Coronary remodeling of proximal and distal stenotic atherosclerotic plaques within the same artery by intravascular ultrasound study.

The aim of this intravascular ultrasound study was to compare the type and the degree of vessel remodeling in proximal and distal de novo lesions within the same coronary artery in patients with stable angina pectoris. Seventy-six de novo coronary artery lesions in 38 coronary arteries of 38 patients were imaged by intravascular ultrasound. The vessel area (VA) within the external elastic lamina and the lumen area (LA) were measured, and the wall area (VA-LA) was calculated at the lesion site, and the proximal and distal reference sites. The VA ratio was defined as (lesion VA/average of the proximal and distal reference VAs) to represent the degree of vessel remodeling. The proximal coronary segments showed compensatory enlargement more often (68% vs 29%, p < 0.01) than the distal segments, and the VA ratio at the lesion site was significantly larger (1.1 +/- 0.3 vs 1.0 +/- 0.2, p <0 .01) in proximal segments than in distal segments. The type of coronary remodeling was discordant in 61% and concordant in only 39% of coronary arteries between the proximal and distal segments. The type of coronary remodeling of proximal and distal coronary lesions was inhomogeneous, even within the same vessel. Proximal coronary segments showed more prominent compensatory enlargement than distal segments, which have a similar degree of luminal narrowings.

Clinical validation of intravascular ultrasound imaging for assessment of coronary stenosis severity: comparison with stress myocardial perfusion imaging.

OBJECTIVES: To validate intravascular ultrasound (IVUS) measurements for differentiating functionally significant from nonsignificant coronary stenosis. BACKGROUND: To date, there are no validated criteria for the definition of a flow-limiting coronary artery stenosis by IVUS. METHODS: Preinterventional IVUS imaging (30-MHz imaging catheter) of 70 de novo coronary lesions was performed. The lesion lumen area and three IVUS-derived stenosis indixes comparing lesion lumen area with the lesion external elastic lamina (EEL) area, the mean reference lumen area and the mean reference EEL area were compared with the results of stress myocardial perfusion imaging. RESULTS: The lesion lumen area and three IVUS-derived stenosis indexes showed sensitivities and specificities ranging between 80% and 90% using stress myocardial perfusion imaging as the gold standard. The lesion lumen area < or =4 mm2 is a simple and highly accurate criterion for significant coronary narrowing. CONCLUSIONS: Quantitative IVUS indices can be reliably used for identifying significant epicardial coronary artery stenoses.

Hypertrophic obstructive cardiomyopathy due to a novel T-to-A transition at codon 624 in the beta-myosin heavy chain (beta-MHC) gene possibly related to the sudden death.

Many missense mutations in the beta-myosin heavy chain have been reported in patients with hypertrophic obstructive cardiomyopathy (HOCM). However, the controversy is present whether the mutation accompanying the change of electric charge is related with poorer prognosis. The proband, a 48-year-old female, of the family was diagnosed clinically as HOCM, and a structural analysis of the cardiac beta-MHC gene showed that the proband and her junior daughter had a novel mutation with T to A transition in codon 624 replacing tyrosine with asparagine, which was not present in her husband, elder daughter and son. The proband's husband, son and two daughters were healthy except that the ECG of junior daughter (15-year-old) showed complete right bundle branch block. Proband's mother died suddenly after the delivery of the proband and the proband also collapsed suddenly. The occurrence of sudden death in proband and her mother suggested that HOCM with this novel mutation might be associated with a high risk of sudden death irrespective of the absence of charge alteration.

Downregulation of adenylylcyclase types V and VI mRNA levels in pacing-induced heart failure in dogs.

We have shown that the heart expresses two distinct forms of adenylylcyclase mRNA, types V and VI. In this study we have characterized the expression of these two mRNA species in heart failure generated by overdrive pacing at a rate of 240 beats/min. After 4 wk, left ventricular end-diastolic pressure and heart rate increased significantly with the appearance of signs of heart failure, i.e., edema, ascites, and exercise intolerance. Basal as well as forskolin-stimulated adenylylcyclase activities decreased significantly, which was accompanied by a reduction in the steady state mRNA levels of adenylylcyclase types V and VI. These data suggest that in this model of cardiomyopathy, the downregulation of adenylylcyclase catalytic activity results, at least in part, from a reduction in the steady state levels of types V and VI adenylylcyclase mRNA levels.

Reduction of beta-adrenergic receptors in atrial cell membranes of patients following mild to moderate heart failure.

The density of cardiac beta-adrenoceptors (Bmax) was measured in eighteen patients [2 with atrial septal defect (ostium secundum), 4 with aortic valve disease, 3 with mitral valve disease, 1 with aortic and mitral valve disease, 5 with a history of myocardial infarction, and 3 with angina pectoris] following mild to moderate cardiac failure. Measures were obtained by cardiac catheterization prior to cardiac surgery and also during the surgical procedures. On the basis of symptoms immediately preceding surgery, the severity of the condition in each patient was categorized as either Class I (n = 5) or Class II (n = 13) following the New York Heart Association (NYHA) functional classification system. The Bmax was measured using right atrial appendage tissue obtained during cardiac surgery. [125I]-iodocyanopindolol was used for the assay. The Bmax of atrial cell membranes in patients with NYHA class II was significantly lower than that of class I (34.1 +/- 2.5 vs 55.4 +/- 9.3 fmol/mg protein, M +/- SE, p < 0.05). Correlation coefficients between the Bmax and hemodynamic parameters measured just prior to cardiac surgery were examined, but only that between Bmax and the minimum value of the time derivative of left ventricular pressure (max negative dp/dt) was significant (r = -0.552, p < 0.05). Further study is needed to understand and clarify the relationship between Bmax and dp/dt min.

Iodine 125-phenylpentadecanoic acid and its beta-methyl substitute metabolism in cultured mouse embryonal myocytes--iodine-labelled fatty acids as tracers of myocardial high energy phosphate.

Iodine-labelled fatty acids have been proposed as new tracers of cardiac metabolisms. However, it is not clear how these tracers would reflect the intracellular metabolism. Therefore, we measured the uptake and release of iodine 125-labelled phenylpentadecanoic acid (IPPA), its beta-methyl substitute (BMIPP) and 201Tl in cultured myocytes of mouse embryos, and compared these values to intracellular adenosine triphosphate (ATP) content after metabolic inhibitions of oxidative phosphorylation by sodium cyanide (CN), glycolysis by 2-deoxyglucose (2-DG) or fatty acid beta-oxidation by lactate. The uptake and release of BMIPP was not changed by any inhibitors suggesting BMIPP would not be metabolized in the myocytes. The uptake of IPPA was significantly reduced by 2DG and 60-80% of IPPA was metabolized to hydrophilic catabolites. The correlation of BMIPP and IPPA uptake to intracellular ATP content were high (r = 0.89, p < 0.05; r = 0.86, p < 0.1), but there was poor correlation of 201Tl to ATP values (r = 0.53, n.s.). These results suggested that iodine-labelled fatty acids could be used as better tracers of myocardial metabolism than 201Tl.

In vivo generation of an adenylylcyclase isoform with a half-molecule motif.

A truncated form of adenylylcyclase (type V-alpha) has been cloned from a cardiac cDNA library. It constitutes a half-molecule of type V adenylylcyclase diverging at the end of the first cytoplasmic loop. Northern blotting study has revealed the presence of such a mRNA species (approximately 3.5 kilobases in size) in the heart. Genomic sequence analysis has revealed that type V-alpha is generated via usage of a polyadenylation signal located within an intronic sequence of type V adenylylcyclase gene. When type V-alpha is co-expressed with an artificially generated half-molecule constituting the latter half of type V adenylylcyclase, the catalytic activity in transfected cell membranes is significantly higher than that of controls. However, when either alone is overexpressed, no significant increase in catalytic activity results. These results indicate that a half-molecule of adenylylcyclase, i.e. a protein containing six-transmembrane spans followed by a single cytoplasmic domain, can be generated in vivo, but catalytic activity is lacking unless heterodimerization can occur. This finding identifies another potential mechanism for generating diversity within this enzyme family.

Cloning and characterization of a sixth adenylyl cyclase isoform: types V and VI constitute a subgroup within the mammalian adenylyl cyclase family.

A sixth member of the mammalian adenylyl cyclase family has been isolated from a canine cardiac cDNA library. This isoform is more highly homologous to type V than to the other adenylyl cyclase types; sequence similarity is apparent even in the transmembrane regions where the greatest divergence among the types exists. Type VI mRNA expression is most abundant in heart and brain; however, unlike type V, a low level of expression is also observed in a variety of other tissues examined. Type VI adenylyl cyclase can be stimulated by NaF, guanosine 5'-[gamma-thio]triphosphate, and forskolin but not by Ca2+/calmodulin, whereas it is inhibited by adenosine and its analogues. Comparison of both their structural and biochemical properties suggests that types V and VI constitute a distinct subgroup of the mammalian adenylyl cyclase family.

Isolation and characterization of a novel cardiac adenylylcyclase cDNA.

A novel adenylylcyclase cDNA (type V) was isolated from a canine heart cDNA library. Northern blotting indicates that the expression of this message is most abundant in heart with a lesser amount in brain but is absent in a variety of other tissues including lung, kidney, skeletal muscle, lymphocyte, and testis. The putative protein product predicted from the cDNA sequence has the motif of tandem six-transmembrane spans separated by a large hydrophilic cytoplasmic loop as seen in other members of the adenylylcyclase family. When this protein is expressed using a CMT cell transient expression system, the adenylylcyclase activity was stimulated by NaF, GTP gamma S, and forskolin, but not by calmodulin. The activity was inhibited in a concentration-dependent manner with either P-site active agents such as adenosine or in the presence of calcium. These data indicate that the protein encoded by this cDNA is adenylylcyclase with the biochemical features characteristic of the cardiac isoform.

Enhanced myocardial adenylate cyclase activity in spontaneously hypertensive rats.

This study was designed to clarify the state of beta-adrenergic signal transduction and the disordered level of its transduction in hypertensive hearts, using myocardium from spontaneously hypertensive rats (SHR) as a generic model of essential hypertension. Beta-adrenergic receptor binding sites and dissociation constants in the extracted membranes of adult (70-100 days of age) SHR heart were not significantly different from those of Wistar-Kyoto (WKY) rats, the non-hypertensive control. The adenylate cyclase activities stimulated by isoproterenol with GTP, NaF and forskolin were significantly higher in SHR compared to those in WKY. To determine whether differences in signal transduction are natural or are a result of hypertension, we evaluated chronotropic responses in cultured cells of fetal hearts which had not been exposed to hypertension. Fetal cardiac muscle cells of SHR were more sensitive than WKY to isoproterenol stimulation over a wide concentration range. However, there were no statistically significant differences between these two strains with respect to the density of binding sites. These results suggest that in the transduction of adrenergic signals, alterations distal to the beta-receptors are present in the adult hearts of hypertensive rats, and, that the adrenergic signal transduction is already exaggerated in the pre-hypertensive fetal stage.

Alterations in cardiac function and subcellular membrane activities after hypervitaminosis D3.

The present study was designed to induce massive accumulation of calcium in the myocardium and to evaluate the effect of calcium overload on myocardial contractile function and biochemical activity of cardiac subcellular membranes. Rats were treated with an oral administration of 500,000 units/kg of vitamin D3 for 3 consecutive days, and their hearts were sampled on the 5th day for biochemical analysis. On the 4th and 5th days, heart rate, mean aortic pressure, left ventricular systolic pressure and left ventricular dP/dt were significantly lowered in vitamin D3-treated rats, demonstrating the existence of appreciable myocardial contractile dysfunction. Marked increases in the myocardial calcium (67-fold increase) and mitochondrial calcium contents (24-fold increase) were observed by hypervitaminosis D3. Mitochondrial oxidative phosphorylation and ATPase activity were significantly reduced by this treatment. A decline in sarcolemmal Na+, K(+)-ATPase activity was also observed, while relatively minor or insignificant changes in calcium uptake and ATPase activities of sarcoplasmic reticulum were detectable. Electron microscopic examination revealed calcium deposits in the mitochondria after vitamin D3 treatment. The results suggest that hypervitaminosis D3 produces massive accumulation of calcium in the myocardium, particularly in the cardiac mitochondrial membrane, which may induce an impairment in the mitochondrial function and eventually may lead to a failure in the cardiac contractile function.

[Diagnosis of left ventricular aneurysm by exercise thallium-201 myocardial single photon emission computed tomography].

To diagnose and characterize post-infarction left ventricular aneurysms, we performed exercise thallium-201 myocardial single photon emission computed tomography (SPECT) combined with selective coronary angiography and left ventriculography. The subjects consisted of 79 patients with acute myocardial infarction; 42 with anteroseptal, three with both anterior and inferior, 29 with inferior and five with posterior infarction. Visual classification of ventricular wall morphology by either a horizontal or a vertical long-axis image was designed into convergent (C), parallel (P) and divergent (D) types, according to the interrelationship between either septal and lateral wall or anterior and inferior wall, respectively. This method was applied in post-stress and delayed images, and these patients were divided into five groups (Group A-E) in accordance with varying morphological types from the post-stress to the delayed as follows: C-C (Group A, 36 patients), P-C (Group B, 8), P-P (Group C, 7), D-P (Group D, 5) and D-D (Group E, 23). A high incidence (21/23) of a left ventricular aneurysm by left ventriculography was recognized in Group E patients in comparison with other Groups. Provided that either Group D or E (all patients had anterior infarction) had left ventricular aneurysms, the diagnostic sensitivity, specificity and accuracy were 89%, 92% and 86%, respectively. Two of three patients with false negative diagnosis had only apical involvement. Furthermore, these two Groups had significantly larger defect scores as calculated by polar maps than did the other three Groups. When patients with anterior infarction with defect scores of 200 or greater were defined positive, the sensitivity, specificity and accuracy of ventricular aneurysms were 96%, 75% and 86%, respectively. One false negative case was apical infarction, and one of the two false positive cases were extensive anteroseptal infarction involving the apex. These results suggest that a left ventricular aneurysm which is important in predicting prognostic sequence could be diagnosed only by exercise SPECT, and that it could be characterized by extensive and severe apicoanterior infarction and a divergent-type ventricular wall arrangement on a post-stress SPECT image.

[Quantitation of the severity of coronary artery disease using thallium-201 tomographic scores].

To evaluate coronary artery disease, a new quantitative thallium-201 (201T1)-tomographic scintigraphic score (TSS: modified Massie's score) using oxygen consumption (METS) was developed and compared with coronary angiographic score (CAG-S) in 27 patients (eight patients with normal coronary angiograms, and five, eight and six patients with one, two and three vessel disease, respectively) without previous myocardial infarction. All patients received both coronary angiography and the treadmill exercise test using 201T1-myocardial single photon emission computed tomography (SPECT) within two weeks. The redistribution area (RA) and washout rate area (WA) were derived from the circumferential profile analysis using apical (A), midventricular (M) and basal (B) short-axis images. To obtain TSS values, the sum of these values was divided both by percentage of the age-predicted maximal heart rate (%PMHR) and the METS value as follows: TSS = [RA (A, M, B) + WA (A, M, B)]/(%PMHR x METS). The results were as follows: 1. TSS values were 6.4 +- 1.6, 9.4 +/- 2.2, 24.2 +/- 12.0 and 30.6 +/- 5.0 (mean +/- SD) in normal, one, two and three vessel disease groups, respectively. Significant differences were found among each group except between two and three vessel disease groups. 2. The detectability of significant coronary artery disease was 89% (17/19) except in two patients with one vessel disease. 3. A high correlation coefficient was found between TSS (X) and CAG-S (Y), i.e., Y = 0.8X - 3.5 (r = 0.944, p less than 0.001). It was concluded that the tomographic scintigraphic score (TSS) is useful not only for detecting, multivessel disease but also for totally-evaluating its severity, extent and influence on collateral supply, and could be used for analyzing prognosis and the selection of therapeutic interventions.