Muscarinic receptor modulation of basal and beta-adrenergic stimulated function of the failing human left ventricle.

The objective of this study was to evaluate the effect of muscarinic receptor modulation on basal and beta-adrenergic stimulated left ventricular function in patients with heart failure. 21 heart failure patients and 14 subjects with normal ventricular function were studied. In Protocol 1 intracoronary acetylcholine resulted in a 60+/-8% inhibition of the left ventricular +dP/dt response to intracoronary dobutamine in the normal group, and a similar 70+/-13% inhibition in the heart failure group. Acetylcholine also attenuated the dobutamine-mediated acceleration of isovolumic relaxation (Tau) in both groups. Acetylcholine alone had no effect on Tau in the normal group, while it prolonged Tau in the heart failure group. In Protocol 2 intracoronary atropine resulted in a 35+/-10% augmentation of the inotropic response to dobutamine in the normal group, versus a non-significant 12+/-15% augmentation of the dobutamine response in the heart failure group. In Protocol 3, in 6 heart failure patients, both effects of acetylcholine, the slowing of ventricular relaxation and the inhibition of beta-adrenergic responses, were reversed by the addition of atropine. Therefore, in the failing human left ventricle muscarinic stimulation has an independent negative lusitropic effect and antagonizes the effects of beta-adrenergic stimulation.

Functional significance of presynaptic alpha-adrenergic receptors in failing and nonfailing human left ventricle.

BACKGROUND: There are alpha-adrenergic receptors on human myocardium that exert positive inotropic effects. The effect of alpha-adrenergic receptor blockade on human left ventricular (LV) performance has not been fully explored. Although alpha-adrenergic receptor blockade might have effects on LV function that are mediated via blockade of postsynaptic myocardial alpha-adrenergic receptors, it is also possible that blockade of presynaptic alpha 2-adrenergic receptors and subsequent increased release of norepinephrine would have effects on LV performance. In the present study, we explored the effects of nonselective alpha-adrenergic receptor blockade on LV performance and transcardiac norepinephrine concentrations in a group of patients with normal LV function and in a group of patients with congestive heart failure secondary to dilated cardiomyopathy. METHODS AND RESULTS: Using an intracoronary drug infusion technique, we administered the nonselective alpha-adrenergic antagonist phentolamine to 13 patients with normal LV function and 19 patients with congestive heart failure secondary to dilated cardiomyopathy. With a high-fidelity LV catheter, the systolic (+dP/dt) and diastolic (-dP/dt and Tau) LV function responses to intracoronary infusion of phentolamine (0.2 mg/min x 5 minutes) were assessed. In 8 patients with normal ventricular function and 10 patients with congestive heart failure, arterial and coronary sinus blood samples were drawn to determine the effects of phentolamine on catecholamine concentrations. Phentolamine had no measurable effect on LV performance or catecholamine concentrations in the normal ventricular function group. In patients with congestive heart failure, intracoronary phentolamine caused a significant increase in +dP/dt and the rate of isovolumic LV relaxation (-dP/dt and Tau). These hemodynamic effects were accompanied by a significant increase in coronary sinus norepinephrine concentration but no change in arterial norepinephrine concentration. CONCLUSIONS: Myocardial alpha-adrenergic receptor blockade causes significant inotropic and lusitropic effects in the failing but not the nonfailing human LV. These effects appear to be mediated by increased release of norepinephrine from cardiac nerves secondary to blockade of presynaptic alpha 2-adrenergic receptors. Differences in the responses of the failing and nonfailing human LV appear to reflect the higher level of sympathetic activation that is seen in the group with congestive heart failure. This suggests that the presynaptic alpha 2-adrenergic receptor exerts a tonic inhibitory effect on the release of norepinephrine from cardiac nerves in patients with congestive heart failure.

Effects of intracoronary acetylcholine and atropine on basal and dobutamine-stimulated left ventricular contractility.

BACKGROUND: The role of cholinergic pathways in modulating left ventricular contractile function in humans is not known. This study evaluated the effect of a cholinergic agonist (acetylcholine) and antagonist (atropine) on basal and beta-adrenergically stimulated left ventricular contractile function in normal subjects and subjects with denervated hearts after cardiac transplantation. METHODS AND RESULTS: Six subjects with normal left ventricular function and seven subjects who were 1 to 3 years after cardiac transplantation were studied. Acetylcholine, atropine, and the beta-adrenergic agonist dobutamine were infused via the left main coronary artery, and changes in left ventricular contractile function were assessed by measurement of peak +dP/dt. Intracoronary dobutamine increased +dP/dt by 70 +/- 15% and 66 +/- 20% in the normal subjects and transplant recipients, respectively. Intracoronary acetylcholine and atropine alone each had no effect on left ventricular +dP/dt in either normal subjects or transplant recipients. The concurrent infusion of acetylcholine with dobutamine reduced the response to dobutamine by 66 +/- 10% and 79 +/- 9% in normal subjects and transplant recipients, respectively. The concurrent infusion of atropine with dobutamine potentiated the response to dobutamine by 25 +/- 7% in normal subjects but had no effect in transplant recipients. CONCLUSIONS: Stimulation and inhibition of cholinergic receptors in the human heart can modulate the positive inotropic response to beta-adrenergic stimulation.

Excimer laser-assisted coronary angioplasty for lesions containing thrombus.

OBJECTIVES: The purpose of this study was to analyze the success rates for excimer laser-assisted coronary angioplasty performed in patients undergoing angioplasty for lesions containing thrombus. BACKGROUND: The presence of intracoronary thrombus increases the risk of a poor clinical outcome after balloon angioplasty. The effect of intracoronary thrombus on the safety and efficacy of excimer laser-assisted coronary angioplasty is unknown. METHODS: Percutaneous excimer laser-assisted coronary angioplasty was attempted in 142 patients, of whom 12 had angiographic evidence of intracoronary thrombus in 14 lesions, defined as a filling defect surrounded by contrast medium or an area of contrast staining. RESULTS: Clinical success (< 50% residual stenosis without myocardial infarction, death or bypass surgery at any time during hospitalization) was achieved in 7 (58%) of the 12 patients with intracoronary thrombus, compared with 123 (95%) of the 130 patients without thrombus (p = 0.00001). Angiographic and clinical complications were more common in patients with thrombus: embolization (25% vs. 1%, p < 0.001), myocardial infarction (33% vs. 2%, p < 0.001), abrupt closure (17% vs. 4%, p = 0.049). Angiographic restenosis at 6 months was seen at 7 (70%) of 10 treated sites with intracoronary thrombus and at 59 (51%) of 116 sites without thrombus (p = 0.245). Presence of intracoronary thrombus was identified as the most important predictor of clinical success (p = 0.013) by multivariable logistic regression analysis, which controlled for other co-variables, such as lesion complexity or lesion location in a saphenous vein graft. CONCLUSIONS: This analysis shows that the success of excimer laser-assisted coronary angioplasty is compromised when thrombus is detected angiographically. Further investigation of other strategies is needed to improve the outcome of angioplasty for this challenging problem.

Etiology of the Austin Flint murmur.

OBJECTIVES: The aim of the study was to determine the mechanism of the Austin Flint murmur. BACKGROUND: More than 100 years after the initial description of the Austin Flint murmur, the etiology of the murmur remains unclear. METHODS: M-mode and two-dimensional echocardiography, conventional and color flow Doppler study, and cine nuclear magnetic resonance (cine NMR) imaging were performed in 24 patients with clinically moderate or severe aortic regurgitation. Mitral valve area was determined by planimetry and pressure half-time measurement. Overlap of the aortic regurgitation and mitral inflow jets was graded 0 (no overlap) to 4 (marked overlap) by Doppler study and cine NMR imaging. The volume of signal loss resulting from turbulent blood flow secondary to the aortic regurgitation jet was determined on cine NMR images, and the extent of contact with the left ventricular endocardium was graded 0 (no contact) to 4 (extensive contact). RESULTS: The presence of an Austin Flint murmur did not correlate with mitral valve area (2.7 +/- 0.8 cm2 with the murmur vs. 2.5 +/- 0.7 cm2 without), overlap of the aortic regurgitation and mitral flow jets (3 +/- 1 vs. 2.3 +/- 1.2), diastolic mitral regurgitation (50% vs. 71%) or fluttering of the anterior mitral valve leaflet (70% vs. 50%). The presence of an Austin Flint murmur correlated best with the volume of signal loss associated with the aortic regurgitation jet on cine NMR imaging (65 +/- 16 ml with the murmur. vs. 38 +/- 11 ml without, p less than 0.001) and the extent of contact of this signal loss with the left ventricular endocardium (2.9 +/- 0.5 vs. 1.5 +/- 0.4, p less than 0.0001). CONCLUSIONS: The Austin Flint murmur is caused by the aortic regurgitation jet abutting the left ventricular endocardium, resulting in the generation of a low-pitched diastolic rumbling.

Effects of myocardial alpha 1-adrenergic receptor stimulation and blockade on contractility in humans.

BACKGROUND: Although alpha-adrenergic receptors are present in both normal and failing human left ventricular myocardium and mediate a positive inotropic effect in several other species, it is not known whether stimulation of myocardial alpha-adrenergic receptors exerts a positive inotropic effect or contributes to basal contractile state in vivo in humans. METHODS AND RESULTS: We studied 15 patients with angiographically normal coronary arteries (seven with normal left ventricular function and eight with left ventricular failure). To avoid the confounding effects of changes in ventricular loading conditions and systemic reflex mechanisms, the alpha-adrenergic receptor-selective antagonist phentolamine and agonist phenylephrine were infused directly into the left main coronary artery, and the change in contractile state was assessed by measuring left ventricular peak (+)dP/dt. Phentolamine alone had no effect on left ventricular contractility. Phenylephrine exerted a concentration-related positive inotropic effect in patients with normal as well as those with failing ventricles. The alpha-adrenergic effect of phenylephrine, defined as the component blocked by phentolamine, was significantly less in patients with ventricular failure (108 +/- 28 mm Hg/sec) than in normal subjects (248 +/- 54 mm Hg/sec; p less than 0.03). CONCLUSIONS: Myocardial alpha-adrenergic receptors do not contribute to the maintenance of basal left ventricular contractile state in humans. However, stimulation of myocardial alpha-adrenergic receptors exerts a positive inotropic effect, the magnitude of which may be attenuated in patients with heart failure.

Effects of beta-adrenergic stimulation with dobutamine on isovolumic relaxation in the normal and failing human left ventricle.

BACKGROUND: We tested the hypothesis that beta-adrenergic receptor-stimulated acceleration of left ventricular (LV) isovolumic relaxation (i.e., positive lusitropic response) is attenuated in patients with severe congestive heart failure (CHF) compared with patients without LV dysfunction or CHF. METHODS AND RESULTS: The beta-adrenergic agonist dobutamine was infused by the intracoronary route in 14 subjects (normal group, six; CHF patients, eight) and by the intravenous route in a second group of 14 subjects (normal group, four; CHF patients, 10). The positive inotropic response to intracoronary or intravenous dobutamine was substantially and significantly reduced in the patients with CHF. LV isovolumic relaxation rate was determined by the methods of Weiss (TL), Mirsky (T1/2), and by a nonlinear regression technique (TNL). LV isovolumic relaxation assessed by all three methods was significantly prolonged in CHF patients compared with normal subjects. Intracoronary and intravenous infusions of dobutamine caused significant acceleration of LV isovolumic relaxation in both normal subjects and patients with CHF. The magnitude of the dobutamine-stimulated acceleration of isovolumic relaxation in patients with CHF was comparable with that in normal subjects. CONCLUSIONS: These data demonstrate that beta-adrenergic receptor stimulation causes significant acceleration of LV isovolumic relaxation in both normal subjects and patients with severe CHF. Coronary to our hypothesis, the lusitropic response to beta-adrenergic stimulation is well preserved in patients with severe CHF despite substantial attenuation of the beta-adrenergic positive inotropic response. These findings have potentially important implications regarding the physiology and pharmacology of adrenergically mediated LV relaxation in humans.

Benefits of physiologic atrioventricular synchronization for pacing with an exercise rate response.

Although the loss of atrioventricular (AV) synchronization may diminish resting cardiac output, previous studies have not shown any impact on exercise capacity as long as an exercise rate response is present. To test the impact of suboptimal atrial activation during treadmill exercise, 12 patients with normal sinoatrial node function and dual chamber pacemakers were evaluated in pacemaker modes with normal AV intervals allowing maximal atrial contribution to ventricular filling and with the shortest programmable nonphysiologic AV delay. During a double-blinded randomized crossover protocol, exercise performance was improved with physiologic AV filling in comparison with nonphysiologic AV filling: (1) mean increase in exercise time was 16 +/- 16% (mean +/- standard deviation) (p less than 0.05); (2) time to anaerobic threshold was increased by 23 +/- 28% (p less than 0.05); and (3) the level of perceived exertion during comparable stages of exercise was decreased. In 3 patients, exercise time was greater by greater than 35% in the physiologic AV filling mode. Resting echo-Doppler parameters of left atrial and ventricular function did not predict benefit from AV synchronization during exercise. During exercise with rate-responsive pacing an appropriate AV relation is beneficial, and in a subset of patients this benefit may be striking.

Comparison of cine MR imaging with Doppler echocardiography for the evaluation of aortic regurgitation.

Regurgitant blood flow is associated with localized signal loss of the blood pool within the recipient chamber on cine MR images, which may be useful for assessing regurgitant valvular disease. To evaluate the potential of this technique for determining the severity of aortic regurgitation, multilevel cine MR imaging was performed in 10 normal volunteers and in 25 patients with aortic regurgitation documented and graded for severity by Doppler echocardiography. Cine MR images were analyzed to obtain cardiac chamber volumes and to measure the extent of the signal loss associated with regurgitation. All regurgitant lesions were visualized on cine MR images as areas of diastolic signal loss extending from the aortic valve into the left ventricle. The extent of signal loss and the regurgitant volume determined from analysis of MR images correlated with the echocardiographic severity of the lesion. The total area of diastolic left ventricular signal loss was 0 cm2 in 10 normal volunteers, 24 +/- 13 (+/- SD) cm2 in eight patients with mild aortic regurgitation, 49 +/- 11 cm2 in nine patients with moderate aortic regurgitation, and 62 +/- 20 cm2 in eight patients with severe aortic regurgitation (p less than .05 for moderate and severe vs mild). Left ventricular volumes calculated from MR images correlated well with echocardiographic volumes (r = .92, SEE = 30 ml, p less than .0001). Regurgitant fraction calculated from analysis of cine MR images was 4 +/- 7% in normal volunteers and 31 +/- 8% in mild, 45 +/- 11% in moderate, and 56 +/- 9% in severe aortic regurgitation (p less than .05 for moderate and severe vs mild and normal). Thus, cine MR imaging can provide useful qualitative and quantitative data regarding cardiac dimensions and regurgitant valvular flow in patients with aortic regurgitation.

Physician recognition and treatment of hypercholesterolemia.

To assess physician behavior regarding hypercholesterolemia, records of patients whose serum cholesterol levels averaged 6.85 mmol/L or greater during a two-month period were reviewed. Of 111 eligible patients, physicians noted hypercholesterolemia in 62 (56%) and prescribed treatment in 34 (31%). Excluding those whose condition had been previously diagnosed and who were receiving treatment at the time of initiation of the study, only 22% of patients with high-risk serum cholesterol levels received treatment. An aggressive physician education program on the definition, evaluation, and management of hypercholesterolemia is needed.

Cardiac consequences of renal transplantation: changes in left ventricular morphology and function.

To characterize changes in left ventricular morphology and function associated with renal transplantation, noninvasive cardiac evaluations were performed in 41 adults at the time of surgery and at follow-up. At the time of transplantation, 36 patients had undergone hemodialysis through a fistula for 2.3 +/- 2.5 years (mean +/- SD); their hematocrit level was 26 +/- 6% and systolic blood pressure was 151 +/- 19 mm Hg. Perioperatively, left ventricular hypertrophy was present in 93% of patients by echocardiography, but in only 37% by electrocardiography. Abnormal left ventricular diastolic function was present in 67% of patients and indicated a high risk for perioperative pulmonary edema. At follow-up (1.5 +/- 1.4 years), mean hematocrit level increased to 39 +/- 7%, systolic blood pressure decreased to 132 +/- 14 mm Hg and spontaneous closure of the fistula occurred in 13 patients. Left ventricular mass by echocardiography decreased from 237 +/- 66 to 182 +/- 47 g (p less than 0.001), a decrease of 23%. Left ventricular volumes and cardiac index also decreased significantly, reflecting the rapid resolution of a pretransplant high output state. Despite proportionate regression of left ventricular hypertrophy within months of transplantation, diastolic function did not improve. The significant regression of left ventricular hypertrophy that occurs after renal transplantation may help explain the improved cardiovascular survival of patients with a renal transplant over that of patients on long-term dialysis.

The transponder system: a new method of precise catheter placement in the right atrium under echocardiographic guidance.

The ability to localize catheters within the heart has gained importance with the use of percutaneous catheter ablation and the transseptal approach for valvuloplasty. A prototype interactive transponder catheter system, specifically designed to mark the catheter tip for echocardiographic visualization, was used to place catheters at the tricuspid anulus and the fossa ovalis in anesthetized dogs. Catheter tip location was marked by lesions produced by radiofrequency energy delivered at the distal catheter electrode. At autopsy, the center of the radiofrequency-induced lesion was located 2.8 +/- 0.7 mm from the edge of the lateral tricuspid anulus and 3.5 +/- 3.1 mm from the center of the fossa ovalis. The transponder catheter system offers the ability to precisely position catheters in the right atrium under echocardiographic guidance.

The echo-transponder electrode catheter: a new method for mapping the left ventricle.

The ability to locate catheter position in the left ventricle with respect to endocardial landmarks might enhance the accuracy of ventricular tachycardia mapping. An echo-transponder system (Telectronics, Inc.) was compared with biplane fluoroscopy for left ventricular endocardial mapping. A 6F electrode catheter was modified with the addition of a piezoelectric crystal 5 mm from the tip. This crystal was connected to a transponder that received and transmitted ultrasound, resulting in a discrete artifact on the two-dimensional echocardiographic image corresponding to the position of the catheter tip. Catheters were introduced percutaneously into the left ventricle of nine anesthetized dogs. Two-dimensional echo-transponder and biplane fluoroscopic images were recorded on videotape with the catheter at multiple endocardial sites. Catheter location was marked by delivering radiofrequency current to the distal electrode, creating a small endocardial lesion. Catheter location by echo-transponder and by fluoroscopy were compared with lesion location without knowledge of other data. Location by echo-transponder was 8.7 +/- 5.1 mm from the center of the radiofrequency lesion versus 14 + 7.8 mm by fluoroscopy (n = 15, p = 0.023). Echo-transponder localization is more precise than is biplane fluoroscopy and may enhance the accuracy of left ventricular electrophysiologic mapping.

Reproducibility of quantitative two-dimensional echocardiography.

In order to assess reproducibility of quantitative planimetry, three physicians trained in two-dimensional echocardiography performed five successive studies on one another over 2 weeks (30 total studies). Then each physician traced each study (90 total tracings) for left ventricular and atrial volumes and ejection fraction by means of a modification of Simpson's rule, and left ventricular mass and average wall thickness by means of a truncated ellipsoid formula. Calculation of intertechnician variability, intertracer variability, and 95% confidence limits showed that measurements of volumes were less reproducible than measurements of ejection fraction, average wall thickness, and mass. Mean intertracer variability of 15% exceeded mean intertechnician variability of 11%; this disparity was magnified in the subject who was technically difficult to image. Ninety-five percent confidence limits were: ejection fraction +/- 7%, average wall thickness +/- 9%, left ventricular mass +/- 12%, left ventricular end-diastolic volume +/- 11%, stroke volume +/- 14%, left ventricular end-systolic volume +/- 15%, and left atrial volume +/- 19%. Reproducible planimetry data can be obtained in normal hearts with the use of a protocol for quantitative imaging and planimetry.