Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease.

BACKGROUND: To determine whether or not a moderate genetic defect of homocysteine metabolism is associated with the development of coronary artery disease, we studied the prevalence of thermolabile methylenetetrahydrofolate reductase, which is probably the most common genetic defect of homocysteine metabolism. METHODS AND RESULTS: Three hundred thirty-nine subjects who underwent coronary angiography were classified into three groups: (1) patients with severe coronary artery stenosis (> or = 70% occlusion in one or more coronary arteries or > or = 50% occlusion in the left main coronary artery), (2) patients with mild to moderate coronary artery stenosis (< 70% occlusion in one or more coronary arteries or < 50% occlusion in the left main coronary artery), and (3) patients with non-coronary heart disease or noncardiac chest pain (nonstenotic coronary arteries). The thermolability of methylenetetrahydrofolate reductase was prospectively determined in all subjects. Plasma homocyst(e)ine levels were then measured in those with thermolabile methylenetetrahydrofolate reductase. The traditional risk factors for coronary artery disease were thereafter ascertained by chart review of all subjects. The prevalence of thermolabile methylenetetrahydrofolate reductase was 18.1% in group 1, 13.4% in group 2, and 7.9% in group 3. There was a significant difference between the prevalence of thermolabile methylenetetrahydrofolate reductase in groups 1 and 3 (P < .04). All individuals with thermolabile methylenetetrahydrofolate reductase irrespective of their clinical grouping had higher plasma homocyst(e)ine levels than normal (group 1, 14.86 +/- 5.85; group 2, 15.36 +/- 5.70; group 3, 13.39 +/- 3.80; normal, 8.50 +/- 2.8 nmol/mL). Nonetheless, there was no statistically significant difference in the plasma homocyst(e)ine concentrations of these patients with or without coronary artery stenosis. Using discriminant function analysis, thermolabile methylenetetrahydrofolate reductase was predictive of angiographically proven coronary artery stenosis. The traditional risk factors--age, sex, diabetes, smoking, hypercholesterolemia, and hypertension--were not significantly associated with the presence of thermolabile methylenetetrahydrofolate reductase. CONCLUSIONS: Thermolabile methylenetetrahydrofolate reductase is a risk factor for coronary artery disease and is unrelated to other risk factors.

Characterization of a saphenous vein graft aneurysm by intravascular ultrasound and computerized three-dimensional reconstruction.

Aneurysmal dilatations in saphenous vein grafts are rare complications of coronary artery bypass surgery that mostly represent thin-wall pseudoaneurysms at anastomotic sites. We describe a case of an enlarging distal saphenous vein graft aneurysm in which intravascular ultrasound (IVUS) and computerized three-dimensional reconstruction (3DR) of the IVUS images was performed to conclusively demonstrate true aneurysm morphology. Although both atherosclerotic and nonatherosclerotic mechanisms for vein graft aneurysm formation have been previously suggested, IVUS images and 3DR of the aneurysm in this case did not reveal any of the features typical for atherosclerotic lesions. Further, the IVUS images and 3DR suggest that progressive atherosclerosis is not the likely cause of aneurysm formation in this case. This application of IVUS and 3DR provides detailed information about saphenous vein graft aneurysm structure, clues to aneurysm formation, and suggests a natural history that may differ from that of pseudoaneurysms.

Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease.

Severe methylenetetrahydrofolate reductase (MTHFR) deficiency with less than 2% of normal enzyme activity is characterized by neurological abnormalities, atherosclerotic changes, and thromboembolism. We have discovered a "new" variant of MTHFR deficiency which is characterized by the absence of neurological abnormalities, an enzyme activity of about 50% of the normal value, and distinctive thermolability under specific conditions of heat inactivation. In this study, lymphocyte MTHFR specific activities in the thermolabile variant and control groups were 5.58 +/- 0.91 and 10.33 +/- 2.89 nmol formaldehyde formed/mg protein/h, respectively. The difference was significant (P less than .01). However, there was overlap among the individual values from the two groups. On the other hand, residual MTHFR activity after heat inactivation was 11.2 +/- 1.43% in the thermolabile variant and 36.3 +/- 5.18% in the controls. There was no overlap. Enzyme studies in 10 subjects with thermolabile MTHFR and their family members support the hypothesis that thermolabile MTHFR is inherited as an autosomal recessive trait. To elucidate the association of thermolabile MTHFR with the development of coronary artery disease, we determined the thermostability of lymphocyte MTHFR in 212 patients with proven coronary artery disease and in 202 controls without clinical evidence of atherosclerotic vascular disease. Thermolabile MTHFR was found in 36 (17.0%) cardiac patients and 10 (5.0%) controls. The difference in incidence between the two groups was statistically significant (P less than .01). The average age at onset of clinical coronary artery disease in 36 patients with thermolabile MTHFR was 57.3 +/- 7.6 years (35-72 years). The mean total plasma homocysteine concentration in patients with thermolabile MTHFR was 13.19 +/- 5.32 nmol/ml and was significantly different from the normal mean of 8.50 +/- 2.80 nmol/ml (P less than .05). There was no association between thermolabile MTHFR and other major risk factors. We conclude that thermolabile MTHFR is a variant(s) of MTHFR deficiency which is inherited as an autosomal recessive trait. In addition, it is positively associated with the development of coronary artery disease. Determination of in vitro thermostability of lymphocyte MTHFR is a reliable method for identifying subjects with this abnormality.

Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease.

Thermostability of lymphocyte methylenetetrahydrofolate reductase (MTHFR) was determined in 21 patients aged less than 50 years with proven coronary artery disease, and in 21 age- and sex-matched controls without clinical evidence of vascular disease. The mean +/- SD of residual activity after heat inactivation at 46 degrees C for five minutes was 37.6% +/- 5.6% in the controls. In contrast, patients with coronary artery disease could be divided into two subgroups. Fifteen of them had 38.1 +/- 5.9% residual activity which was similar to that of the controls. In six of them the mean +/- SD residual activity after heat inactivation was 13.6% +/- 5.1% which was below 2 SD of the normal mean. These observations suggested that thermolabile MTHFR was associated with development of coronary artery disease.

Findings on routine right heart catheterization in patients with suspected coronary artery disease.

Whether catheterization of the right heart should be performed routinely in all patients undergoing coronary angiography for assessment of coronary artery disease is controversial. To objectively assess the utility of routine right heart catheterization, hemodynamic data from 2,178 patients studied for angina having no signs, symptoms, or history of congestive heart failure were analyzed retrospectively. The salient results are as follows: 0.9% patients had unsuspected mitral valve gradients greater than or equal to 5 mm Hg; 0.4% had occult left-to-right shunts; 1% had pulmonary hypertension (pulmonary artery systolic pressure greater than or equal to 40 mm Hg) not attributable to an elevated mean pulmonary capillary wedge pressure (PCWP); 4.8% had PCWP greater than or equal to 18 mm Hg; 6% had cardiac indexes less than or equal to 2.0 L/min/m2, suggesting subclinical left ventricular failure. Overall, 14.5% of patients had at least one abnormal right-sided hemodynamic variable revealed by right heart catheterization. The frequency of abnormalities increased with increasing Canadian Cardiovascular Society grade of angina. Ten percent of grade 1, 14% of grade 2, 15% of grade 3, and 19% of patient 4 patients had at least one abnormality (phi 2 test, p less than or equal to 0.005). It is concluded that the right heart catheterization adds an important dimension to the diagnosis and treatment of patients undergoing coronary angiography for assessment of coronary artery disease and might significantly influence subsequent patient management.

Congestive heart failure.

A review of the epidemiology, pathophysiology, and treatment of congestive heart failure is presented, with particular attention given to newer modalities of therapy.

Relation of ventricular premature beats to underlying heart disease.

The relation between ventricular premature beats (VPBs) and physiologic disease was investigated in 305 patients who had 24-hour Holter monitoring tests, cardiac catheterization and angiography. Both frequency and Lown class of VPBs were measured. Analyses showed that occurrence of VPBs at an average frequency of more than 2 per hour or occurrence of complex VPBs (Lown class greater than 2) have the highest association with the presence and severity of cardiac disease. Using these criteria, VPB severity was then compared with extent of ventricular wall motion abnormality (right anterior oblique projection segments), ejection fraction, end-diastolic pressure, category of disease (normal, coronary artery disease [CAD], valvular heart disease, dilated cardiomyopathy), age and severity of CAD (major coronary arteries with greater than 75% diameter reduction). Severe VPBs defined either by complexity or frequency were significantly correlated with extent of wall motion abnormality, ejection fraction, category of disease and age. Severe VPBs were not significantly correlated with end-diastolic pressure or severity of CAD. Discriminant analysis then showed that in addition to wall motion abnormality and ejection fraction, category of disease and age are independently correlated with VPB severity.

Coronary artery disease: detection by phase analysis of rest/exercise radionuclide angiocardiograms.

Thirty-six patients with chest pain but no myocardial infarction or conduction defects and 4 volunteers (3 normals and 1 with asymptomatic aortic insufficiency) underwent radionuclide angiocardiography. Phase analysis was performed and the standard deviation (SD) ("spread") and skewness ("asymmetry") of the left ventricular (LV) phase histogram determined at rest and during maximum exercise. The SD of the LV phase histogram was of no value; however, when -0.1 was taken as the upper limit of normal skewness at maximum exercise, skewness was equally as sensitive as conventional criteria for coronary artery disease (CAD) and also more specific. The authors conclude that LV histogram skewness during maximum exercise may be superior to conventional criteria for detection of CAD with rest/exercise radionuclide angiocardiograms.

Sequence and timing of ventricular wall motion in patients with bundle branch block. Assessment by radionuclide cineangiography.

We determined the sequence and timing of inward ventricular wall motion by least-square phase analysis of radionuclide cineangiograms in 10 patients with left bundle branch block (LBBB), five patients with right bundle branch block (RBBB) and 11 patients with normal conduction. All LBBB and RBBB patients had normal coronary arteries and no segmental wall motion abnormalities. The left ventricle (LV) was divided into eight segments and the right ventricle (RV) into three; sequence and timing were scored by three observers. In normal subjects, wall motion begins in either or both ventricles and ends in the LV or both ventricles. In patients with LBBB it begins in the RV and ends in the LV; in patients with RBBB is begins in the LV and ends in the RV or both ventricles. The intraventricular wall motion is also altered in the ventricle ipsilateral to a bundle branch block. In LBBB, the mean time of onset of LV wall motion is delayed 1.9 frames (38 msec), whereas RV wall motion is normal. In RBBB, the onset of RV wall motion is delayed 1.3 frames (26 msec), whereas LV wall motion is not delayed.

Noninvasive identification of initial site of abnormal ventricular activation by least-square phase analysis of radionuclide cineangiograms.

Least-square phase analysis (LSPA) of radionuclide cineangiograms demonstrates the sequence of onset of inward ventricular movement noninvasively. To validate the method and explore its ability to identify abnormal initial sites of ventricular activation, LSPA was applied to 14 patients with pacemakers (one with electrodes in two locations) (group 1) and three patients with recurrent ventricular tachycardia (VT) (group 2) who had undergone electrophysiologic endocardial mapping. The segment in which the site of initial ventricular activation was located was correctly identified in 13 of 15 paced studies and in two of three group 2 patients during VT. Pacing increased the duration of spread of onset of inward ventricular movement, and the duration of spread of onset correlated well with the duration of the QRS (r = 0.80). The sequence of onset of inward ventricular movement during VT was similar to the sequence of depolarization in all three group 2 patients. These preliminary results suggest that the sequence of onset of ventricular contraction as depicted by LSPA is a valid representation of the actual contraction sequence and that LSPA or radionuclide cineangiography correctly identifies abnormal sites of initial ventricular activation.

The effect of left ventricular aneurysmectomy on the electrocardiogram: a study of 77 patients and review of the literature.

UNLABELLED: Electrocardiograms (ECGs) were reviewed in patients undergoing left ventricular aneurysmectomy. Post-operatively, significant decreases were noted in ST segment elevation (p less than 0.001) and anterior (p less than 0.03) and inferior R wave heights (p less than 0.002). In addition, abnormal Q waves disappeared in 50% of patients. Comparison of ECG changes between survivors and patients dying of cardiac related events revealed that patients with a preoperative axis of greater than or equal to 60 degrees, postoperative leftward axis shifts and a marked decrease in ST segment elevation and/or R wave height had significantly higher mortality. CONCLUSION: 1) Left ventricular aneurysmectomy affects ventricular depolarization as evidenced by a significant loss of R wave height and changes in infarct pattern; 2) LVA affects ventricular repolarization as evidenced by a significant decrease in ST elevation; 3) the ventricular aneurysm appears to contain "viable muscle" that contributes to ventricular depolarization and remains partially depolarized during diastole; and 4) there are prognostic electrocardiographic parameters, which correlate with mortality during postoperative follow-up.

Diaphragmatic left ventricular aneurysm. Clinical features, surgical treatment, and long-term follow-up in 22 patients.

Although the formation of a left ventricular aneurysm (LVA) is a common and well-recognized complication of myocardial infarction (MI), diaphragmatic LVA is a rare clinical entity. Of 354 consecutive patients who underwent LVA resection, we describe the clinical features and surgical results of 22 patients (6%) with diaphragmatic LVA. All patients had a history of MI. The principal clinical indication for surgery was heart failure in nine patients, angina pectoris in ten patients, and recurrent ventricular tachycardia unresponsive to medical therapy in three patients. A ventricular septal defect was present in two patients, and moderate to severe mitral regurgitation was present in four patients. Three of the four surgical deaths (operative mortality, 18%) occurred in patients with mitral regurgitation or with ventricular septal defect. Eleven patients are alive at a mean follow-up of 40 months. Six of them are asymptomatic and two have angina at a higher level of physical activity than before surgery. Notable differences exist in the clinical presentation and surgical findings between patients with diaphragmatic and anterior LVA.

Atrial septal defect: repair in patients over thirty-five years of age.

Fifty-eight patients over age 35 underwent repair of atrial septal defect. The operative mortality was zero for the seven N.Y.H.A. class I and 26 N.Y.H.A. class II patients. One of 16 class III patients and two of nine class IV patients died; consequently, overall hospital mortality was five percent. The operative mortality was not related to age or level of pulmonary hypertension. Long-term clinical improvement was documented in 75 percent of patients who had been symptomatic preoperatively. The suggestion in early reports that pulmonary hypertension, or age per se, many contraindicate repair of an ASD cannot be supported by our results.