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Reproducibility of radionuclide left ventricular ejection fraction in patients awaiting cardiac transplantation.

Radionuclide-derived left ventricular ejection fraction (LVEF) is used to assess LV systolic function, to follow trends in the natural history of dilated cardiomyopathy, and to prioritize patients waiting for cardiac transplantation. Reproducibility of LVEF at extremely low levels has not, however, been reported. To assess the reproducibility of radionuclide LVEF at levels below 0.30 EF U, 17 highly symptomatic patients (NYHA Class III/IV) with dilated cardiomyopathy were studied on two occasions, 72 hours apart. Sequential scans were analyzed by two independent observers. Mean LVEF was 0.18 +/- 0.06 U (scan 1) and 0.17 +/- 0.06 U (scan 2). Interoperator reproducibility (SD) was 0.03 U (R = 0.76), interscan reproducibility (SD) was 0.03 U (R = 0.62), and overall reproducibility (SD) was 0.04 U (R = 0.50). The interobserver variation of 0.03 (actually 0.027) was just over one half that seen in normal volunteers (variation 0.05, n = 29) studied previously in this department. A change of greater than or equal to 0.08 U (2SD) in either direction is highly likely to represent a real change in LV function in those with LVEF less than or equal to 0.30 units, compared with the change of at least 0.10 units required in those with normal LV function. Lower interobserver and interscan reproducibility should be taken into account when interpreting sequential scans in patients with severe LV dysfunction.

Adolescent↗

New method for calculating right ventricular ejection fraction using gated myocardial perfusion studies.

BACKGROUND: Quantification of right ventricular ejection fraction (RVEF) is important in patients who have right heart failure or cor pulmonale. When Tl-201 was the primary radiotracer used to evaluate myocardial perfusion, the outline of the right ventricle could vary and was not visualized in most patients. However, visualization of the right ventricle has become easier with the use of Tc-99m-labeled myocardial perfusion agents. PURPOSE: This study describes a new method for quantifying RVEF using gated stress myocardial perfusion (GMP) slices. The results are compared with those of first-pass radionuclide ventriculography (FPRNA) in the same patients. METHODS: Fifty-two consecutive patients referred for routine GMP imaging were included. After administration of Tc-99m tetrofosmin, all patients underwent FPRNA using a single crystal gamma camera and a GMP study. Regions of interest (ROI) were drawn to outline the right ventricular cavity at end diastole and end systole from three pairs of GMP slices. The RVEF was calculated from the number of pixels within the ROIs. The mean RVEF obtained using FPRNA and GMP imaging was 51.8 +/- 10.8% and 51.9 +/- 12.3%, respectively. The two methods showed good correlation with r = 0.81. In addition, there was no significant difference in the RVEFs calculated using these methods (P = 0.85). Bland-Altman analysis also showed good agreement between the two methods (limits of agreement +14.4% to -14.0%, slope = 0.19). Intraobserver and interobserver correlation were evaluated by reanalyzing 12 patients using the new RVEF quantification method and were good at r = 0.87 and 0.82, respectively. Therefore, this is a new convenient method for evaluating RVEF as part of a routine tomographic gated myocardial perfusion study.

Adult↗

The effect of various background protocols on the measurement of left ventricular ejection fraction in equilibrium radionuclide angiography.

Four methods of calculating left ventricular ejection fraction from equilibrium radionuclide angiography have been assessed for inter-observer variability and compared to single-plane contrast cineangiography. The superiority of data-processing methods which use a left ventricular region of interest which follows the changing size of the left ventricle into systole is demonstrated. A simple method of correcting for background is suggested as an alternative for those centres not possessing the necessary software for methods involving a changing region of interest.

Angiocardiography↗

[Clinical application of left ventricular volume and ejection fraction derived from gated SPECT data].

Left ventricular (LV) volume and ejection fraction (LVEF) derived from ECG-gated myocardial SPECT data are reproducible and objective. Those quantitative values, however, interacted according to varied factors such as a frame number per R-R interval, tracers, and processing-algorisms. A decrease of frame number per R-R interval yields underestimation of end-diastolic volume and overestimation of end-systolic volume, resulting in underestimation of LVEF. Thus, it is important to change a frame number per R-R interval by the examination purpose. A good correlation of LVEF is usually obtained, independent of a combination of tracer and processing-algorism. On the other hand, LV volume does not always show linearity between combinations of tracer and processing-algorism. An extraction of myocardial edge using QGS program is deteriorating in patients with small LV below 20 ml. It is crucial to assess LV functional values derived from ECG-gated SPECT data as clinical indices, taking the varied effects into consideration.

Algorithms↗

Discrepancy between thermodilution and radionuclide right ventricular ejection fraction measurements: the importance of tricuspid regurgitation.

Measurement of right ventricular ejection fraction (RVEF) by the thermodilution technique has become routinely available at the bedside of the critically ill. We describe 2 patients with tricuspid regurgitation in whom RVEF values were considerably lower by thermodilution than by radionuclide techniques. Discrepancies could be due to the regurgitation of the thermodilution signal and possibly to the different nature of the two measurements (forward stroke volume with the thermodilution technique and total stroke volume with the radionuclide technique). We suggest that lower RVEF measurement by the thermodilution technique could be related to unrecognized tricuspid regurgitation. Measurement of an unexpectedly low RVEF by the thermodilution technique should suggest the presence of tricuspid regurgitation.

Heart↗

Ejection fraction by count rate from gated images.

Left-ventricular (LV) ejection fraction (EF) was determined from ECG-gated images of the cardiac blood pool, by computing the relative change in net LV counts occurring in these images during systole. EFs obtained with this method gave satisfactory interobserver agreement in 20 studies reviewed by three independent observers (average r = 0.95) and also compared favorably with EFs obtained by contrast ventriculography in 39 patients (r = 0.92). The technique appears suitable for use in the evaluation of systolic function in patients with heart disease.

Coronary Circulation↗

Radionuclide ejection fraction in doxorubicin cardiotoxicity.

Serial assessment of cardiac function by radionuclide ejection fraction (EF), using a "first-pass" technique, was performed prior to each dose in 292 patients receiving doxorubicin. Detailed analysis was undertaken in 98 patients, consisting of all 91 patients who had received greater than 200 mg/m2 and seven with risk factors (RFs) who had received between 100 and 200 mg/m2. Thirty-two patients had RFs and 66 had no risk factors (NRFs). RFs were: (a) cardiovascular disease, (b) mediastinal irradiation within 6 months of starting doxorubicin treatment, and (c) total doxorubicin dose greater than 550 mg/m2. The criteria for discontinuing doxorubicin were EF less than 0.40 in RF patients or less than 0.35 in NRF patients or decrease in EF of greater than or equal to 0.14 over three successive readings. In the NRF group, no patient met these criteria nor did any develop cardiac failure. In the RF group, discontinuation was indicated in eight patients: two stopped receiving doxorubicin at total doses of 730 mg/m2 and 680 mg/m2, respectively, and it was discontinued in the other six at total doses ranging from 120 to 420 mg/m2. Prior to the first dose of doxorubicin, all patients should have a baseline EF and assessment of RFs. An EF study is required before each subsequent dose in patients with RFs or with initial EF less than 0.45, but in the remaining patients, serial studies are not required until there is a cumulative dose of 450 mg/m2. Use of these guidelines and our criteria for discontinuation may prevent development of doxorubicin cardiotoxicity.

Adolescent↗

Elevated ejection fractions in patients with the anginal syndrome and normal coronary arteriograms.

The etiology of chest pain in patients with the anginal syndrome and normal coronary arteriograms has not been established. There has been no explanation for the association of electrocardiographic, hemodynamic, and myocardial metabolic abnormalities consistent with myocardial ischemia observed in some patients with this disorder. Historical, clinical, laboratory, and hemodynamic data of 45 patients (24 females, 21 males), mean age 47.5 years, with chest pain and normal coronary arteriograms are reviewed. Left ventriculograms were analyzed utilizing the single-plane cineangiographic measurement of left ventricular volume. Systolic ejection fractions for the 45 patients ranged from 0.66 to 0.91 (mean 0.80 +/- 0.01 SEM). Ventricular volumes determined angiographically revealed mean end-diastolic and end-systolic volumes of 83 +/- 5 ml and 18 +/- 2 ml, respectively. The mean changes in longitudinal and transverse segmental axis shortening that occurred during ventricular systole were 28.8% and 50.7%, respectively. These elevated values for ejection fraction, and reduced measurements of ventricular volumes, indicate that some patients with chest pain and normal coronary arteriograms may have small hearts with hyperdynamic ventricular contraction. These findings suggest that hyperdynamic ventricular contraction may play a causative role in the development of transient, angina-like chest pain in these patients. The etiology of the proposed hyperdynamic ventricle is unknown, but it may be attributable to increased beta-sympathetic stimulation of the myocardium.

Adult↗

Ejection fraction response to upright exercise in hypertension: relation to loading conditions and to contractility.

The respective roles of peripheral and myocardial determinants of exercise ventricular performance were studied in 10 normal volunteers and in 9 mildly hypertensive patients without evidence of coronary disease. Hemodynamic measurements and equilibrium blood pool scintigraphy were simultaneously performed at rest and during maximal upright exercise. In hypertensive patients, mean systolic and diastolic blood pressure were, respectively, 199 +/- 23 and 102 +/- 12 mm Hg at rest, and 271 +/- 28 and 113 +/- 8 mm Hg at peak exercise. Ejection fraction response to exercise was normal (increase by more than 5%) in 4 hypertensive patients (normal hypertensive group: 63 +/- 4 to 77 +/- 6%) and in volunteers (65 +/- 3 to 78 +/- 4%) and abnormal in 5 hypertensive patients (abnormal hypertensive group: 66 +/- 6 to 58 +/- 10% at peak exercise). The abnormal response in the abnormal hypertensive group was not due to an inadequate decrease in systemic vascular resistance during exercise. By contrast, the ratio systolic blood pressure/end-systolic volume, an index of contractility, decreased by 2.3 +/- 4.9 in the abnormal hypertensive group, whereas it increased by 9.8 +/- 9.1 in the normal hypertensive group and by 7.3 +/- 2 in volunteers. Thus, abnormal exercise ejection fraction response in mild hypertension was not related to increased afterload but rather to intrinsic myocardial factors.

Adult↗

Left ventricular ejection fraction and prevalence of new left ventricular wall motion abnormality at long-term follow-up in patients with automatic implantable cardioverter-defibrillators treated with dual-chamber rate-responsive pacing at a rate of 70/minute versus backup ventricular pacing at a rate of 40/minute.

Baseline and long-term follow-up 2-dimensional echocardiograms were obtained in 160 patients with automatic implantable cardioverter-defibrillators without indications for antibradycardia pacing, who had backup ventricular pacing at a rate of 40/minute (VVI-40) or dual-chamber rate-responsive pacing at a rate of 70/minute (DDDR-70). At 37 months of follow-up for 80 patients treated with VVI-40 and 23 months of follow-up for 80 patients treated with DDDR-70, the mean left ventricular ejection fraction was 36 +/- 8% at baseline and 36 +/- 8% at follow-up and 36 +/- 7% at baseline and 30 +/- 7% at follow-up (p <0.01), respectively. At follow-up, the left ventricular ejection fraction was decreased >7% in 25 of 80 patients (31%)treated with DDDR-70 and in 9 of 80 patients (11%) treated with VVI-40 (p <0.01). A new left ventricular wall motion abnormality developed in 23 of 80 patients (29%) treated with DDDR-70 and in 11 of 80 patients (14%) treated with VVI-40 (p <0.025).

Aged↗

Left ventricular function at 3 months after successful thrombolysis. Impact of reocclusion without reinfarction on ejection fraction, regional function, and remodeling.

BACKGROUND: After successful thrombolysis for acute myocardial infarction, reocclusion is observed in about 30% of patients after 3 months and usually occurs without reinfarction. We studied the impact of reocclusion without reinfarction on global and regional left ventricular function and on remodeling during that period. METHODS AND RESULTS: The patients for this analysis constituted a subset of those enrolled in the APRICOT-trial, which was designed to study the efficacy of antithrombotics on the prevention of reocclusion. Patients were selected who had a left anterior descending- or right coronary artery-related myocardial infarction, had an angiographically patent infarct-related vessel when studied < 48 hours after intravenous thrombolysis, and underwent repeat cardiac catheterization at 3 months. Paired contrast ventriculograms of quality sufficient to analyze regional wall motion, global ejection fraction, and ventricular volumes were analyzed in 129 patients. Enzymatic infarct size and baseline left ventricular function as well as other baseline characteristics were similar in patients with (n = 34) and without (n = 95) reocclusion. Ejection fraction improved in anterior infarction without reocclusion from 47 +/- 10% to 54 +/- 13% (P = .0001) but not with reocclusion (baseline, 48 +/- 13%; 3 months, 48 +/- 16%). No improvement was seen in inferior infarction with or without reocclusion. Persistent patency allowed preservation of end-systolic volume index (ESVI) at 3 months (37 +/- 14 mL/m2) to baseline level (38 +/- 13 mL/m2), with a better chance for improvement of > 10 mL/m2 without reocclusion in those with baseline values > 40 mL/m2. After reocclusion, in contrast, ESVI increased from 37 +/- 14 to 43 +/- 20 mL/m2 (P = .08). Comparable mean changes of ESVI in response to persistent patency or reocclusion were seen in anterior versus inferior infarction. Recovery of infarct zone contractility was impaired by reocclusion, both in terms of abnormality of segment shortening and expressed in the number of segments showing abnormal wall motion. In anterior but not in inferior infarction, infarct zone contractility was better with good collaterals to the reoccluded artery compared with poor collaterals. CONCLUSIONS: After successful thrombolysis for acute myocardial infarction, reocclusion without reinfarction withholds salvaged myocardium from regaining contractility. This has deleterious consequences for regional and global left ventricular function and for remodeling. To further optimize prognosis in patients after thrombolysis, future research should focus on the prevention of reocclusion and should evaluate revascularization therapy in patients with reocclusion.

Collateral Circulation↗

Hypertrophy, increased ejection fraction, and reduced Na-K-ATPase activity in phospholemman-deficient mice.

Phospholemman (FXYD1), a 72-amino acid transmembrane protein abundantly expressed in the heart and skeletal muscle, is a major substrate for phosphorylation in the cardiomyocyte sarcolemma. Biochemical, cellular, and electrophysiological studies have suggested a number of possible roles for this protein, including ion channel modulator, taurine-release channel, Na(+)/Ca(2+) exchanger modulator, and Na-K-ATPase-associated subunit. We have generated a phospholemman-deficient mouse. The adult null mice exhibited increased cardiac mass, larger cardiomyocytes, and ejection fractions that were 9% higher by magnetic resonance imaging compared with wild-type animals. Notably, this occurred in the absence of hypertension. Total Na-K-ATPase activity was 50% lower in the phospholemman-deficient hearts. Expression (per unit of membrane protein) of total Na-K-ATPase was only slightly diminished, but expression of the minor alpha(2)-isoform, which has been specifically implicated in the control of contractility, was reduced by 60%. The absence of phospholemman thus results in a complex response, including a surprisingly large reduction in intrinsic Na-K-ATPase activity, changes in Na-K-ATPase isoform expression, increase in ejection fraction, and increase in cardiac mass. We hypothesize that a primary effect of phospholemman is to modulate the Na-K-ATPase and that its reduced activity initiates compensatory responses.

Animals↗

Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure.

BACKGROUND: With beta-blocker use becoming more prevalent in treating chronic heart failure (CHF), the choice of drugs raises important theoretical and practical questions. Although the second-generation compound metoprolol is beta1-selective, the third-generation compound carvedilol is beta-nonselective, with ancillary pharmacological properties including alpha-blockade and antioxidant effects. A prospective comparison of these 2 agents can address the issue of optimal adrenergic blockade in selecting agents for therapy in CHF. METHODS AND RESULTS: Sixty-seven patients with symptomatic stable heart failure were randomly assigned to receive either carvedilol or metoprolol in addition to standard therapy for CHF. Measured variables included symptoms, exercise, ejection fraction, and thiobarbituric acid-reactive substances (TBARS) as an indirect marker of free radical activity. Metoprolol and carvedilol were well tolerated, and both patient groups showed beneficial effects of beta-blocker therapy in each of the measured parameters, with no between-group differences. Ejection fraction increased over 6 months from 18+/-6.3% to 23+/-8.7% (P<0.005) with metoprolol and from 19+/-8.5% to 25+/-9.9% (P<0.0005) with carvedilol (P=NS between groups). With metoprolol, TBARS values decreased from 4.7+/-0.9 nmol/mL at baseline to 4.2+/-1.5 nmol/mL at month 4 to 3.9+/-1.0 nmol/mL at month 6 (P<0.0001). With carvedilol, there was a parallel decline from 4.7+/-1.4 to 4.2+/-1.3 to 4.1+/-1.2 nmol/mL over the same time frame (P<0.025), with no between-group difference in these changes. CONCLUSIONS: Carvedilol and metoprolol showed parallel beneficial effects in the measured parameters over 6 months, with no relevant between-group differences in this heart failure population.

Adrenergic beta-Antagonists↗

Angiotensin II inhibition during myocardial ischemia-reperfusion in dogs: effects on leukocyte infiltration, nitric oxide synthase isoenzymes activity and left ventricular ejection fraction.

Leukocyte infiltration and activation in myocardial reperfusion injury may be modulated by nitric oxide synthase isoforms. Angiotensin II influences leukocyte activation directly or by nitric oxide generation mechanisms. The effects of angiotensin II inhibition before reperfusion on myocardial function, leukocyte accumulation and nitric oxide synthase were evaluated on three groups of eight dogs. They were submitted to occlusion of the left anterior descending coronary artery for 90 min, followed by 120 min of reperfusion. The first group received captopril, the second losartan and the third received normal saline solution. Left ventricular ejection fraction significantly improved after reperfusion in the groups under captopril (15+/-5.1%, p=0.029) and losartan (16+/-4.3%, p=0.014) when compared to the control group (7+/-2.5%). Myeloperoxidase activity was significantly lower in captopril group (6.6+/-1.0 U/100 mg, p=0,036) and losartan (6.8+/-1.7 U/100 mg, p=0.044) than in the control group (12.5+/-4.7 U/100 mg). Significant difference on constitutive nitric oxide synthase activity was not observed when all three groups were compared simultaneously (10.1+/-1.8 versus 8.5+/-1.3 versus 7.3+/-1.9 fM/mg/min, p=0.447). Inducible nitric oxide synthase activity was significantly lower in the losartan group (9.0+/-4.1 fM/mg/min) than in the captopril (29.2+/-5.1 fM/mg/min, p=0.0001) and control groups (26.2+/-4.6 fM/mg/min, p=0.0001). Angiotensin II inhibition reduced leukocyte infiltration and improved left ventricular ejection fraction during reperfusion by angiotensin-converting enzyme inhibition or by angiotensin II type 1 receptor blocker. This was observed without influencing the constitutive nitric oxide synthase activity. Only losartan reduced inducible nitric oxide synthase activity but did not influence the leukocyte infiltration and myocardial contractile function.

Angiotensin-Converting Enzyme Inhibitors↗

Early and subtle abnormalities of left ventricular function in clinically stable coronary artery disease patients with normal ejection fraction.

BACKGROUND: It has been reported that, in the initial phase of ischemic cardiomyopathy, the earliest alterations of left ventricular function are detected during the relaxation phase. The aim of this study was to look for precocious abnormalities in the early stage of ischemic cardiomyopathy in both left ventricular systolic and diastolic phases. METHODS AND RESULTS: Using simultaneous left ventricular catheterization and echo-Doppler techniques, we studied both systolic and diastolic function in 44 (37 males and 7 females, mean age 55.7+/-8) normotensive, clinically stable, coronary artery disease patients with normal left ventricular ejection fraction in comparison to 9 age- and sex-matched normal control subjects (7 males and 2 females, mean age 54.7+/-9). Mean values of E deceleration time, tau, left ventricular end-diastolic volume and pressure, and end-systolic volume and lowest diastolic pressure were significantly higher (from P<.05 to P<.01), whereas mean dP/dt/P values significantly lower (P<.05) in coronary artery disease patients than in controls. A strict relationship (P<.001) between dP/dt/P and tau, left ventricular lowest and end-diastolic pressure was found in all subjects studied. CONCLUSION: Early and subtle abnormalities in parameters of both systolic and diastolic function can be found in the majority of coronary artery disease patients with normal ejection fraction.

Coronary Artery Disease↗

MR imaging of the heart in patients after myocardial infarction: effect of increasing intersection gap on measurements of left ventricular volume, ejection fraction, and wall thickness.

PURPOSE: To determine the extent to which the number of planes imaged at magnetic resonance (MR) imaging could be reduced without modifying the calculated volume and thickness of the left ventricle. MATERIALS AND METHODS: Sixty-one patients were examined after a myocardial infarction. The whole left ventricle was imaged by using 5-mm contiguous breath-hold cine MR short-axis sections with no gap (SAng) (two-dimensional fast low-angle shot sequence, 9/4.8 [repetition time msec/echo time msec]). The effect of omitting one section in two (short-axis sections with 5-mm gap [SA5 mm]) or two sections in three (short-axis sections with 10-mm gap [SA10 mm]) was studied. RESULTS: In the comparison of SA5 mm or SA10 mm with respect to the reference SAng, the standard error of the estimate (SEE) for the diastolic volume did not exceed the 6.1% interobserver SEE, and the SEE for the ejection fraction remained lower than the 3% interobserver SEE. The measured wall thickness was not affected. In addition, six simple geometric models were compared with SAng and yielded an SEE of 9.5%-28.1% for the diastolic volume and 3.8%-13.3% for the ejection fraction. CONCLUSION: In the study of left ventricles with heterogeneous contractility, short-axis imaging is more accurate than geometric modeling and permits wall thickness measurements when an intersection gap of 5 or 10 mm is used.

Adult↗

Improvement in forward cardiac output without a change in ejection fraction during nitroglycerin therapy in patients with functional mitral regurgitation.

Left ventricular volumes and forward aortic flow were measured using combined two-dimensional echocardiography and doppler cardiography in seven patients with decompensated congestive heart failure and functional mitral regurgitation prior to and during intravenous administration of nitroglycerin. Total stroke volume was calculated from the difference between end-diastolic and end-systolic volumes, and regurgitant mitral volume from the difference between total stroke volume and forward aortic flow. Regurgitant mitral volume fell from 19 +/- 9 to 3 +/- 3 mL/beat (p less than 0.001), while forward stroke volume increased from 35 +/- 8 to 45 +/- 9 mL/beat (p less than 0.001). The changes were well correlated (r = 0.8, p less than 0.001). Total stroke volume decreased from 54 +/- 12 to 48 +/- 6 mL/beat (p less than 0.05), and ventricular end-diastolic volume from 173 +/- 66 to 158 +/- 66 mL (p less than 0.05). Left ventricular ejection fraction did not change significantly: 33 +/- 9% vs 32 +/- 9% (NS). Thus, in patients with severe congestive heart failure and functional mitral regurgitation, intravenous nitroglycerin redistributes blood flow within the heart by decreasing mitral regurgitation and increasing forward aortic flow, without affecting left ventricular ejection fraction.

Aged↗

Metoprolol CR/XL in patients with heart failure: A pilot study examining the tolerability, safety, and effect on left ventricular ejection fraction.

BACKGROUND: This study was designed to investigate the tolerability, safety, and effect on left ventricular function of a new long-acting preparation of metoprolol, metoprolol succinate (CR/XL). METHODS AND RESULTS: Sixty patients were randomly assigned with a 2:1 ratio, drug versus placebo, administered with a gradually increasing dose of 12.5 to 150 mg of blinded medication during an 8-week period and continued for 6 months. The average peak dose achieved was 99 mg and 132 mg in the metoprolol succinate and placebo groups, respectively. The drug was well tolerated and there was no significant difference in drug withdrawals, New York Heart Association class, or quality of life assessment. The increase in left ventricular ejection fraction measure at baseline and 6 months measured by radioisotopic ventriculography was greater in the metoprolol succinate group (27. 5% to 36.3%) than in the placebo group (26% to 27.9%) (P <.015). Examination of serial Holter electrocardiographic recordings indicate that metoprolol succinate therapy was associated with a significant (P <.05) decrease in total ventricular ectopy at 8 weeks of therapy and a decrease in ventricular couplets and nonsustained ventricular tachycardia at 8 through 26 weeks of therapy. No changes were observed in plasma norepinephrine during therapy except a transitory significant (P <.05) increase in N terminal proatrial natriuretic factor at 8 weeks in the metoprolol succinate group. CONCLUSIONS: This study indicates that treatment with metoprolol succinate for a 6-month period is safe and well tolerated and is associated with an increase in left ventricular ejection fraction and a decrease in ventricular ectopic beats.

Double-Blind Method↗