Myocardial hypoxia and ischemia are characterized by the depletion of ATP and the development of intracellular acidosis, which alter cellular ionic homeostasis. Specifically, elevated cytosolic free Ca⁺⁺ concentrations cause cellular injury during hypoxia/ischemia and lead to irreversible myocardial damage during reoxygenation/reperfusion. An increase in the intracellular Na⁺ concentration has been shown to correlate with Ca⁺⁺ overload. Although inhibition of Na⁺/K⁺ exchange because of decreased ATP production may be involved, it is more likely that intracellular acidosis drives Na⁺ into the cells via Na⁺/H⁺ exchange. Experimental evidence supports the notion that Na⁺/H⁺ exchange is primarily responsible for Na⁺ influx during hypoxia/ischemia. The accumulation of intracellular Na⁺ may then activate the Na⁺/Ca⁺⁺ exchanger causing Ca⁺⁺ overload. Therefore, the Na⁺/Ca⁺⁺ exchanger plays a crucial role in cellular injury during hypoxia/ischemia and in cell death during reoxygenation/reperfusion. In the past few years, the Na⁺/Ca⁺⁺ exchanger has been cloned and the structure/function relationship studied intensively. Agents which inhibit the Na⁺/Ca⁺⁺ exchanger may have therapeutic potential for the treatment of ischemic heart disease. These advances will greatly accelerate the understanding of the cellular and molecular mechanisms underlying the role of the Na⁺/Ca⁺⁺ exchanger in the development of myocardial damage during hypoxia/ischemia and reoxygenation/reperfusion.

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Hemoconcentration has been observed during paroxysms of atrial fibrillation and at the early stage of chronic atrial fibrillation. The present study was designed to determine how long the hemoconcentration continues after complete transition to atrial fibrillation from sinus rhythm by retrospective long-term observation of 9 patients with chronic atrial fibrillation and 18 age-gender matched control patients. Hematocrit levels significantly increased with transition to chronic atrial fibrillation from sinus rhythm (from 44.88±0.87% to 46.87±1.12%, p<0.01) and remained high for at least another 4 years. They remained unchanged throughout the observation period in the control patients. There is a significant difference in the hematcrit level between patients with chronic atrial fibrillation and control patients (p<0.001). The hemoconcentration may present a potential risk for stroke and thromboembolic complications.

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To investigate the relationship between left atrial (LA) flow dynamics and hemostatic markers in nonvalvular atrial fibrillation (AF), 45 patients with nonvalvular AF who had not received anticoagulants were evaluated by transesophageal echocardiography. We determined the LA appendage flow and the presence of LA spontaneous echo contrast (SEC) or thrombus. We measured plasma levels of thrombin-antithrombin III complex (TAT), fibrinopeptide A, D-dimer, β-thromboglobulin, and platelet factor 4 in peripheral blood as hemostatic markers. The patients were divided into a low-velocity group (n=19; sum of peak emptying and filling LA appendage flow velocities<40cm/s) and a high-velocity group (n=26;≥40cm/s). The maximum LA diameter was significantly greater and the LA expansion fraction was significantly smaller in the low-velocity group than in the high-velocity group. LA SEC or thrombus was observed in 11 patients (58%) in the low-velocity group, but not in any patients in the high-velocity group (p<0.001). The plasma levels of TAT, fibrinopeptide A, D-dimer, β-thromboglobulin, and platelet facfor 4 were significantly higher in the low-velocity group than in the highvelocity group. The plasma levels of TAT, fibrinopeptide A, β-thromboglobulin, and platelet factor 4 were significantly higher in 8 patients without LA SEC or thrombus in the low-velocity group than in 26 patients in the high-velocity group. Patients with nonvalvular AF accompanied by an enlarged and dysfunctioning LA and a decreased LA appendage flow velocity had increased intravascular coagulation-fibrinolysis activity and platelet activation. These abnormalities may be closely related to the thrombogenetic state in patients with nonvalvular AF.

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We studied non-dipolarity characteristics during ventricular excitation in normal adults and children by magnetocardiography (MCG) by recording magnetic field on the thorax. The source and currents of the electrical dipole from the onset up to 60ms of ventricular excitation were analyzed in 16 adults and 5 children. A single equivalent current dipole (ECD) was estimated by Sarvas' formula for the sphere model at 1ms intervals. The non-dipole value (NDV) was calculated from the magnetic field strength at each recording point and theoretically estimated by ECD, representing an index for the nondipolarity. At 32-34ms from the beginning of QRS, the mean NDV was a minimum in all subjects suggesting at least a non-dipole component during this period. High NDV (over 5%) were present in most subjects in both the early and late phase compared to this period. Thirteen of 16 adults had a high NDV in the early phase (9.3±3.0%, mean±SD) and all 16 subjects had a high NDV in the late phase (21.5±10.5%). All 5 children had high NDV in both the early (10.5±5.4%) and late phases (16.8±7.9%). A single ECD estimation by MCG showed a relatively low non dipolar component and MCG could be applied to the clinical evaluation of cardiac excitation in both normal and pathological conditions.

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To examine the long-term effects of the angiotensin-converting enzyme (ACE) inhibitor enalapril on chronic heart failure, 10 patients (7 men and 3 women, mean age: 62±11 years) with chronic stable heart failure, classified as New York Heart Association (NYHA) functional class 2-3 for more than 3 months, and a left ventricular ejection fraction less than 45% were treated with 2.5-5.0mg of enalapril once a day for 3-15 months (mean 7 months). The causes of heart failure were old myocardial infarction (n=7), hypertension (n=2), and atrial fibrillation (n=1). Radioiodinated metaiodobenzyl guanidine (¹²³I-MIBG) imaging, radionuclide angiography, and treadmill exercise test were performed before and after the treatment. With enalapril treatment, (1) left ventricular ejection fraction (LVEF) increased significantly from 38.3±6.9% to 47.5±14.7%; (2) sub-maximal exercise time increased significantly from 205±112 to 272±120 seconds; (3) the heart to mediastinum (H/M) ratio of ¹²³I-MIBG increased significantly (early image: 1.99±0.38 versus 2.20±0.50; delayed image: 1.86±0.44 versus 2.09±0.51); and (4) the washout rate of ¹²³I-MIBG decreased slightly from 29.1±9.1% to 25.4±7.0%. The improvement rate of LVEF was significantly correlated with the improvement rates of the H/M ratio and washout rate after treatment with enalapril. Thus, the long-term effects of enalapril can be observed in the cardiac sympathetic nervous system, and ¹²³I-MIBG imaging appears to be useful for evaluating the therapeutic effects of enalapril on the cardiac sympathetic nervous system in patients with chronic heart failure.

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A total of 6 α chains [α1 (IV) to α6 (IV)] have been identified in type IV collagen. We examined the localization of these chains in the myocardium of patients with dilated (DCM) and hypertrophic (HCM) cardiomyopathy. The localization of α1 (IV)-α6 (IV) in biopsy specimens of 5 patients with DCM and 4 with HCM was examined using immunohistochemistry with monoclonal antibodies. Both α1 (IV) and α2 (IV) immunostaining formed thin homogeneous outlines around myocytes in control hearts. In the DCM specimens, α1 (IV) and α2 (IV) immunostaining formed thick and irregular patterns around myocytes. Staining for α1 (IV) and α2 (IV) was also obscrved in some enlarged intercellular spaces. In 3 DCM hearts, moderate staining for α1 (IV) and α2 (IV) was observed in small replacement fibrotic lesions. In large replacement fibrotic lesions, no α1 (IV) or α2 (IV) staining was observed. In the HCM specimcns, α1 (IV) and α2 (IV) staining formed thick homogeneous patterns around myocytes. In the enlargcd intercellular spaces, no α1 (IV) or α2 (IV) staining was observcd. No labeling for α3 (IV)-α6 (IV) was observed in any heart examined. In conclusion, the present results demonstrate that type IV collagen consisting of α1 and α2 chains appears in the fibrotic lesions of DCM, indicating its contribution to the development of fibrotic changes in the myocardium of DCM patients. In contrast, type IV collagen was restricted to the myocyte membrane in the HCM hearts. Fibrotic processes in the intercellular spaces may differ between DCM and HCM hearts.

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This study was designed to evaluate the differences in clinical findings between patients with and without Q waves in acute myocarditis. Among a total of 24 patients, eleven patients had Q waves and thirteen did not. Echocardiographic findings, in-hospital complications and follow-up results were compared between the two groups. In the acute stage, the Q wave group showed significantly higher creatine kinase (CK) values and a more impaired left ventricular ejection fraction than the non-Q wave group (40±11% vs 57±10%, p<0.001). Transient left ventricular hypertrophy was also prominent in the Q wave group. The incidence of cardiogenic shock (55%) and conduction disturbances (64%) were higher in the Q wave group than in the non-Q wave group (0% and 15%, respectively). In-hospital mortality rate was 27% in the Q wave group and 8% in the non-Q wave group, respectively. Since rapid improvement occurred in survivors with Q waves, long-term prognosis was favorable for the two groups. In conclusion, Q waves might indicate a more severe course in early illness.

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The ratio of two wave components Ιb/aΙ constituting the second derivative of the plethysmogram (SDPTG) was correlated with arterial distensibility. Eighty-two subjects (33-93 years old) were classified into three groups according to the thickness of the intima-media complex of the common carotid artery measured by B-mode ultrasonography. One group was non-atherosclerotic (without pathologic thickening) (nAS) and the other two groups atherosclerotic (mild and severe thickening, or plaque formation) (AS-1 and AS-2). Distensibility (D) of the common carotid artery was calculated from arterial dimensions and blood pressure: h/p=D, where h=(Ds-Dd)/Dd; Ds, Dd and p represent the inner diameter of the carotid artery at peak systole, at end diastole and brachial pulse pressure, respectively. The plethysmogram was recorded at the cuticle of the 2nd digit of the left hand, and the SDPTG was determined with a 10 msec time constant. D showed a significant negative correlation with age in all subjects and in the three separate groups. The correlation between age and Ιb/aΙ was significantly negative in all subjects. This negative correlation was not observed in the nAS group, while it was significant in both AS-1 and AS-2. The correlation between Ιb/aΙ and D was significantly positive in all subjects and in each group. Significant differences were found among the three groups for Ιb/aΙ and D. These results suggest that a decrease in Ιb/aΙ or in D was proportional to the thickness of the intima-media complex of the carotid artery, that is, the development of atherosclerosis. These results provide direct evidence that Ιb/aΙ of the SDPTG is related to the distensibility of the peripheral artery, and suggest that Ιb/aΙ is a useful non-invasive index of atherosclerosis and altered arterial distensibility.

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In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To determine the genetic etiology of the lipoprotein abnormalities, we screened DNA samples for mutations in all 18 exons and the exon- intron boundaries of the low-density lipoprotein (LDL) receptor gene. Novel point mutations were identified in the proband: a T-to-A transversion at nucleotide position 223, causing substitution of Ser for Cys at codon 54 in exon 3 of the receptor gene. This amino acid replacement would disrupt one of the disulfide bonds necessary for maintenance of the secondary structure of the repeat at the N-terminal of the receptor, prevent correct folding of the receptor, and result in defective intracellular transport of the receptor.

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A canine model of postischemic myocardial dysfunction (15min ischemia, 60min reperfusion) was used to evaluate the relationship between energy metabolism and myocardial contractile function by on-line measurements of ECG, left ventricular pressure, coronary blood flow and regional segment shortening (%SS) with the continuous acquisition of ³¹PMR spectra. Two groups emerged from these studies; the first (n=7) in which regional myocardial %SS remained significantly depressed after 60min of reperfusion (stunned) and the second (n=5) in which regional %SS returned to control levels after 60min of reperfusion (non-stunned). Both groups exhibited rapid, similar decreases in %SS and parallel rapid decreases in the phosphocreatine to inorganic phosphate (PCr/Pi) ratio with the onset of ischemia. The PCr/ATP ratio exceeded control levels in the stunned group immediately upon reperfusion and remained significantly above control after 60min of reperfusion. Measurements of tissue myocardial creatine kinase (CK) revealed a significant decrease in total tissue CK activity in stunned myocardium compared to control. A significant inverse relationship (r=-0.904, p<0.003) was found between myocardial tissue CK specific activity and the PCr/ATP ratios. We postulate that the elevated PCr/ATP ratio caused by the impairment of energy transfer to the contractile apparatus constitutes a contractile dysfunction in the postischemic heart.

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Repair processes of cells submitted to an injury may exhibit an indirect identifying feature of its activity, based on the amount of connective tissue that could be traced with special stains and morphometry. Hydroxyproline concentration in tissue is also an index with which the presence and amount of repair mechanisms can be assessed. They may be quantitated appropriately in correlation with the end products of collagen, which represent the amount of cicatricial tissue.
In order to correlate the size of the scar in myocardial infarcts with the amount of connective tissue, a determination of hydroxyproline levels after 30 days of acute experimental infarctions was performed in 3 groups of rats: 10 received a single dose of 21 U of human growth hormone (HGH) per week for 4 weeks, in a bolus injection immediately after the infarction was surgically induced; 10 received the same dose as above in daily injections during a week. Finally, another group of 10 animals which did not receive an active treatment served as controls. All animals were sacrificed at the end of a month. A morphometric study with Van Gieson stain was performed. Hydroxyproline levels were determined.
Hydroxyproline levels were considerably lower in hGH-treated rats (T) compared to control (C) rats: 3.30ug/mg±0.1vs. 4.10±0.29 (p<0.05). Morphometry: T.: 5.23±2.45vs. C.: 4.22±2.15 of the left ventricular wall. Three aneurysms were found in C group versus 1 in T.
Human growth hormone administered to a group of rats with myocardial infarction showed obvious dose-effects consisting of a significant diminution of scar tissue in treated rats with a proportional fall in the hydroxyproline levels.

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