Protective effect of SM-20550, a selective Na+ - H+ exchange inhibitor, on ischemia-reperfusion-injured hearts.

The protective effects of Na+ - H+ exchange inhibitors SM-20550 (SM) and 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) against ischemia-reperfusion injury were investigated in guinea pig Langendorff hearts. The changes in intracellular pH (pHi), high-energy phosphates, and biologic intracellular active ions ([Na+]i and [Ca2+]i) were regarded using the 31P-NMR and specific fluorescent signals from the heart tissues together with simultaneous recordings of the left ventricular developed pressure (LVDP). The recovery rate of LVDP from ischemia (40 min) by reperfusion was 36.8% in the control experiments, whereas in the presence of SM 10(-7) M, a gradual increase to 75.9% (55.5% with 10(-8) M), in contrast to EIPA (10(-7) M), 47.5% was observed. SM 10(-7) M restored the ATP level by 70% in 40-min reperfusion, which was already higher than the control in the latter half (20-40 min) of the ischemic period. The recovery rate of phosphocreatine by pretreatment of the heart with SM 10(-7) M was 75% in 40 min reperfusion. The pHi estimated from Pi/phosphocreatine chemical shift became highly acidic in ischemic heart so that SM 10(-7) M caused slight but significant pHi reduction from control pHi of 5.89 to 5.75. The level returned to pHi at around 7.38 during 30-40 min reperfusion, and the recovery was significantly greater than the control pHi of 7.24. The fura-2 Ca2+ or SBFI-Na+ signals during Langendorff ischemia heart increased, and rapidly returned to the control level after the reperfusion. SM suppressed the [Na+]i or [Ca2+]i elevation induced in the late stage during ischemia, resulting in LVDP restoration after reperfusion; Diastolic Ca2+ in the end period of ischemia, SM 10(-7) M 194% versus drug-free 220.7%. Na+: SM 10(-7) M 121.6% versus drug-free 128.0%. The present results suggest that the selective Na+ - H+ exchange inhibitor SM is promising as a potent and specific protective agent against ischemia-reperfusion injuries with Ca2+ overload induced via Na+ - H+, Na+ - Ca2+ exchange.

Circadian heart rate rhythms in Japanese centenarians.

OBJECTIVE: To investigate age-associated changes in the circadian rhythm of the heart rate. DESIGN: The circadian rhythm was extracted from diurnal heart rate (HR) variations, and patterns of HR rhythm were compared in centenarians and controls. SETTING: Centenarians living in the metropolitan area of Tokyo and in Aichi prefecture in 1992. PARTICIPANTS: Fifty centenarians underwent 24-hour ambulatory electrocardiogram (Holter) monitoring. The control group, comprised of 100 clinically healthy subjects who underwent similar Holter monitoring, was subdivided, by age, into two groups: the younger controls (age range 23 to 54 years, mean age 41) and the older controls (age range 55 to 82 years, mean age 69). MEASUREMENTS: Harmonic analysis was used to approximate the 24-hour RR interval (the interval between two neighboring R waves on the electrocardiogram) data obtained by Holter monitoring to a summation of three cosine waves with 24-hour, 12-hour, and 8-hour periods. The power of the period was adjusted for the goodness of curve-fit. The power of each period and the circadian acrophase (the timing of the peak in a 24-hour rhythm) were compared among the centenarians, older controls, and younger controls. HR rhythms were classified by k-means cluster analysis based on the power of the period. The prevalence of each pattern was compared among the three age groups. In the centenarians, the relationship between clinical parameters (activities of daily living, cognitive function, nutritional status, and present illness) and patterns of HR rhythm was investigated. RESULTS: The power of the 24-hour period in the centenarians was significantly smaller than that in the older (P < .05) and younger (P < .001) controls. The power of the 8-hour period in the centenarians was significantly larger than that in the younger controls (P < .05). Advances or delays in the circadian acrophase were frequently observed in the centenarians compared with the younger controls. The power of each period did not differ between centenarians with (n = 11) and without (n = 39) overt diseases capable of altering HR rhythms. Five patterns of HR rhythm were identified: 24-hour period dominant (n = 84), 24-hour+12-hour period (n = 18), 12-hour period dominant (n = 11), 8-hour period dominant (n = 7), and low goodness of curve-fit (n = 30). The 8-hour period dominant pattern and the low goodness of curve-fit pattern were observed commonly in the centenarians, whereas the 24-hour period dominant pattern and the 24-hour+12-hour period pattern were observed frequently in the younger controls. Patterns of HR rhythm were not related to clinical parameters in the centenarians. CONCLUSIONS: The circadian rhythm of HR changed with aging: there was reduction in the power of the 24-hour period, augmentation in the power of the 8-hour period, and a shift in the circadian acrophase.

[Circadian rhythmicity of heart rates in centenarians].

Holter electrocardiography was used to study the circadian rhythm of heart rate in 50 centenarians living in Tokyo and in Aichi prefecture. As a control group, 50 healthy subjects aged under 65 years old underwent medical check-ups including Holter electrocardiography at Keio Health Consulting Center. Harmonic analysis was used to approximate the 24-h time-series data on the RR intervals to a summation of three cosine waves with 24-h, 12-h and 8-h periods. The power of each period was adjusted for the goodness of the curve-fit, and the powers of the centenarians were compared with those of the controls. Then all the subjects were classified by k-means cluster analysis into k groups based on the power of the period, and patterns of heart rate rhythms were then identified. The power of the 24-h period in centenarians (32.7 +/- 16.0%) was significantly lower than that in controls (45.8 +/- 17.8%). Although there were no significant differences in the powers of the 12-h and 8-h periods, the power of the 8-h period in centenarians (7.0 +/- 8.4%) was slightly higher than that in controls (4.2 +/- 3.3%). Advances or delays in acrophase (acrophasal shift) were more common in centenarians than in controls. Five patterns of heart rate rhythms were identified: 24-h period dominant (n = 58). 24-h + 12-h period (n = 15), 12-h period dominant (n = 7), 8-h period augmented (n = 7), and low curve-fitting (n = 13). Both the 8-h period augmented pattern and the low curve-fitting pattern were more common in centenarians than in controls. Both the 24-h period dominant pattern and the 24-h + 12-h period pattern were less common in centenarians than in controls. These data indicate that the circadian rhythm of heart rate changes with aging.

A survey of habitual snoring in centenarians.

OBJECTIVE: To ascertain whether centenarians in the surveyed group would be nonhabitual snorers. DESIGN AND SETTING: A cross-sectional survey of centenarians residing in the Aichi Prefecture of Japan. PARTICIPANTS: A total of 103 centenarians (21 men and 82 women). MEASUREMENTS: Questionnaire on sleep habits, breathing, and snoring. RESULTS: Nineteen centenarians (18.4%; 5 men and 14 women) were habitual snorers and two (1.9%) were suspected of having sleep apnea syndrome because of the presence of heavy snoring and nocturnal respiratory arrest. CONCLUSION: Most centenarian subjects were nonsnorers and without breathing pauses during sleep; their snoring rates were no different from those of younger aged older adults in the same population.

Role of Na(+)-H+ exchange on reperfusion related myocardial injury and arrhythmias in an open-chest swine model.

The inhibition of Na(+)-H+ exchange (NHE) with amiloride analogues in vitro has been shown to prevent reperfusion arrhythmias and additional cell necrosis. Inhibition of intracellular Ca2+ overload via NHE inhibition has been suggested as a mechanism of these protective effects. The aim of this study was to examine whether treatment with amiloride analogues reduces the incidence of reperfusion arrhythmias and limits infarct size in vivo. Open-chest swine were exposed to a 30-minute left anterior descending artery (LAD) occlusion and 180 minutes of reperfusion during atrial pacing at 150 ppm. Intravenous 5-(N,N-dimethyl)-amiloride (AML, 5 micrograms/kg per min) was administered in the treatment group (n = 7) and intravenous saline in the control group (n = 7), starting 10 minutes before coronary occlusion. The infusion was continued during ischemia and reperfusion. The area at risk was defined by monastral blue dye and infarct size by triphenyltetrazolium chloride staining. Limb leads ECG and monophasic action potentials (MAPs) from the epicardium in the ischemic area were recorded. There was no significant difference in the size of the area at risk and hemodynamic parameters between the groups. However, the infarcted area was 0.4% +/- 1.0% of the area at risk in the treatment group, whereas it was 62% +/- 29% in the control group (P < 0.05). Pathological examination (Hematoxylin-eosin and Mallory's phosphotungstic acid-hematoxylin staining) revealed that all of the infarcted area consisted of contraction band necrosis. MAP duration in both groups was significantly shortened during ischemia. After reperfusion, MAP duration in the treatment group recovered earlier than that of control group. However, there was no significant difference in the incidence of ventricular tachyarrhythmia between the groups. Inhibition of NHE with AML prevented reperfusion related cell necrosis in the in vivo swine model, but did not reduce the incidence of ventricular tachyarrhythmia.

Arrhythmias in centenarians.

BACKGROUND: Many studies have shown an increase in the prevalence of arrhythmias with advancing age. However, little is known about arrhythmias in centenarians. METHOD AND RESULTS: Thirty-two Japanese centenarians aged 100-106 years (14 males, 18 females) were studied. All of them had 12-lead ECGs, and 22 also had 24-hour ambulatory monitoring. As controls, 89 healthy Japanese elderly from the same geographic area underwent 12-lead ECG. Their mean age was 75 +/- 6 years with a range of 63-93 years, and there were 28 males and 61 females. Twenty-three of them also had Holter ECGs. On the 12-lead ECG, the heart rate was slightly, but significantly, higher in the centenarians (76.8 +/- 12.7 beats/min) than that in the elderly subjects (74.9 +/- 5.9 beats/min, P < 0.005). PQ and QTc were significantly longer in the centenarians (174 +/- 29 and 439 +/- 33 msec, respectively) compared with the elderly subjects (158 +/- 23 and 417 +/- 31 msec, P < 0.005 and P < 0.001, respectively). Supraventricular premature beats (SVPBs) were observed in 31% of the centenarians and in 4% of the elderly subjects (P < 0.001). First- and second-degree AV block was recorded in 25% of the centenarians and 1% of the elderly subjects (P < 0.001). Right bundle branch block was found in 19% of the centenarians and 7% of the elderly subjects (P < 0.05). There were no differences in the frequency of ventricular premature beats (VPBs) or QRS voltage. On the Holter ECG, there were no significant differences in average heart rate, maximum heart rate, minimum heart rate, or the longest RR interval. A subgroup of centenarians had frequent SVPBs. However, none of them had > 1,000 VPBs/day as opposed to four elderly subjects (P < 0.01). Atrial fibrillation was not observed in any records of the centenarians despite the presence of frequent SVPBs. CONCLUSION: These data suggest that conduction disturbances of the AV nodal--His-Purkinje system and frequent SVPBs are common in centenarians, whereas very frequent VPBs and atrial fibrillation seem less common.

Short-term synchronized retroperfusion before reperfusion reduces infarct size after prolonged ischemia in dogs.

BACKGROUND: Previous studies have demonstrated that synchronized coronary venous retroperfusion (SRP) can restore blood flow to the ischemic myocardium, resulting in infarct size reduction and improvement of the left ventricular function. Despite the nutritive blood flow achieved by SRP being relatively limited, SRP has been shown to improve washout of by-products from the ischemic myocardium. The aim of this study was to investigate whether short-term SRP immediately prior to reperfusion would attenuate the deteriorative phenomena following reperfusion. METHODS AND RESULTS: Closed-chest anesthetized dogs underwent 3 hours of left anterior descending coronary artery (LAD) occlusion. The dogs were then randomized into two groups: (1) control group (n = 9), in which the occlusion was immediately followed by 3-hour reperfusion; or (2) SRP group (n = 9), in which SRP was started 3 hours after occlusion and maintained for 30 minutes with sustained occlusion followed by 2.5-hour reperfusion with simultaneous discontinuation of SRP. There were no statistical differences between the groups in global hemodynamics and degree of ischemia measured by radiolabeled microspheres. Myocardial infarct size (triphenyltetrazolium method) expressed as percentage of risk area was significantly smaller in the SRP group (24 +/- 7%, mean +/- SEM) than in the control group (54 +/- 9%). The extent of myocardial hemorrhage expressed as percentage of infarct size was also significantly reduced in the SRP group (3 +/- 2%) compared with the control group (24 +/- 6%). The increase in end-diastolic wall thickness in the ischemic area after reperfusion assessed by two-dimensional echocardiography was significantly less in the SRP group. Blood flow measurements after reperfusion demonstrated the occurrence of no-reflow phenomenon only in the control group. Histological examination revealed extensive myocardial hemorrhages only in the control group, which extended into the nonnecrotic myocardium in four of nine hearts and extensive contraction band necrosis compared with the SRP group. CONCLUSIONS: Short-term SRP prior to reperfusion can reduce infarct size, myocardial hemorrhage, wall swelling, and no-reflow phenomenon. The mechanism of this beneficial effect is not clear but might be due to gradual reperfusion and washout of by-products from the ischemic myocardium before fully oxygenated arterial blood reperfusion.

The high-risk unstable angina patient. An approach to treatment.

Unstable angina, an intermediate stage in acute coronary ischaemic syndromes, accounts for about 50% of all admissions to the coronary care units in the United States today. It may progress to myocardial infarction in 15% of cases in the first 2 days, and the in-hospital mortality rate is 5%. The pathological hallmark of this syndrome, confirmed by angioscopy, is fissure of the atherosclerotic plaque within the coronary artery, leading to platelet adhesion and aggregation and fibrin-platelet thrombus formation, which may accelerate progression of the stenotic lesion. Management of unstable angina is aimed at ameliorating symptoms and reducing ischaemia, improving ventricular function, preventing recurrent ischaemia, myocardial infarction and death, and lastly, containing progression of the underlying coronary artery disease. Acute management includes bedrest, aspirin, heparin, nitroglycerin (glyceryl trinitrate) infusion and beta-blockers and calcium channel blockers in selected cases. After the patient is clinically stabilised, provocative tests and angiography may be performed, to be followed by angioplasty or bypass surgery, if necessary. In cases that are refractory to optimal medical therapy, interventions should be performed on a more emergent basis. Long term management includes aspirin and beta-blockers, if there is prior infarction, and control of the conventional risk factors.

Coronary venous retroinfusion of deferoxamine reduces infarct size in pigs.

The efficacy of coronary venous retroinfusion of the iron chelator deferoxamine was studied in 24 pentobarbital-anesthetized open chest pigs with a 60 min occlusion of the left anterior descending coronary artery followed by 3 h of reperfusion. Eight retrogradely treated pigs were given 10 mg/kg body weight of deferoxamine by way of the anterior interventricular vein and eight systemically treated pigs received the same doses of deferoxamine intravenously. Drug infusions lasted for 5 min, beginning 15 min before reperfusion. Eight control pigs received systemic intravenous saline solution. Myocardial area at risk and necrotic area were assessed by the monastral blue dye and the triphenyltetrazolium chloride staining method, respectively. There were no significant differences in hemodynamics or regional myocardial function (sonomicrometry) among the groups. Infarct size expressed as percent of risk area was 73.9 +/- 13.5% in the control group, 70.6 +/- 16.4% in the systemically treated group and 48.5 +/- 21.4% (p less than 0.05) in the retrogradely treated group. In conclusion, deferoxamine significantly reduced infarct size after coronary occlusion only when given regionally by way of the coronary vein. Because there was no significant hemodynamic effect caused by deferoxamine infusion, it is suggested that this drug prevents postischemic reperfusion injury by a direct cardioprotective effect.

Synchronized coronary venous retroperfusion for support and salvage of ischemic myocardium during elective and failed angioplasty.

To determine the safety and efficacy of synchronized coronary venous retroperfusion during brief periods of ischemia, 30 patients undergoing angioplasty of the left anterior descending coronary artery were studied. Each patient underwent a minimum of two angioplasty balloon inflations. Alternate dilations were supported with retroperfusion; the unsupported inflations served as the control inflations. Synchronized retroperfusion was performed by pumping autologous femoral artery blood by means of an electrocardiogram-triggered retroperfusion pump into the great cardiac vein through a triple lumen 8.5F balloon-tipped retroperfusion catheter inserted percutaneously from the right internal jugular vein. Clinical symptoms, hemodynamics and two-dimensional echocardiographic wall motion abnormalities were analyzed. Retroperfusion was associated with a lower angina severity score (0.8 +/- 1 vs. 1.2 +/- 1) and delay in onset of angina (53 +/- 31 vs. 37 +/- 14 s; p less than 0.05) compared with the control inflations. The magnitude of ST segment change was 0.11 +/- 0.14 mV with retroperfusion and 0.16 +/- 0.17 mV without treatment (p less than 0.05). The severity of left ventricular wall motion abnormality was also significantly (p less than 0.01) reduced with retroperfusion compared with control (0.7 +/- 1.4 [hypokinesia] vs. -0.3 +/- 1.6 [dyskinesia]). There were no significant changes in hemodynamics, except in mean coronary venous pressure, which increased from 8 +/- 3 mm Hg at baseline to 13 +/- 6 mm Hg with retroperfusion. Four patients required prolonged retroperfusion for treatment of angioplasty-induced complications. The mean retroperfusion duration in these patients was 4 +/- 2 h (range 2 to 7). In the three patients who underwent emergency bypass surgery, the coronary sinus was directly visualized during surgery and found to be without significant injury. There were no major complications. Minor adverse effects were transient atrial fibrillation (n = 2), jugular venous catheter insertion site hematomas (n = 4) and atrial wall staining (n = 1), all of which subsided spontaneously. Thus, retroperfusion significantly reduced and delayed the onset of coronary angioplasty-induced myocardial ischemia and provided effective supportive therapy for failed and complicated angioplasty.

Percutaneous cooling of ischemic myocardium by hypothermic retroperfusion of autologous arterial blood: effects on regional myocardial temperature distribution and infarct size.

The effects of synchronized coronary venous retroperfusion of cooled autologous arterial blood on regional myocardial temperature distribution and infarct size were studied in open chest dogs with 3.5 h of left anterior descending coronary artery occlusion. After 30 min of occlusion, the dogs were randomly assigned to one of three groups: 1) untreated control group (n = 5), 2) normothermic retroperfusion group (infusion temperature 32 degrees C) (n = 7), and 3) hypothermic retroperfusion group (infusion temperature 15 degrees C) (n = 7). Regional myocardial temperatures were measured by using needle-tipped thermistors stabbed in the 1) anterior wall distal to the occlusion site, 2) anterior wall proximal to the occlusion site, 3) left lateral wall, 4) posterior wall, and 5) right ventricular free wall. Rectal and pulmonary artery temperatures were also measured. In the hypothermic retroperfusion group, the anterior wall temperature decreased rapidly by 5 degrees C at 15 min of retroperfusion (p less than 0.05 vs. normothermic retroperfusion or untreated control groups), whereas the temperature at other sites decreased with a linear trend over time. Myocardial temperatures in the ischemic area (distal anterior wall) were generally lower than those in the other sites during the first 60 min of hypothermic retroperfusion and the largest intramyocardial temperature difference (3.6 degrees C) was found at 15 min after retroperfusion. Infarct size expressed as a percent of the risk area was significantly smaller in the hypothermic retroperfusion group (6.2 +/- 3.3%) than in the control (64.9 +/- 14%) or normothermic retroperfusion groups (24.1 +/- 6.7%).(ABSTRACT TRUNCATED AT 250 WORDS)