractility and the sum of ST segment elevation measured on a simultaneous 12-lead electrocardiogram recorded during each inflation. Collateral filling during balloon occlusion and indexes of ischemia were assessed at 30 to 40 sec into inflation. Aortic pressure and heart rate did not correlate with the percent hypocontractile perimeter nor the sum of ST segment elevation. There was a significant correlation between the grade of collateral filling during inflation and both percent hypocontractile perimeter (r = -.85) and the sum of ST segment elevation (r = -.87). Anginal pain occurred in all patients with grade 0 or 1 collateral filling but in only 36% of patients with grade 2 or 3 collaterals. In conclusion, collateral circulation limits myocardial ischemia as assessed by the extent of new ventricular asynergy and electrocardiographic changes during coronary occlusion in patients.

Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion.

Abstract: Dilatation of infarcted segments (infarct expansion) may occur during recovery from myocardial infarction, but the fate of noninfarcted segments is uncertain. Accordingly, left ventricular geometric changes were assessed by left ventricular angiography and M mode echocardiography on admission and 2 weeks later in 30 patients with their first acute transmural myocardial infarction. All patients demonstrated chest pain, ST segment elevation with subsequent development of Q waves (15 anterior, 15 inferior), and elevation of cardiac enzymes. Sequential left ventricular angiographic and hemodynamic findings were available in these patients by virtue of their participation in a study of thrombolysis in acute myocardial infarction. By that study design, all patients treated successfully with thrombolytic therapy and demonstrating improvement of flow in an occluded coronary artery underwent repeat cardiac catheterization. At 2 weeks there was a significant decrease in left ventricular and pulmonary capillary wedg...

Intracoronary papaverine: An ideal coronary vasodilator for studies of the coronary circulation in conscious humans

Abstract: An ideal coronary vasodilator for studying coronary flow reserve in humans would rapidly produce maximal coronary vasodilation, be short acting to permit repeated measurements, and not alter systemic hemodynamics. The two commonly used vasodilators (dipyridamole and meglumine diatrizoate) do not satisfy these criteria; meglumine diatrizoate does not produce maximal hyperemia and dipyridamole has a long duration of effect (greater than 30 min). In this study we used a subselective coronary Doppler catheter to measure the dose-response kinetics of a shorter acting vasodilator, intracoronary papaverine. In 10 patients with normal coronary vessels, the maximal vasodilator response to papaverine was compared with that to intravenous dipyridamole (0.56 mg/kg infused over 4 min) and intracoronary meglumine diatrizoate. The increase in coronary blood flow velocity after the maximal dose of papaverine (4.8 +/- 0.4 peak/resting velocity ratio, mean +/- SEM) was nearly identical to that seen after infusion of dipyridamole (4.8 +/- 0.6) and was significantly greater than that after meglumine diatrizoate (3.1 +/- 0.2, p less than .01). At maximal hyperemia, mean arterial blood pressure fell 9 +/- 2% (mean +/- SEM) after intracoronary papaverine, 8 +/- 4% after dipyridamole, and 3 +/- 3% after meglumine diatrizoate. The dose-response kinetics of intracoronary papaverine were studied in 13 patients with normal coronary arteries. In the left coronary artery, maximal vasodilation (5.4 +/- 0.6) was achieved with 8 mg in six of eight patients and with 12 mg in all patients. In the right coronary artery, maximal vasodilation (4.8 +/- 0.7) was achieved with 6 mg in four or five patients and with 8 mg in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of propranolol after acute myocardial infarction in patients with congestive heart failure.

Abstract: The incidence of congestive heart failure was studied in the Beta Blocker Heart Attack Trial in which postmyocardial infarction patients between the ages of 30 and 69 years, with no contraindication to propranolol, were randomly assigned to receive placebo (n = 1921) or propranolol 180 or 240 mg daily (n = 1916) 5 to 21 days after admission to the hospital for the event. Survivors of acute myocardial infarction with compensated or mild congestive heart failure, including those on digitalis and diuretics, were included in the study. A history of congestive heart failure before randomization characterized 710 (18.5%) patients: 345 (18.0%) in the propranolol group and 365 (19.0%) in the placebo group. The incidence of definite congestive heart failure after randomization and during the study was 6.7% in both groups. In patients with a history of congestive heart failure before randomization, 51 of 345 (14.8%) in the propranolol group and 46 of 365 (12.6%) in the placebo group developed congestive heart failure during an average 25 month follow-up. In the patients with no history of congestive heart failure, 5% in the propranolol group developed congestive heart failure and 5.3% in the placebo group developed congestive heart failure. Baseline characteristics predictive of the occurrence of congestive heart failure by multivariate analyses included an increased cardiothoracic ratio, diabetes, increased heart rate, low baseline weight, prior myocardial infarction, age, and more than 10 ventricular premature beats per hour.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid ventricular pacing in the dog: pathophysiologic studies of heart failure.

Abstract: We examined rapid ventricular cardiac pacing as a means of inducing heart failure in the dog to establish the sequence and nature of physiologic compensation in this preparation. Seven animals paced at 250 beats/min for 3 weeks (VP1 group) showed an increase in cardiac size from 78.5 +/- 9.5(SD) to 105.8 +/- 13.0 cm2, a reduction in mean arterial pressure from 149 +/- 7 to 130 +/- 21 mm Hg, a fall in cardiac index from 196 +/- 57 to 125 +/- 37 ml/kg/min, and an increase in left ventricular filling pressure from 6 +/- 5 to 22 +/- 9 mm Hg and in right atrial pressure from 2 +/- 2 to 5 +/- 3 mm Hg. An additional series of six animals (VP2 group) was paced until a clear biologic end point for heart failure was reached (average 5.3 +/- 1.9 weeks) and they showed similar but more advanced changes compared with the VP1 group. The changes in cardiac size and hemodynamics in the VP1 and VP2 groups were significantly different from those in parallel studies of 10 sham-operated animals. Plasma norepinephrine and renin activity were unchanged in sham-operated animals, whereas in the VP1 group, plasma norepinephrine rose from 338 +/- 118 to 764 +/- 567 pg/ml (p less than .05), but plasma renin activity did not change. In the VP2 group norepinephrine rose from 471 +/- 285 to 999 +/- 425 pg/ml (p less than .025) and plasma renin rose from 2.1 +/- 1.5 to 8.0 +/- 7.1 ng/ml/hr (p less than .05). There was an excellent correlation between plasma norepinephrine and renin activity before the animals were killed in both the VP1 and VP2 groups (r = .88, p less than .001). No change was evident in atrial natriuretic factor content, as determined by bioassay, in sham-operated or VP1 group animals. However, there was a significant reduction in atrial natriuretic activity from the right atrium that was inversely correlated with the level of right atrial pressure in the VP2 group.

Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin.

Abstract: To study the vasomotility of normal and diseased coronary arteries during dynamic exercise, symptom-limited supine bicycle exercise during cardiac catheterization was performed by 18 patients with classic angina pectoris The cardiovascular response was assessed by hemodynamic measurements and computer-assisted determination of normal and stenotic coronary artery luminal areas from biplane coronary angiograms made before, during, and after exercise After baseline measurements were recorded, 12 patients (group 1) performed bicycle exercise for 34 min (mean), reaching a maximum workload of 81 W (mean); at the end of exercise they received 16 mg sublingual nitroglycerin After measurements at rest in six other patients (group 2), 01 mg intracoronary nitroglycerin was given, followed by exercise (38 min, 96 W; NS) and sublingual nitroglycerin as in group 1 During exercise in group 1, luminal area of the coronary stenosis decreased to 71% of resting levels (p less than 001), while area of the normal coronary artery increased to 123% of control (p less than 001) After sublingual nitroglycerin at the end of exercise, area of the normal vessel further increased to 140% of control (p less than 001), while luminal area of the stenosis dilated to 112% of resting levels (p less than 001 vs exercise, NS vs rest) Pretreatment with intracoronary nitroglycerin increased both normal (121%; p less than 05) and stenotic (122%; p less than 05) luminal areas, while preventing the previously observed narrowing of stenosis during exercise (114%; NS) Exercise resulted in a similar heart rate-systolic pressure product and caused angina pectoris in two-thirds of the patients in each group However, patients pretreated with intracoronary nitroglycerin (group 2) had a lower mean pulmonary arterial pressure during maximum exercise (35 mm Hg) than those patients (group 1) not receiving pretreatment (47 mm Hg; p less than 001) Group 2 patients reached a percentage of their predicted work capacity (65%) that was about the same as that during previous upright bicycle exercise (71%; NS), while group 1 patients had a significantly lower work capacity (51% of predicted) than that before catheterization (82%; p less than 001) Hence, narrowing of coronary artery stenosis during dynamic exercise is attributable to active vasoconstriction due to its reversibility by preexercise intracoronary nitroglycerin Patients who did not experience narrowing of stenosis during exercise (group 2) had less evidence of myocardial ischemia (lower mean pulmonary arterial pressure) and maintained their work capacity(ABSTRACT TRUNCATED AT 400 WORDS)

Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure.

Abstract: Although past reports have identified a variety of prognostic factors in patients with severe chronic heart failure, previous studies have not evaluated the interaction of prognostic variables and drug treatment. We analyzed the association of 30 clinical, hemodynamic, and biochemical variables with survival in 203 consecutive patients with severe heart failure; all variables were assessed just before initiation of treatment with a variety of vasodilator drugs, and all patients were subsequently followed for 6 to 94 months. By regression analysis, pretreatment serum sodium concentration was the most powerful predictor of cardiovascular mortality, with hyponatremic patients having a substantially shorter median survival than did patients with a normal serum sodium concentration (164 vs 373 days, p = .006). The unfavorable prognosis for hyponatremic patients appeared to be related to the marked elevation of plasma renin activity that we noted in these individuals (10.0 +/- 2.0 ng/ml/hr), since hyponatremic ...

Accurate noninvasive quantification of stenotic aortic valve area by Doppler echocardiography.

Abstract: Laminar flow through a conduit is equal to the mean velocity times the cross-sectional area of the orifice. Therefore, volume is equal to the time-velocity integral multiplied by the cross-sectional area. In aortic stenosis, flow in the stenotic jet is laminar and the aortic valve area should be equal to the volume of blood ejected through the valve divided by the time-velocity integral of the aortic jet velocity recorded by continuous-wave Doppler echocardiography. To test whether this concept can be used to accurately determine aortic valve area noninvasively by the Doppler method, 39 patients (age 35 to 82 years, mean 63) underwent pulsed Doppler combined with two-dimensional echocardiography for measurement of stroke volume at the aortic, pulmonic, and mitral anulus as well as continuous-wave Doppler recording of the aortic jet. Aortic valve area determined at cardiac catheterization by the Gorlin equation ranged between 0.4 and 2.07 cm2 (mean 0.89 +/- 0.45). Doppler-derived valve area, determined with the stroke volume value from either the aortic, pulmonic, or mitral anulus, correlated well with the area determined at cardiac catheterization (r = .95, .97, and .96, respectively). A simplified method for measuring aortic valve area derived as the cross-sectional area of the aortic anulus times peak velocity just proximal to the aortic valve divided by peak aortic jet velocity correlated well with measurements obtained at cardiac catheterization (r = .94). An excellent separation between critical and noncritical aortic stenosis was seen using either one of the Doppler methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction in experimental infarct size by recombinant human superoxide dismutase: insights into the pathophysiology of reperfusion injury.

Abstract: To determine the importance of reperfusion injury and the ability of the free-radical scavenger recombinant human superoxide dismutase (h-SOD) to prevent it, open-chest dogs underwent 90 min of proximal circumflex coronary artery occlusion, and only at the moment of reperfusion received either h-SOD (400,000 IU bolus into the left atrium followed by a 300,000 IU iv infusion over 1 hr) or saline. After 48 hr the surviving animals were killed and measurements were made of the risk region (by postmortem angiography) and infarct size (by gross pathology). All measurements were made by investigators blinded to treatment given, and the code was broken only at the end of the study. Hemodynamic variables and collateral flow during ischemia were similar in the two groups. Infarct size in control animals (n = 8) averaged 22.4 +/- 3.1% of the left ventricle and 52.2 +/- 7.1% of the risk region, compared with 13.3 +/- 0.8% of the left ventricle and 33.6 +/- 2.1% of the risk region in h-SOD-treated dogs (n = 8) (p less than .05). Infarcts in treated animals were not only smaller, but also exhibited a distinctive "patchiness," suggesting protection along vascular distributions. Furthermore, analysis of the relationship between infarct size and collateral flow measured during ischemia in the two groups indicated that protection by h-SOD was greatest in animals with the lowest collateral flows. This study supports the concept that reperfusion of ischemic myocardium results in a separate component of cell damage, presumably linked to the generation of oxygen free radicals on reflow. Since the h-SOD preventable reperfusion component of injury was most pronounced in hearts with the most severe ischemia, scavenging of oxygen radicals at the time of reflow may offer a novel and particularly promising therapeutic approach for the protection of ischemic myocardium.

Determination of left ventricular end-systolic pressure-volume relationships by the conductance (volume) catheter technique.

Abstract: Using a multielectrode conductance catheter to estimate continuous left ventricular volume we determined the end-systolic pressure-volume relationship (ESPVR) in situ in open-chest anesthetized dogs. Dogs (n = 8) were studied in the control state and after pharmacologic sympathectomy (hexamethonium) and surgical vagotomy both before and after the administration of dobutamine. ESPVR was measured during brief (5 to 6 sec) preload reduction by balloon occlusion of the inferior vena cava (IVCBO). The relationship was highly reproducible. The slope (Ecs) and volume intercept (Vo) (mean +/- SD) in the control series were 5.8 +/- 3.6 mm Hg/ml and 6.5 +/- 12.5 ml, respectively. Upon release of the IVCBO (preload recovery), Ecs was 7.7 +/- 3.6 mm Hg/ml and Vo was 12.4 +/- 9.6 ml (p less than .01). Autonomic blockade produced a 50% reduction in Ecs and a concomitant decrease in Vo (p less than .01), and eliminated the difference between ESPVR generated by preload reduction (IVCBO) and preload recovery (IVCBO release). Subsequent dobutamine infusion increased Ecs to 6.1 +/- 3.5 mm Hg/ml and Vo to 4.1 +/- 6.9 ml, consistent with reported changes of the ESPVR with positive inotropic intervention. A small artifact of right ventricular filling was observed in the left ventricular volume catheter signal, but this did not appreciably alter the ESPVR. These results demonstrate the feasibility of the determination of ESPVR in situ by the conductance catheter and brief IVCBO and underline the importance of the use of rapid load changes to minimize reflex activation during the measurements.

The effects of changes in physical activity on major cardiovascular risk factors, hemodynamics, sympathetic function, and glucose utilization in man: a controlled study of four levels of activity.

Abstract: The effects of four levels of activity on heart rate, blood pressure, cardiac index, total peripheral resistance index (TPRI), norepinephrine (NE) spillover rate, insulin sensitivity, and levels of lipids and some hormones were studied in 12 normal subjects. The randomized periods were (1) 4 weeks of below-sedentary activity, (2) 4 weeks of sedentary activity, (3) 4 weeks of 40 min of bicycling three times per week, and (4) 4 weeks of similar bicycling seven times per week. Exercise three times per week reduced resting blood pressure by 10/7 mm Hg (p less than .01) and it was reduced by 12/7 mm Hg after exercise seven times per week (both p less than .01). This was associated with reduction in TPRI, an increase in cardiac index, and cardiac slowing. At the highest level of activity, NE spillover rate, an index of sympathetic activity, fell to 35% of the sedentary value (p less than .001) in eight of 10 subjects. In two other subjects NE spillover rate rose, although blood pressure and TPRI were reduced. Metabolic changes included lowering of total cholesterol, but high-density lipoprotein level was unchanged. Insulin sensitivity rose by 27% after exercise three times per week, but declined to sedentary levels with seven times per week exercise. Maximum oxygen uptake increased linearly with activity. Exercise performed three times per week lowers blood pressure and should reduce cardiovascular risk. The same exercise seven times per week enhances physical performance with little further reduction in cardiovascular risk factors. Exercise is potentially a major nonpharmacologic method of lowering blood pressure.

Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: prevention by a maintenance infusion.

Abstract: Twenty-nine patients with acute myocardial infarction were treated with recombinant human tissue-type plasminogen activator (rt-PA). The incidence of acute coronary reocclusion and its prevention by a maintenance infusion of rt-PA were studied. Intravenous rt-PA was given at a rate of 0.4 to 0.75 mg/kg over 60 to 120 min after angiographic documentation of complete coronary occlusion. Reperfusion was accomplished within 1 hr in 24 of 29 patients (83%) and was associated with a decrease of the plasma fibrinogen level by 20%. In a first group of 13 patients, 11 of whom were successfully reperfused, prevention of reocclusion was attempted with heparin anticoagulation. However, acute reocclusion within 1 hr after cessation of rt-PA was demonstrated angiographically in five of these patients (45%). Quantitative angiographic analysis indicated that acute reocclusion only occurred in patients with 80% or greater residual stenosis. In patients with less than 80% residual stenosis, heparin anticoagulation was sufficient to maintain patency during the hospital stay in four of five patients. In a second group of patients (n = 16), 13 of whom underwent reperfusion with intravenous rt-PA, seven demonstrated a residual stenosis of 80% or greater. These patients were given heparin and, in addition, 10 mg of rt-PA per hour for 4 hr. None developed acute angiographic reocclusion or clinical signs of reocclusion during the hospital stay. Repeat angiography at 10 to 14 days confirmed persistent patency in six of the seven patients. The maintenance infusion resulted in only a moderate additional drop in fibrinogen, while a steady-state plasma rt-PA level of 750 +/- 250 ng/ml was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: the Lipid Research Clinics Coronary Primary Prevention Trial.

Abstract: Plasma levels of high-density lipoprotein cholesterol (HDL-C) at entry and subsequent changes from these baseline levels were inversely predictive of coronary heart disease (CHD) end points in hypercholesterolemic men followed for 7 to 10 years in the Lipid Research Clinics Coronary Primary Prevention Trial, especially in the 1907 participants receiving cholestyramine. When the men in this cohort were compared, each 1 mg/dl increment in baseline HDL-C (mean 44.3 mg/dl) was associated with a 5.5% decrement in risk of "definite" CHD death or myocardial infarction (Z = -5.4), and each 1 mg/dl increase from baseline HDL-C levels (mean increase = 1.6 mg/dl) during the trial was associated with a 4.4% risk reduction (Z = -2.2). In the 1899 participants receiving placebo, the corresponding risk decrements were 3.4% and 1.1%. Although baseline HDL-C level (mean = 44.4 mg/dl) remained a significant risk predictor (Z = -3.8) in the placebo cohort, increases in HDL-C (mean increase 0.5 mg/dl) were not significantly predictive of CHD (Z = -0.6) unless "suspect" as well as "definite" end points were analyzed (Z = -2.0). When the associations between HDL-C (baseline plus change) and incidence of definite CHD end points within each treatment cohort were compared, their difference approached nominal significance (Z = 1.9). The results suggest a synergistic interaction, in which cholestyramine treatment reduced CHD risk most substantially in men maintaining the highest HDL-C levels.