Citations

Background —Genetic defects are being increasingly recognized in the etiology of primary cardiomyopathy (CM). Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first step in the β-oxidation spiral of fatty acid metabolism, the crucial pathway for cardiac energy production. Methods and Results —We studied 37 patients with CM, nonketotic hypoglycemia and hepatic dysfunction, skeletal myopathy, or sudden death in infancy with hepatic steatosis, features suggestive of fatty acid oxidation disorders. Single-stranded conformational variance was used to screen genomic DNA. DNA sequencing and mutational analysis revealed 21 different mutations on the VLCAD gene in 18 patients. Of the mutations, 80% were associated with CM. Severe CM in infancy was recognized in most patients (67%) at presentation. Hepatic dysfunction was common (33%). RNA blot analysis and VLCAD enzyme assays showed a severe reduction in VLCAD mRNA in patients with frame-shift or splice-site mutations and absent or severe reduction in enzyme activity in all. Conclusions —Infantile CM is the most common clinical phenotype of VLCAD deficiency. Mutations in the human VLCAD gene are heterogeneous. Although mortality at presentation is high, both the metabolic disorder and cardiomyopathy are reversible.

Background —The Bypass Angioplasty Revascularization Investigation (BARI) included 4039 patients with multivessel coronary artery disease; 1829 consented to randomization, and 2010 did not but were followed up in a registry. Thus, we can evaluate the outcome of physician-guided versus random assignment of percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass graft surgery (CABG). Methods and Results —We compared the baseline features and outcomes for PTCA and CABG in the overall registry and its predesignated subgroups. We assessed the impact of treatment by choice versus random assignment by comparing the results in the registry with those of the randomized trial. Statistical adjustments for differences in baseline characteristics were made. Within the registry, nearly twice as many patients were selected for PTCA (1189) as CABG (625); mortality at 7 years was similar for PTCA (13.9%) and CABG (14.2%) ( P =0.66) before and after adjustment for baseline differences between patients selected for PTCA versus CABG (adjusted RR, 1.02; P =0.86). In contrast to the randomized trial, the 7-year mortality rate of treated diabetics in the registry was equally high (26%) with PTCA or CABG. Seven-year mortality was higher for patients undergoing PTCA in the randomized trial than in the registry (19.1% versus 13.9%, P <0.01) but not for those undergoing CABG (15.6% versus 14.2%, P =0.57). The adjusted relative mortality risk for PTCA in the randomized versus registry population was 1.17 ( P =0.16). Conclusions —BARI physicians were able to select PTCA rather than CABG for 65% of registry patients who underwent revascularization without compromising long-term survival either in the overall population or in treated diabetics.

Background —Use of mortality as an end point in randomized trials of reperfusion therapy requires increasingly large sample sizes to test advances compared with existing therapy, which is already highly effective. There has been a growing interest in infarct size measurements by 99m Tc-sestamibi SPECT (single photon emission computed tomographic) imaging as a surrogate end point. Methods and Results —We reviewed the reports published in English regarding infarct size measurements by 99m Tc-sestamibi. Four separate lines of published evidence support the validity of SPECT imaging with 99m Tc-sestamibi for determination of infarct size. This end point has been used in a total of 7 randomized trials—1 single center and 6 multicenter. The end point compares favorably with left ventricular function and infarct size measurements with the use of other radiopharmaceuticals. The most important limitation of this approach is the absence thus far of a randomized trial that has shown a corresponding decrease in mortality in association with a therapy that reduces infarct size. Conclusions —SPECT imaging with 99m Tc-sestamibi is the best available measurement tool for infarct size. It has already served as an end point in early pilot studies to evaluate potential efficacy and in dose-ranging studies. It has the potential to serve as a surrogate end point to uncover advantages of new therapies that may be equivalent to existing therapies with respect to early mortality.

Background —Quantitative measures of myocardial perfusion defect severity from acute 99m Tc-sestamibi tomographic images (nadir) have correlated closely with collateral and residual antegrade blood flow during acute myocardial infarction. The purpose of this study was to determine whether a viability threshold could be identified from this measure in patients with acute myocardial infarction treated in a homogeneous manner with successful reperfusion therapy. Methods and Results —The study group consisted of 61 patients with acute myocardial infarction with a risk area of >6% LV treated with primary angioplasty between 120 and 240 minutes after symptom onset. All patients were injected with 20 to 30 mCi of 99m Tc-sestamibi before primary angioplasty and imaged after the procedure. Acute myocardium at risk (MAR) and subsequent infarct size (IS) were quantified by a threshold program. Severity (nadir) from the acute image was the lowest ratio of minimal/maximum counts from 5 short-axis slices. Infarct location was anterior in 22 and inferior in 39 patients. MAR was 33±15% LV and IS was 13±15% LV: 23 patients had no infarction despite MAR similar to those with infarction. Receiver-operator characteristic curve analysis identified a nadir value of 0.26 as providing the best separation of patients with and without infarction (sensitivity, 74%; specificity, 74%). This nadir threshold varied by infarct location: anterior defect, 0.21; inferior defect, 0.31. The sensitivity and specificity for absent infarction for these values were anterior, 69% and 67%, and inferior, 88% and 84%, respectively. Conclusions —In a time frame in which the presence of residual blood flow is important, the severity of the acute 99m Tc-sestamibi defect can be used to predict whether infarction will develop despite successful reperfusion.

Background —The appropriate management of patients with intermediate-risk Duke treadmill scores is not established. The purpose of this study was to determine the long-term risk of subsequent cardiovascular events in patients with an intermediate-risk treadmill score who do not have myocardial perfusion defects on radionuclide imaging. Methods and Results —The existing databases of the nuclear cardiology laboratories of 4 academic institutions were searched retrospectively. A total of 4649 patients were identified who had intermediate-risk Duke treadmill scores (−10 to 4), normal or near-normal exercise single photon-emission computed tomographic myocardial perfusion images using either thallium-201 or technetium-99m sestamibi, and no previous coronary revascularization. Follow-up was 95% complete. Cardiovascular survival was 99.8% at 1 year, 99.0% at 5 years, and 98.5% at 7 years. Cardiac survival free of myocardial infarction was similarly high at 96.6% at 7 years. Cardiac survival free of myocardial infarction or revascularization was 87.1% at 7 years. Near-normal scans and cardiac enlargement were independent predictors of time to cardiac death. Seven-year cardiac survival was still high at 97.0% in the 357 patients with near-normal scans and normal cardiac size and somewhat lower, at 89.0%, in the 167 patients with cardiac enlargement. Conclusions —Patients with an intermediate-risk treadmill score but with normal or near-normal exercise myocardial perfusion images and normal cardiac sizes are at low risk for subsequent cardiac death and can be safely managed medically until their symptoms warrant revascularization. The appropriate management of patients with cardiac enlargement will remain a matter of clinical judgment.

Background —Coronary endothelial dysfunction is characterized by an imbalance between endothelium-derived vasodilating and vasoconstricting factors and coronary vasoconstriction in response to the endothelium-dependent vasodilator acetylcholine. Thus, the present double-blind, randomized study was designed to test the hypothesis that long-term, 6-month supplementation of l -arginine, the precursor of the endothelium-derived vasodilator NO, reverses coronary endothelial dysfunction to acetylcholine in humans with nonobstructive coronary artery disease. Methods and Results —Twenty-six patients without significant coronary artery disease on coronary angiography and intravascular ultrasound were blindly randomized to either oral l -arginine or placebo, 3 g TID. Endothelium-dependent coronary blood flow reserve to acetylcholine (10 −6 to 10 −4 mol/L) was assessed at baseline and after 6 months of therapy. There was no difference between the two study groups in clinical characteristics or in the coronary blood flow in the response to acetylcholine at baseline. After 6 months, the coronary blood flow in response to acetylcholine in the subjects who were taking l -arginine increased compared with the placebo group (149±20% versus 6±9%, P <0.05). This was associated with a decrease in plasma endothelin concentrations and an improvement in patients’ symptoms scores in the l -arginine treatment group compared with the placebo group. Conclusions —Long-term oral l -arginine supplementation for 6 months in humans improves coronary small-vessel endothelial function in association with a significant improvement in symptoms and a decrease in plasma endothelin concentrations. This study proposes a role for l -arginine as a therapeutic option for patients with coronary endothelial dysfunction and nonobstructive coronary artery disease.

Background —The prognostic value of tomographic myocardial perfusion imaging with dipyridamole or adenosine in patients with left bundle-branch block has not been established. Methods and Results —The study group consisted of 245 patients with left bundle-branch block who underwent tomographic (single photon emission tomography) myocardial perfusion imaging with thallium-201 (n=173) or technetium-99m sestamibi (n=72) and either dipyridamole (n=153) or adenosine (n=92) stress. Patients were prospectively classified into two groups. Patients were classified as “high risk” if they had (1) a large severe fixed defect (n=28), (2) a large reversible defect (n=36), or (3) cardiac enlargement and either increased pulmonary uptake (thallium) or a decreased resting ejection fraction (sestamibi) (n=20). The remaining 161 patients (66% of the study group) were at “low risk.” Follow-up was 99% complete at 3±1.4 years. Three-year overall survival was 57% in the high-risk group compared with 87% in the low-risk group ( P <.0001). Survival free of cardiac death/nonfatal myocardial infarction/cardiac transplantation was 55% in the high-risk group and 93% in the low-risk group ( P <.0001). The presence of a high-risk scan had significant incremental prognostic value after adjustment for age, sex, diabetes, and previous myocardial infarction ( P <.0001). Patients with a low-risk scan had an overall survival that was not significantly different from that of a US age-matched population ( P =.86). Conclusions —Tomographic myocardial perfusion imaging with adenosine or dipyridamole stress provides important prognostic information in patients with left bundle-branch block, which is incremental to clinical assessment.

BackgroundRight heart failure is an important cause of morbidity and mortality in primary pulmonary hypertension. In a recent prospective, randomized study of severely symptomatic patients, treatment with prostacyclin (epoprostenol) produced improvements in hemodynamics, quality of life, and survival. This article describes the echocardiographic characteristics of participants in this trial; the relationships of echocardiographic variables to hemodynamic parameters, exercise capacity, and quality of life; and the echocardiographic changes associated with prostacyclin therapy.Methods and ResultsThe 81 patients enrolled in this multicenter trial were randomized to treatment with a long-term infusion of prostacyclin in addition to conventional therapy (n=41) or conventional therapy alone (n=40) for 12 weeks. Echocardiograms and assessments of hemodynamics, exercise capacity, and quality of life were performed before and after the treatment phase. On baseline evaluation, patients had marked right ventricular dilatation and dysfunction, abnormal septal curvature, and significant tricuspid regurgitation with a high regurgitant velocity. Pericardial effusions were common. More pronounced abnormalities in right heart structure and function were associated with higher pulmonary arterial and mean right atrial pressures, lower cardiac index, and impaired exercise capacity but had no predictable relationship to quality-of-life indicators. The 12-week infusion of prostacyclin had beneficial effects on right ventricular size, curvature of the interventricular septum, and maximal tricuspid regurgitant jet velocity.ConclusionsThe echocardiographic manifestations of severe primary pulmonary hypertension reflect abnormalities in hemodynamics and exercise capacity. Prostacyclin has beneficial effects on right heart structure and function that may contribute to the clinical improvement and prolonged survival observed with this drug.

Background 99m Tc sestamibi is a recently developed radioisotope that has been used to measure myocardium at risk and infarct size. The relation between these measurements and subsequent patient outcome has not yet been demonstrated. Methods and Results Two hundred seventy-four consecutive patients with acute myocardial infarction underwent tomographic 99m Tc sestamibi imaging on arrival at the hospital (to measure myocardium at risk before reperfusion therapy) and at hospital discharge (to measure the amount of salvaged myocardium and final infarct size). Defect size on the sestamibi images was quantified using a threshold value of 60% of peak counts from the circumferential count profile curves generated for five representative slices of the left ventricle. Patients were followed after hospital discharge to evaluate the association between final infarct size and subsequent mortality. The median defect size measured was 27% of the left ventricle at presentation to the hospital (range, 0% to 77%) and was 12% of the left ventricle at hospital discharge (range, 0% to 68%). Almost one half of the patients had a final infarct size of ≤10%. The median amount of myocardium salvaged was 9% (range, −31% to 75%). During a median duration of follow-up of 12 months, there were 10 deaths (7 cardiac and 3 noncardiac) and 1 resuscitated out-of-hospital cardiac arrest. There was a significant association between infarct size and overall mortality (χ 2 =8.66, P =.003) and cardiac mortality (χ 2 =11.89, P <.001). Two-year mortality was 7% for patients whose infarct size was ≥12% versus 0% for patients whose infarct size was <12%. There also was a significant association between myocardium at risk and cardiac mortality (χ 2 =6.87, P =.009). There was no association between myocardium at risk and overall mortality or between amount of myocardium salvaged and either overall mortality or cardiac mortality. Conclusions Larger infarct size measured by 99m Tc sestamibi imaging after acute myocardial infarction is associated with increased mortality risk during short-term follow-up.

Background Women who undergo coronary angioplasty have a higher in-hospital mortality than men, although much of this difference can be accounted for by their poorer clinical characteristics at the time of their procedures. However, whether or not there are important long-term differences in outcome between women and men after coronary angioplasty is not clear. Methods and Results A retrospective analysis was performed of 3027 consecutive patients (824 women and 2203 men) who underwent successful angioplasty and who have been followed continuously for a mean of 5.5 years (range, 0.5 to 14 years). Follow-up is 100% complete. Event-free survival was assessed by the Kaplan-Meier method, and clinical end points were also examined by Cox proportional-hazards models to account for important baseline differences when appropriate. There was a trend toward lower survival among women during follow-up, but this was not significant ( P =.06). The relative risk of death among women compared with men after adjustment for baseline differences was 0.94 (CI, 0.76 to 1.15; P =NS). No significant sex differences in occurrence of Q-wave myocardial infarction were observed. Women were less likely to remain free of angina after 10 years (34% versus 37%, respectively; P =.008), but after adjustment for baseline differences, this difference was not significant (relative risk of angina, 1.07; CI, 0.95 to 1.21). Women tended to have less coronary artery bypass surgery performed during follow-up ( P =.06); adjusting for baseline differences made this difference more significant (relative risk, 0.79; CI, 0.64 to 0.96; P =.02). Among patients who were not treated in the setting of acute infarction, no sex differences in survival and freedom from myocardial infarction were noted. Conclusions After successful coronary angioplasty, the long-term prognosis for women is excellent and is similar to that observed in men. Risk-adjusted survival did not differ significantly between the sexes, but less frequent use of subsequent surgical revascularization was observed in women.