This is a brief review of agents that stabilize calcium release from the sarcoplasmic reticulum in cardiac muscle. An excess intracellular calcium concentration (calcium overload) is a common feature in a variety of cardiac cell injuries. Calcium overload elicits diastolic and systolic failure, and is involved in the genesis of arrhythmias. These abnormalities appear in part to be caused by the spontaneous release of calcium ions from the sarcoplasmic reticulum. Previous efforts to treat calcium overload were made with the intention to decrease the total intracellular content of calcium ions. However, such procedures would result in a decrease in contractility. Agents that stabilized calcium release from the sarcoplasmic reticulum may therefore be useful to correct abnormalities in calcium overload. In this review, after briefly describing intracellular calcium homeostasis, strategies against calcium overload, especially those involving magnesium ion, ryanodine, caffeine, dantrolene, phenytoin, R56865, KT361 and flunarizine will be discussed.

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Vascular endothelial cells are constantly exposed to wall shear stress generated by blood flow. Endothelial cells act as mechanoceptors sensing and responding to shear stress, and play a role in flow-dependent phenomena such as angiogenesis, vascular remodeling and atherosclerosis. Numerous recent studies have demonstrated that endothelial cell functions change in response to shear stress, and that the responses are often accompanied by changes in related gene expression. More recently there has been evidence that genes known to be regulated by shear stress may have a common cis-element (shear stress responsive element; SSRE) in their promoter regions. A molecular mechanism for endothelial cell responses to mechanical stress is close to being elucidated. In this paper, shear-stress-mediated regulation of endothelial gene expression is reviewed.

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Effects of therapy with urokinase (UK) and with recombinant tissue plasminogen activator (rtPA) were compared in patients with acute myocardial infarction (AMI). To achieve homogenous therapeutic conditions the comparison was restricted to patients having their first AMI and to cases of clinically successful thrombolytic therapy (defined by non-invasive criteria, such as a 50% decrease in elevated ST-segment in the worst lead of a 12 lead ECG within 300min after onset of thrombolytic therapy, complete pain resolution during thrombolytic therapy, and later confirmed by angiography 10 days after AMI).Effects of UK and rtPA on continuous multilead ST-segment analysis and cardiac proteins (creatine kinase and its isoenzyme CK-MB, aspartate transaminase and hydroxybutyrate dehydrogenase) were analyzed during 24 hours following onset of therapy.
Continuous ST analysis showed a faster resolution of the elevated ST-segments after thrombolytic therapy with rtPA than with UK (p<0.01). Accelerated idioventricular rhythms (p<0.05) occurred sooner following rtPA than UK treatment. The washout of creatine kinase was increased (p<0.01) after rtPA. Although both drugs induced comparable, angiographically controlled reperfusion, the results suggest that the process of reperfusion was accelerated during thrombolysis with rtPA compared to UK. Thrombolytic therapy of AMI with rtPA may hence improve myocardial salvage.

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To investigate the mechanism of sympathovagal imbalance due to myocardial ischemia, we studied 42 consecutive patients undergoing successful percutaneous transluminal coronary angioplasty by correlating frequency domain and time domain measures of heart rate variability with parameters such as echocardiography, stress thallium scanning and radionuclide angiography before, immediately after and 2 months after the procedure. Of these, 20 patients (Group N) had normal and 22 patients (Group A) had abnormal regional wall motion. A control group of 20 healthy subjects (Group C) underwent echocardiography and examination of heart rate variability twice at 2-month intervals to check for spontaneous variations. At baseline, frequency domain measures such as low and high frequency power and time domain measures such as SDANN index (the mean of the standard deviations of the average of RR intervals) were lower in Group A than in Groups N and C, whereas no differences were detectable in ultra low and very low frequency, total power, SDNN index (the mean of the standard deviations of the mean of normal RR intervals), and r-MSSD (the root mean square of successive RR differences). There was high association between the diastolic wall stress index and both high frequency (r=-0.82) and low frequency power (r=-0.77). There were similar findings for the systolic wall stress index (r=-0.72 for high frequency and r=-0.64 for low frequency power). After successful coronary angioplasty, regional wall motion, left ventricular wall stress indices and all measures of heart rate variability were unchanged in Group N. In Group A the mean summed segment score improved from 15.9±2.6 to 12.2±1.7 (p<0.0001), and mean low frequency, mean high frequency power (logarithmic units), and SDANN index (msec) increased from 6.10±0.23 to 6.36±0.28 (p<0.005), from 5.36±0.40 to 5.70±0.39 (p<0.01) and from 70±18 to 83±18 (p<0.01) respectively. In addition, low and high frequency power and SDANN index, lower at baseline in Group A than in the other two groups, were comparable in the three groups after coronary angioplasty. The evolution of diastolic and systolic wall stress indices paralleled that of the above three parameters. In conclusion, diastolic and systolic wall stress indices, in addition to segmental left ventricular dysfunction, were synergistically involved in determining sympathovagal imbalance in patients with significant coronary artery disease; the reversal of left ventricular dysfunction and wall stress indices improves the profile of heart rate variability. Alterations in cardiac geometry and wall stress influence mainly the discharge of afferent sympathetic and efferent parasympathetic innervations and also principally the long-term heart rate variations instead of short-term modulation.

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We investigated the role of myocardial ischemia in acute myocardial infarction and cardiac death in 253 patients with asymptomatic coronary disease (206 men, 47 women, mean age: 55±8 years). Patients were divided into two groups: those with angina pectoris with no history of myocardial infarction (AP group, 93 patients) and those with a history of myocardial infarction (MI group, 160 patients). We also examined the usefulness of exercise electrocardiographic and Holter electrocardiographic findings as prognostic indicators of cardiac events. After 24-hour Holter electrocardiograms were obtained in both groups, patients were assigned to subgroups with or without silent myocardial ischemia (SMI) based on the presence or absence of transient ST-segment depression. Prognostic indicators were evaluated by multiple regression analysis. Cardiac events occurred in 26 (10.3%) of 253 patients; in 6 patients these events were fatal. The incidence of cardiac events was significantly higher in the SMI group than in the non-SMI group (16.4% versus 5.6%, p<0.05). SMI was identified as a significant prognostic indicator in the overall population (p=0.0088), as were the number of diseased coronary arteries in the AP group (p=0.0152), and SMI (p=0.0022) in the MI group. There were 3 deaths related to cardiac events in each group. The mean time from onset of angina pectoris to death was 73±41 months compared with 33±43 months in the MI group. Our findings suggest that the severity of the coronary lesion and SMI were important predictors of major cardiac events, and that the mechanism of the onset of cardiac events was different in the AP and MI groups.

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One hundred and forty-two consecutive patients with sustained monomorphic ventricular tachycardia (VT) were investigated. Only 26.1% of VTs were associated with ischemic heart disease (IHD). The induction rate of sustained VT upon electrophysiologic study (EPS) was 82.9% in patients with IHD and 65.3% in non-IHD. Of 76 inducible sustained VTs, pharmacologic therapy was finally selected in 35 cases, ablative therapy in 25 and surgical therapy in 12. Long-term prognosis was compared between groups divided according to type of ventricular arrhythmia induced at final EPS after antiarrhythmic therapy as follows: Group A: complete suppression of VT, Group B: clinical or non-clinical nonsustained VT, Group C: clinical sustained VT. The event rate in IHD was 6.3% in Group A, 44.4% in Group B and 100% in Group C. In non-IHD, the event rate was 24.0%, 25.0% and 75.0% (Groups A, B and C, respectively). Complete suppression of VT showed a good prognosis in IHD, however, a slightly higher recurrence rate was observed in non-IHD. In ablative therapy, some recurrences and sudden deaths were observed in spite of complete suppression of both VTs in both the IHD and nonIHD groups. Review of the efficacy of antiarrhythmic procedures is recommended during the follow-up period.

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Several hypotheses have been proposed for the pathophysiology of the congenital long QT syndrome, however, the underlying mechanism has not yet been elucidated. This study evaluated G protein function in patients with congenital long QT syndrome (LQTS) and compared it with that of normal subjects.
Platelet-rich plasma was collected and the cyclic AMP (cAMP) level of platelets was measured in three conditions utilizing radioimmunoassay: the basal state (Basal cAMP), after stimulation by PGE1 (PGE1-cAMP), and after stimulation by PGE1 followed by inhibition by adrenaline (Adr-cAMP), and the results were compared between 7 LQTS patients and 10 healthy volunteers (control). Gs function was defined as (PGE1-cAMP)/(Basal cAMP) and Gi function as {(PGE1-cAMP)-(Adr-cAMP)}/(PGE1-cAMP).
Basal cAMP was lower in patients than in the controls: 2.9±0.6pmol/10⁸ cells vs. 4.2±0.7pmol/10⁸ cells (p<0.05). The increase in cAMP after PGE1 was similar in the two groups but the peak was lower in the patients: 16.8±6.2pmol/10⁸ cells vs. 24.8±7.4pmol/10⁸ cells (PGE1-cAMP). After addition of adrenaline, cAMP decreased to 14.2±5.8pmol/10⁸ cells vs. 16.2±7.6pmol/10⁸ cells and the change was significantly smaller in the patients than in the controls: 0.17±0.12 vs. 0.38±0.16 (p<0.05).
Basal cAMP was weakly correlated with sinus cycle length (r=-0.48, p>0.3) and QTc was correlated with Gs function (r=0.52, p>0.3) but not with Gi function. Patients with associated Torsade de Pointes had a significantly lower Gi function compared to those without (p<0.05).
In LQTS patients, G protein function was abnormal and the abnormality was associated with clinical characteristics of long QT syndrome. The relationship between the abnormal G protein function and the regulation of the repolarization of the ventricular myocardium needs to be studied further.

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Fifteen (2.1%) patients were diagnosed as having congenital coronary artery fistula (CAF) in a consecutive series of 704 adult patients undergoing selective coronary arteriography; the incidence was astonishingly higher than previous observations. The presentation of clinical symptoms and the electrocardiographic changes at rest and/or after exercise testing probably attributable to the CAF were observed unexpectedly often in spite of the fact that the magnitude of the shunt seemed not to be significant. With respect to the anatomy of the CAF, the incidence of origination from plural coronary arteries and that of fistulation into the left ventricle were also unexpectedly high. These observations presented a striking contrast to those of previous reports, but we were unable to determine the reason. In four cases, the CAF was ligated either electively or concurrently with mitral valve surgery, and the results were satisfactory. Taking these circumstances into consideration, we should not minimize the impact of a CAF with a seemingly small shunt.

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The present study was undertaken to determine whether myocardial energy or ion levels are related to oxygen-replenishment-induced recovery of cardiac contractile force after hypoxia. Isolated rat hearts were perfused for 3 to 40min under hypoxic conditions, followed by 45min of reoxygenation. Hypoxia induced a cessation of cardiac contractile force, a rise in resting tension, a decrease in high energy phosphates, and an increase in lactate. Myocardial ATP, creatine phosphate (CP) and lactate reached steady-state levels after 15, 10 and 5min of hypoxia, respectively. Hypoxic conditions in the present study also caused an increase in sodium content and a decrease in potassium content, but not changes in calcium content, along with a prolonged hypoxic period. When the hearts were perfused for more than 25min under hypoxic conditions, no recovery of contractile force was observed following 45-min of reoxygenation. Hypoxic perfusion for more than 25min induced an accumulation of tissue sodium content approximately 3 fold higher than the pre-hypoxic value at the end of hypoxia, and also induced a marked increase in myocardial calcium content upon reoxygenation. When tissue sodium content accumulated by less than 300% of the pre-hypoxic value, cardiac contractile function was partially reversed by reoxygenation and calcium-overload was not observed. The recovery of post-hypoxic cardiac contractility correlated with tissue sodium content during hypoxia rather than with myocardial high energy phosphate content at the end of hypoxia. These results suggest that accumulation of tissue sodium content in the hypoxic myocardium and calcium content in the reoxygenated myocardium may be indicative of hypoxia/reoxygenation-induced cardiac contractile failure.

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Restenosis after balloon dilitation of atherosclerotic arteries reflects migration and proliferation of vascular smooth muscle cells and infiltration of monocyte/macrophages. Hypercholesterolemia may contribute to this phenomenon. Accordingly, we used the lipid-lowering agent gemfibrozil to determine whether potentially detrimental effects of hypercholesterolemia on vascular remodeling after mechanical injury could be attenuated. New Zealand white rabbits fed either a chow diet (control), a 0.25% cholesterol-enriched diet, or a 0.25% cholesterol-enriched diet supplemented with gemfibrozil (0.05%, 0.1%, or 0.2%) for one week were subjected to balloon-induced carotid injury and maintained on the same diet for an additional 4 weeks. Histology of the vascular wall was then characterized. Plasma triglycerides before and 4 weeks after injury did not change in any of the treatment groups (p=0.24). Plasma cholesterol increased in all animals receiving the high cholesterol diet, and the increases remained unaffected by supplementation with gemfibrozil. In control rabbits, intimal thickening area [intima (mm²)/(intima+media (mm²))] 4 weeks after injury was 27.0±7.7% (n=16). Values were the same in hypercholesterolemic rabbits (29.7±11.8%, n=12; p=ns). However, in 16% the lumen was completely occluded by thrombus and intimal thickening could not be quantified. In hypercholesterolemic rabbits given gemfibrozil, intimal thickening was increased by 33% compared with controls (35.9±11.6%, n=39, p _??_0.05) and by 21% compared with hypercholesterolemic animals not given gemfibrozil (p=ns). None had thrombotic luminal occlusion.
Macrophages detected immunohistochemically were only modest in number in vessels from control animals. In vessels from hypercholesterolemic animals and from animals whose diets were supplemented with gemfibrozil, macrophages were increased in number in both intima and media. Thus, gemfibrozil did not appear to attenuate processes implicated in restenosis. Its attenuation of thrombotic occlusion may be related to effects we have noted it exerts on fibrinolytic systems independent of lipid metabolism.

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We report a case who had myocardial ischemia after release of the aortic cross clamp during mitral valve replacement. Myocardial ischemia was visually estimated by use of intraoperative MCE (myocardial contrast echocardiography). After appropriate treatment the ischemic area disappeared and the patient showed a good postoperative course. MCE is a useful method with which to detect visually the wash out pattern of cardioplegia from myocardium after reperfusion during open heart surgery.

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Percutaneous transvenous mitral commissurotomy (PTMC) was performed successfully without complications in 3 patients with severe mitral stenosis and hyperthyroidism. All 3 patients had pliable, noncalcified mitral valves. One patient who had been treated with methimazole for 6 months was still in a hyperthyroid state when she presented with intractable congestive heart failure and was found to have severe mitral stenosis. The heart failure improved immediately after PTMC, but the patient remained in New York Heart Association functional class 2 until a euthyroid state was achieved with I¹³¹ therapy. In the other 2 patients, hyperthyroidism was unsuspected at the time of PTMC. Unexpectedly suboptimal symptom improvement led to the diagnosis of hyperthyroidism 1 month after the intervention. In all 3 patients, PTMC resulted in an immediate hemodynamic and clinical improvement. However, complete clinical improvement occurred only when euthyroid state was achieved after antithyroid treatment. The present study suggests that PTMC is a safe and effective intervention modality in patients with coexisting hyperthyroidism and severe mitral stenosis. The procedure may be considered a therapeutic option in patients with hyperthyroidism and severe mitral stenosis.

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A 57-year-old woman with chronic hepatitis C was treated with alpha-2b interferon (IFN). Forty-five days after the initiation of IFN therapy, she developed cardiogenic shock. Acute perimyocarditis as a cause of cardiogenic shock was clinically suspected by the findings of complete atrioventricular block, regional wall motion abnormality and pericardial effusion. Since IFN therapy may induce cardiogenic shock in some patients, it is important to carefully monitor patients under treatment with IFN for abnormal cardiac signs.

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