Chuichi Kawai

From Myocarditis to Cardiomyopathy: Mechanisms of Inflammation and Cell Death Learning From the Past for the Future

A progression from viral myocarditis to dilated cardiomyopathy has long been hypothesized, but the actual extent of this progression has been uncertain. However, a causal link between viral myocarditis and dilated cardiomyopathy has become more evident than before with the tremendous developments in the molecular analyses of autopsy and endomyocardial biopsy specimens, new techniques of viral gene amplification, and modern immunology. The persistence of viral RNA in the myocardium beyond 90 days after inoculation, confirmed by the method of polymerase chain reaction, has given us new insights into the pathogenesis of dilated cardiomyopathy. Moreover, new knowledge of T-cell-mediated immune responses in murine viral myocarditis has contributed a great deal to the understanding of the mechanisms of ongoing disease processes. Apoptotic cell death may provide the third concept to explain the pathogenesis of dilated cardiomyopathy, in addition to persistent viral RNA in the heart tissue and an immune system-mediated mechanism. Beneficial effects of alpha1-adrenergic blocking agents, carteolol, verapamil, and ACE inhibitors have been shown clinically and experimentally in the treatment of viral myocarditis and dilated cardiomyopathy. Antiviral agents should be more extensively investigated for clinical use. The rather discouraging results obtained to date with immunosuppressive agents in the treatment of viral myocarditis indicated the importance of sparing neutralizing antibody production, which may be controlled by B cells, and raised the possibility of promising developments in immunomodulating therapy.

Quantitative analysis of narrowings of intramyocardial small arteries in normal hearts, hypertensive hearts, and hearts with hypertrophic cardiomyopathy.

To clarify the pathophysiologic role of intramyocardial small artery (IMSA) diseases in hypertrophied hearts, narrowings of the IMSA were quantitatively evaluated in 39 autopsied hearts, 10 from patients with typical hypertrophic cardiomyopathy (HCM), four from patients with HCM showing features mimicking dilated cardiomyopathy (DCM-like HCM), 10 from patients with hypertension, and 15 from normal adults. The relations of narrowings of the IMSA to myocytic hypertrophy, myocardial fiber disarray, and fibrosis were also examined. The external caliber and the ratio of the luminal area to the total vascular area (percent luminal area, % lumen) were calculated by an image analyzer in 85 to 203 IMSAs from each patient. The external calibers of the IMSAs were similar among groups of hearts with HCM, hypertensive hearts, and normal hearts but were greater in those with DCM-like HCM. The mean % lumen of the IMSAs was similarly reduced in the hearts with HCM (29 +/- 5% in the ventricular septum and 31 +/- 5% in the left ventricular free wall) and in hypertensive hearts (30 +/- 8% and 31 +/- 7%) compared with that in normal hearts (40 +/- 5% and 38 +/- 5%) and was the lowest in the ventricular septum of hearts with DCM-like HCM (17 +/- 3%). The mean % lumen of the IMSA was inversely correlated with heart weight (r = -.59), the mean size of myocytes (r = -.66 in the ventricular septum, r = -.63 in the free wall), and percent fibrotic area in the septum (r = -.68). The mean % lumen values of the IMSAs in the tissues with and without disarray in the hearts with HCM were similar. Thus IMSA disease is of pathophysiologic importance in patients with HCM, DCM-like HCM in particular, or with hypertension.

Contractile performance of the hypertrophied ventricle in patients with systemic hypertension.

SUMMARYIn this investigation we determined the reproducibility of radionuclide measurements of left ventricular ejection fraction, end-diastolic volume, end-systolic volume, stroke volume, pulmonary transit time, pulmonary blood volume and cardiac output in 10 normal subjects. First-pass radionuclide angiocardiograms were performed at rest and during upright, submaximal bicycle exercise on day 1 and day 3. The resting heart rate for the group decreased from 79 ± 17 beats/min on day 1 to 71 ± 14 beats/min on day 3 (p < 0.01). This biologic variation probably contributed to the small but significant decreases in ejection fraction (62 ± 7 to 59 ± 7%, p < 0.05) and cardiac output (7.7 ± 1.9 to 6.6 ± 1.5 l/min, p < 0.02), and the increase in pulmonary transit time (5.8 ± 1.6 to 6.2 ± 1.3 seconds, p < 0.05) between day 1 and day 3. The mean variabilities in ejection fraction, cardiac output and pulmonary transit time were 4.0 ± 3.8%, 1.24 ± 1.23 1/min and 0.65 ± 0.64 second, respectively. No significant differences between studies were observed in resting end-diastolic volume, end-systolic volume and stroke volume. The mean variability in enddiastolic volume was 9.9 ± 5.1 ml. Heart rate varied less during exercise to the same work load, and only pulmonary transit time and blood volume differed significantly between studies. During exercise the mean variabilities in ejection fraction, enddiastolic volume, cardiac output and pulmonary transit time were 3.2 ± 2.5%, 9.8 ± 6.2 ml, 1.59 ± 0.67 1/min and 0.25 ± 0.25 second, respectively. Radionuclide measurements of left ventricular function are highly reproducible if obtained under comparable hemodynamic conditions.

Comparative effects of three calcium antagonists, diltiazem, verapamil and nifedipine, on the sinoatrial and atrioventricular nodes. Experimental and clinical studies.

Diltiazem, verapamil and nifedipine suppress sinoatrial (SA) nodal function in the excised rabbit heart. Clinically, however, their suppressive effect on the SA node is modified considerably by the reflex increase in sympathetic tone as a result of the fall in blood pressure caused by the vasodilating action of the calcium antagonists.Diltiazem, verapamil and nifedipine suppress atrioventricular (AV) nodal conduction and prolong refractory periods in the excised rabbit AV node. Clinically, diltiazem and verapamil exert a similar suppressive effect on the AV node and are useful for treating and preventing AV nodal reentrant tachycardia. Nifedipine, in clinically practical doses, has no antiarrhythmic properties, probably because of reflex activation of the sympathetic system secondary to its hypotensive effect, which is greater than that of the other two calcium antagonists.Diltiazem and verapamil may sometimes worsen AV conduction, especially in patients with conduction disturbances. Nifedipine, on the other hand, can be used as a coronary vasodilator with the least untoward effect on AV conduction.

Ischemic preconditioning preserves creatine phosphate and intracellular pH.

BackgroundIschemic preconditioning slows ATP depletion and ultrastructural damage during the final episode of ischemia. To define the influence of creatine phosphate (CP) and intracellular pH (pHi) on this effect, CP and pHi were serially measured in porcine hearts without collateral circulation by using 31P-NMR spectroscopy and ultrastructural examination. Methods and ResultsFarm pigs weighing 12–15 kg were anesthetized with Fluothane. The control group underwent a single occlusion (20 minutes or 60 minutes); the preconditioned group underwent four episodes of 5-minute occlusion and 5-minute reperfusion followed by a sustained occlusion (20 minutes or 60 minutes). After ischemic preconditioning, CP increased to 115 ± 11% (p < 0.05) of preischemic value and ATP decreased to 84 ± 8% (p < 0.05) of preischemic value, but pH; returned to preischemic value. At 5 and 10 minutes of sustained ischemia, CP was significantly preserved in the preconditioned group (control group, 19 ± 3% versus preconditioned group, 29 ± 4% at 5 minutes; control group, 5 ± 3% versus preconditioned group, 11 ± 3% at 10 minutes; p < 0.05). At 15 and 20 minutes of sustained ischemia, ATP was significantly preserved in the preconditioned group (control group, 64 ± 3% versus preconditioned group, 73 ± 3% at 15 minutes; control group, 51 ± 7% versus preconditioned group, 62 2% at 20 minutes; p < 0.05). At 10, 15, 20, and 25 minutes of sustained ischemia, pH; was significantly higher in the preconditioned group (control group, 6.5 0.05 versus preconditioned group, 6.7 ± 0.1 at 10 minutes; control group, 6.3 0.05 versus preconditioned group, 6.6 0.06 at 15 minutes; control group, 6.1 ± 0.1 versus preconditioned group, 6.4 % 0.1 at 20 minutes; control group, 6.0 0.2 versus preconditioned group, 6.3 ± 0.1 at 25 minutes; p < 0.05). Ultrastructural changes were milder in the preconditioned group at 20 minutes of sustained ischemia. ConclusionsIn addition to ATP and ultrastructure, preconditioning preserved CP and pHi during sustained ischemia. These protective effects might be due to overshoot phenomenon of CP and/or reduced ATP consumption. The relatively longer period of preservation of pH;, which probably is the result of reduced ATP consumption, indicates its greater contribution to reducing infarct size than that of CP and ATP.

Serum prostacyclin stabilizing factor is identical to apolipoprotein A-I (Apo A-I). A novel function of Apo A-I.

Serum PGI2 stabilizing factor (PSF) was purified from human serum to a single protein with a molecular weight of 28,000 D by SDS-PAGE. Analyses of NH2-terminal sequence (32 residues), COOH-terminal sequence (3 residues) and the composition of amino acids disclosed its homology with human apolipoprotein A-I (Apo A-I), a major apolipoprotein of HDL. Apolipoprotein A-II, C-I, C-II, C-III, D and E, as well as LDL, and VLDL did not possess this activity. The alpha-helix structure of Apo A-I is necessary for the binding of PGI2. HDL and nascent HDL reconstituted from Apo A-I and phospholipid significantly prolonged the half-life of PGI2. PGI2 stabilization by HDL and Apo A-I may be an important protective action against the accumulation of platelet thrombi at sites of vascular damage. The beneficial effect of HDL in the prevention of coronary artery disease may be partly due to this action.

Long-term nitrate use may be deleterious in ischemic heart disease : A study using the databases from two large-scale postinfarction studies

BACKGROUND Secondary coronary prevention studies have generally focused on specific medications, often to the exclusion of commonly used therapies. To date, long-term nitrate use has not been investigated in large-scale clinical trials. METHODS AND RESULTS We examined the relation between long-acting nitrates given during the chronic phase of the disease and the outcome. We analyzed data prospectively acquired in a large, observational study involving 1042 patients enrolled for the Multicenter Study of Myocardial Ischemia (MSMI) in North America, Israel, and Japan as well as 1779 patients enrolled for the Multicenter Diltiazem Post Infarction Trial (MDPIT). The Cox analyses with all the variables retained revealed that nitrates were associated with a significantly increased mortality risk (MSMI: hazard ratio 3.78, P =.011; MDPIT: hazard ratio 1.61, P =.019) in patients who had recovered from an acute coronary event. The analyses with the propensity score method on the MSMI and the MSMI databases also showed that the risk for cardiac death with use of nitrates was increased in most of the 5 subclasses according to the score. CONCLUSION These analyses raise concern about the potential adverse effects of long-acting nitrate therapy in chronic coronary disease.

Regional myocardial perfusion and glucose metabolism in experimental left bundle branch block.

BackgroundSeveral authors have reported cases in which 201TI scintigraphy demonstrated perfusion abnormality in the septum of patients with left bundle branch block (LBBB) and normal coronary arteriogram. The mechanism of this abnormality, however, remains to be clarified. Methods and ResultsTo determine whether LBBB itself induces abnormal myocardial perfusion and ischemia and to elucidate its mechanism, we used an in vivo animal model. LBBB was induced by right ventricular pacing in 17 open-chest dogs. We examined myocardial perfusion and glucose uptake using 201T1 and 18F-labeled 2-fluoro-2-deoxy-D-glucose. 201T1 activity in the septum was reduced to 74.7±14.5% of its maximal activity, and mean activity was 86.5±5.3% in the free wall (p<0.05). 18F activity in the septum was also reduced compared with that in the free wall (67.4±12.1% versus 88.0plusmn;5.2%, p<0.05). Regional myocardial blood flow was significantly reduced in the septum compared with the free wall, averaging 0.53±0.18 ml/min/g versus 0.84±0.14 ml/min/g, respectively (p<0.01). Systolic thickening in the septum was reduced from 1.36±0.20 to 0.98±0.04 (p<0.01) after the induction of LBBB, and the intramyocardial pressure in the septum in diastolic phase, in which the major flow of left anterior descending coronary artery (LAD) exists, increased from 26.6±10.5 to 57.8±22.2 mm Hg (p<0.02). Mean aortic pressure, IAD flow, and lactate extraction rate showed no significant change. ConclusionsLBBB itself may reduce myocardial perfusion and glucose uptake in the septum because of impaired systolic thickening and augmented intramyocardial pressure in the septum; however, this is not necessarily related to septal ischemia.

Detection and evaluation of tricuspid regurgitation using a real-time, two-dimensional, color-coded, Doppler flow imaging system: Comparison with contrast two-dimensional echocardiography and right ventriculography

To detect and evaluate regurgitant flow in tricuspid regurgitation (TR) with a newly developed, realtime, 2-dimensional (2-D), color-coded, Doppler flow imaging system (Doppler 2-D echo), 27 patients (18 with suspected TR and 9 normal subjects) were examined and the findings were compared with those obtained using contrast 2-D echocardiography (contrast 2-D echo) and right ventriculography. In 16 of 18 patients with suspected TR, Doppler 2-D echo easily visualized the color-coded regurgitant flow in the right atrium and estimated the severity of TR from the distance of the visible TR jet. On the basis of the QRS synchronized appearance of contrast in the inferior vena cava by the subxiphoid approach or of the negative contrast effect above the tricuspid valve just after the contrast entered the right ventricle with its subsequent back-and-forth movements across the tricuspid valve, Doppler 2-D echo was more sensitive and specific in detecting TR (100% and 100%) than contrast 2-D echo (75% and 82% in the subxiphoid view, 56% and 100% in the 4-chamber view) when the fast Fourier transformation frequency analysis was used as the standard of TR, and it was more sensitive in detecting TR (85%) than contrast 2-D echo (69% in the subxiphoid approach, 46% in the 4-chamber view) when right ventriculography was used as the standard of TR. Additionally, the severity of TR as shown by Doppler 2-D echo correlated fairly well with that shown by right ventriculography. Thus, Doppler 2-D echo is clinically useful for detecting and evaluating TR.

Multiple receptors for modified low density lipoproteins in mouse peritoneal macrophages: Different uptake mechanisms for acetylated and oxidized low density lipoproteins

Receptor-mediated incorporations of two modified low density lipoproteins (LDL), acetylated LDL (acetyl-LDL) and oxidized LDL were compared in vitro in mouse peritoneal macrophages by cross-competition experiments. Excess amount of oxidized LDL inhibits the binding of [125I]acetyl-LDL only partially, and excess amount of acetyl-LDL inhibits that of [125I]oxidized LDL also only partially, suggesting that the uptake of the two LDL by macrophages is mediated by partially overlapped yet different mechanisms. Scatchard analysis of [125I]acetyl-LDL binding showed a linear plot and addition of excess amount of oxidized LDL partially displaced the binding sites without changing the affinity, suggesting that there are two classes of receptors with similar affinity; one is specific for acetyl-LDL and the other is common. And the plot of [125I]oxidized LDL binding showed a curvilinear plot and excess amount of acetyl-LDL partially displaced the binding sites of the low affinity, suggesting that there are two classes of binding sites with different affinities and the low affinity one is shared with acetyl-LDL. These results indicate that macrophage receptors for modified LDL consist of at least three receptors, two of which are specific for each LDL and the rest is a common receptor.