Effects of carvedilol in heart failure due to dilated cardiomyopathy. Results of a double-blind randomized placebo-controlled study (CARIBE study).

OBJECTIVE: To assess the effects of carvedilol in patients with idiopathic dilated cardiomyopathy. METHODS: In a double-blind randomized placebo-controlled study, 30 patients (7 women) with functional class II and III heart failure were assessed. Their ages ranged from 28 to 66 years (mean of 43 +/- 9 years), and their left ventricular ejection fraction varied from 8% to 35%. Carvedilol was added to the usual therapy of 20 patients; placebo was added to the usual therapy of 10 patients. The initial dose of carvedilol was 12.5 mg, which was increased weekly until it reached 75 mg/day, according to the patient's tolerance. Clinical assessment, electrocardiogram, echocardiogram, and radionuclide ventriculography were performed in the pretreatment phase, being repeated after 2 and 6 months of medication use. RESULTS: A reduction in heart rate (p = 0.016) as well as an increase in left ventricular shortening fraction (p = 0.02) and in left ventricular ejection fraction (p = 0.017) occurred in the group using carvedilol as compared with that using placebo. CONCLUSION: Carvedilol added to the usual therapy for heart failure resulted in better heart function.

Coronary revascularization in the treatment of moderate and severe postischemic left ventricular dysfunction.

Chronic postischemic left ventricular (LV) dysfunction can improve following coronary revascularization (hibernating myocardium). However, it is not clear whether the severity of LV dysfunction determines functional outcome after revascularization and the accuracy of tests to predict myocardial viability. We studied 47 patients with coronary artery disease and chronic LV dysfunction. Before coronary bypass, patients underwent (18F)2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) during euglycemic hyperinsulinemic clamp to assess viability. Global and regional LV function were assessed before and 4 to 6 months after surgery. Patients were arbitrarily divided into 2 groups with moderate and severe LV dysfunction. Group 1 (n = 26) had an ejection fraction (EF) of < or = 30% and group 2 (n = 21) > 30%. After bypass, the EF (22+/-6% vs 31+/-10%; p <0.0001) and global wall motion score (WMS) (2.05+/-0.39 vs 1.56+/-0.34; p <0.001) improved in group 1, whereas the EF (43+/-9% vs 43+/-12%; p = NS) was unchanged in group 2, although WMS tended to improve (1.42+/-0.38 vs 1.32+/-0.39; p = 0.09). The proportion of dysfunctional segments (72% vs 32%; p <0.0001) and FDG uptake in these segments (0.44+/-0.15 vs 0.34+/-0.15 micromol/g/min, p <0.0001) were greater in group 1 than in group 2. The baseline EF influenced the predictive accuracy of PET, with highest positive predictive accuracy in group 2 and highest negative predictive accuracy in group 1. Thus, coronary revascularization has the potential for greatest benefit in patients with the most severe dysfunction, but with evidence of viability, and the entity of LV dysfunction affects the predictive accuracy of viability studies.

Non-invasive measurement of left ventricular volumes and function by gated positron emission tomography.

To date cardiac positron emission tomography (PET) studies have focussed on the measurement of myocardial blood flow, metabolism and receptors while left ventricular (LV) function and dimensions have been derived from other modalities. The main drawback of this approach is the difficulty of data co-registration, which limits clinical interpretation. The aim of this study was to evaluate whether it is possible to measure absolute cardiac volumes, and consequently LV function parameters such as ejection fraction, and wall motion with gated PET. Nineteen patients underwent a PET scan and planar radionuclide ventriculography (MUGA) within 9+/-9 days. A 9-min scan (16 gates/cardiac cycle) was acquired after inhalation of 3 MBq/ml of oxygen-15 labelled carbon monoxide at the rate of 500 ml/min over 4 min using a multislice PET camera. Noise reduction was performed on the gated image to enhance the definition of the ventricles before reslicing to the short-axis view. A threshold value was used to detect the edge of the LV at each gate. LV volumes at each gate were estimated by summing the volume of voxels within the LV boundary. PET measurements of LV volumes were as follows: LV end-diastolic volume ranged from 72 to 233 ml and LV end-systolic volume ranged from 24 to 203 ml. Phantom experiments supported the validity of this approach for estimating volumes. LV ejection fraction measured with MUGA was 38.4%+/-16.3% (range 15%-71%) and that measured with PET was 39.6%+/-17.7% (range 9%-72%) (P=NS). The LV ejection fraction measurements were highly correlated (r2=0.824). These results indicate that: (1) absolute end-diastolic and end-systolic volumes can be quantified using gated PET and (2) LV ejection fraction can be accurately measured by gated PET simultaneously with the other physiological PET parameters.

Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease. A study with positron emission tomography.

Patients with coronary artery disease or heart failure have been shown to be insulin resistant. Whether in these patients heart muscle participates in the insulin resistance, and whether reduced blood flow is a mechanism for such resistance is not known. We measured heart and skeletal muscle blood flow and glucose uptake during euglycemic hyperinsulinemia (insulin clamp) in 15 male patients with angiographically proven coronary artery disease and chronic regional wall motion abnormalities. Six age- and weight-matched healthy subjects served as controls. Regional glucose uptake was measured by positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose (FDG), blood flow was measured by the H2(15)O method. Myocardial glucose utilization was measured in regions with normal perfusion and wall motion as assessed by radionuclide ventriculography. Whole-body glucose uptake was 37+/-4 micromol x min(-1) x kg(-1) in controls and 14+/-2 mciromol x min(-1) x kg(-1) in patients (P = 0.001). Myocardial blood flow (1.09+/-0.06 vs. 0.97+/-0.04 ml x min(-1) x g(-1), controls vs. patients) and skeletal muscle (arm) blood flow (0.046+/-0.012 vs. 0.043+/-0.006 ml x min(-1) x g(-1)) were similar in the two groups (P = NS for both). In contrast, in patients both myocardial (0.38+/-0.03 vs. 0.70+/-0.03 micromol x min(-1) x g(-1), P = 0.0005) and muscle glucose uptake (0.026+/-0.004 vs. 0.056+/-0.006 micromol x min(-1) x g(-1), P = 0.005) were markedly reduced in comparison with controls. In the whole dataset, a direct relationship existed between insulin-stimulated glucose uptake in heart and skeletal muscle. Patients with a history of myocardial infarction and a low ejection fraction are insulin resistant. This insulin resistance affects both the myocardium and skeletal muscle and is independent of blood flow.

Pathophysiology of chronic left ventricular dysfunction. New insights from the measurement of absolute myocardial blood flow and glucose utilization.

BACKGROUND: Chronically dysfunctional myocardium may improve after coronary revascularization. This condition was thought to be due to a chronically reduced myocardial blood flow (MBF). Recently, however, it has been shown that in patients without previous infarction but with chronic left ventricular dysfunction, baseline MBF was normal. METHODS AND RESULTS: To study the pathophysiology of chronic left ventricular dysfunction in patients with previous infarction, regional MBF (milliliter per minute per gram of water-perfusable tissue) and glucose utilization (MRG; micromoles per minute per gram) during hyperinsulinemic euglycemic clamp were measured with positron emission tomography in 30 patients before bypass. At baseline, 133 myocardial segments were normal, and 107 were dysfunctional. After revascularization, 59 of 107 segments improved, while 48 of 107 were unchanged. MBF was 0.92 +/- 0.25 mL.min-1.g-1 in normal segments, 0.87 +/- 0.31 mL.min-1.g-1 in improved segments (P = NS versus normal), and 0.82 +/- 0.40 mL.min-1.g-1 in unchanged segments (P < .05 versus normal). In 90% of the dysfunctional segments, MBF was > 0.42 mL.min-1.g-1, a cutoff value corresponding to the mean MBF minus 2 SD in normal segments. The MRG was 0.71 +/- 0.14 mumol.min-1.g-1 in 9 age-matched normal subjects, 0.45 +/- 0.19 mumol.min-1.g-1 (P < .01) in normal segments, 0.44 +/- 0.14 mumol.min-1.g-1 in improved segments (P = NS versus normal), and 0.34 +/- 0.17 mumol.min-1.g-1 in unchanged segments (P < .01 versus normal and improved). CONCLUSIONS: The results suggest that resting MBF measured with 15O-labeled water in chronically dysfunctional segments is not reduced and that the myocardium of these patients is less sensitive to insulin than that of normal subjects.

Assessment of myocardial viability and the role of surgery.

The importance of accurately predicting functional recovery of the myocardium has become clear with the advent of interventional techniques for coronary revascularization. Detection of hibernating myocardium (reversibly dysfunctional myocardial segments subtended by stenosed arteries) has been approached by techniques that assess different characteristics of this condition, such as contractile reserve, membrane integrity, and metabolic activity. The standard for detecting viable myocardium is considered to be metabolic imaging with positron-emission tomography using the glucose analogue 18F-fluorodeoxyglucose, which makes it possible to quantitate regional glucose utilization in myocardium. However, recently, a new approach has been proposed based on the use of 15O-labeled water, which does not require metabolic imaging and appears to offer advantages in terms of scanning time and quantitation of viable tissue.