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Moderate alcohol consumption has been associated with a lower risk of coronary artery disease (CAD) in the general population but has not been well studied in US veterans. We obtained self-reported alcohol consumption from Million Veteran Program participants. Using electronic health records, CAD events were defined as 1 inpatient or 2 outpatient diagnosis codes for CAD, or 1 code for a coronary procedure. We excluded participants with prevalent CAD (n = 69,995) or incomplete alcohol information (n = 8,449). We used a Cox proportional hazards model to estimate hazard ratios and 95% confidence intervals for CAD, adjusting for age, gender, body mass index, race, smoking, education, and exercise. Among 156,728 participants, the mean age was 65.3 years (standard deviation = 12.1) and 91% were men. There were 6,153 CAD events during a mean follow-up of 2.9 years. Adjusted hazard ratios (95% confidence intervals) for CAD were 1.00 (reference), 1.02 (0.92 to 1.13), 0.83 (0.74 to 0.93), 0.77 (0.67 to 0.87), 0.71 (0.62 to 0.81), 0.62 (0.51 to 0.76), 0.58 (0.46 to 0.74), and 0.95 (0.85 to 1.06) for categories of never drinker; former drinker; current drinkers of ≤0.5 drink/day, >0.5 to 1 drink/day, >1 to 2 drinks/day, >2 to 3 drinks/day, and >3 to 4 drinks/day; and heavy drinkers (>4 drinks/day) or alcohol use disorder, respectively. For a fixed amount of ethanol, intake at ≥3 days/week was associated with lower CAD risk compared with ≤1 day/week. Beverage preference (beer, wine, or liquor) did not influence the alcohol-CAD relation. Our data show a lower risk of CAD with light-to-moderate alcohol consumption among US veterans, and drinking frequency may provide a further reduction in risk.

Background While adherence to healthful dietary patterns has been associated with a lower risk of coronary artery disease (CAD) in the general population, limited data are available among US veterans. We tested the hypothesis that adherence to Dietary Approach to Stop Hypertension (DASH) food pattern is associated with a lower risk of developing CAD among veterans. Methods and Results We analyzed data on 153 802 participants of the Million Veteran Program enrolled between 2011 and 2016. Information on dietary habits was obtained using a food frequency questionnaire at enrollment. We used electronic health records to assess the development of CAD during follow‐up. Of the 153 802 veterans who provided information on diet and were free of CAD at baseline, the mean age was 64.0 (SD=11.8) years and 90.4% were men. During a mean follow‐up of 2.8 years, 5451 CAD cases occurred. The crude incidence rate of CAD was 14.0, 13.1, 12.6, 12.3, and 11.1 cases per 1000 person‐years across consecutive quintiles of Dietary Approach to Stop Hypertension score. Hazard ratios (95% confidence interval) for CAD were 1.0 (ref), 0.91 (0.84–0.99), 0.87 (0.80–0.95), 0.86 (0.79–0.94), and 0.80 (0.73–0.87) from the lowest to highest quintile of Dietary Approach to Stop Hypertension score controlling for age, sex, body mass index, race, smoking, exercise, alcohol intake, and statin use ( P linear trend, Conclusions Our data are consistent with an inverse association between Dietary Approach to Stop Hypertension diet score and incidence of CAD among US veterans.

We introduce a technique for ultrasensitive absorption spectroscopy using the GHz-rate pulse train from a phase-locked free-electron laser (FEL), in which the fractional power absorbed from one or more laser lines reappears as a signal on the dark background between the pulses emerging from the sample. Preliminary absorption experiments in 15 Torr cm of methane at 3.25mgr;m, using phase-locked pulses from the Mark III FEL, clearly reveal an interpulse beat signal due to absorption by adjacent molecular rotational lines which is generated only in the presence of interpulse phase coherence.

Background and Objectives We used the MARK III free electron laser (FEL) tuned to molecular vibrational absorbance maxima in the infrared (IR) wavelength range of 3.0–6.45 μm to study the effect of these various wavelengths and a power level of 5 mJ/2 microseconds macropulse on photoablation of CNS tissue. Study Design/Materials and Methods Laser lesions were produced in the parietal cortex of anesthetized rats using thermal confined mid-IR (infrared) laser pulses tuned to the -OH, -CH, amide 1, and amide 2 absorbance bands. Histological assessments following recovery periods of 4 hours, 4 days, and 3 weeks were performed to determine the size, shape, and character of the photoablative lesions. Cell density studies were done in adjacent edematous tissue. Results Significant differences in lesion size and shape were observed as a function of wavelength. Although maximum ablation and collateral damage seemed to coincide with spectral peaks in the mid-IR, area and depth/width ratios did not. Conclusions It was found in these experiments that wavelengths in the mid-IR could be selected for optimal ablative properties. Using tunable, high-peak-power pulsed lasers, it will be possible to produce well-defined photoablative lesions that conform to small, irregularly shaped neurosurgical targets. Lasers Surg. Med. 33:81–92, 2003. © 2003 Wiley-Liss, Inc.

Controlled versus uncontrolled reperfusion of ischemic myocardium after experimental coronary artery occlusion was studied to determine the effect on regional ventricular wall motion and associated blochemical alterations. Fourteen pigs underwent coronary artery occlusion for 1 hour followed by 2 hours of reperfusion. In seven animals uncontrolled reperfusion was achieved by complete release of the arterial occlusion resulting in hyperemic flow. In seven other animals coronary flow during reperfusion was controlled at baseline levels eliminating hyperemic flow. Our results show that controlled reperfusion lessens end-diastolic wall thickness, reduces myocardial calcium deposition, increases the rate of mitochondrial oxidative phosphorylation, and preserves cellular high-energy phosphate stores in the ischemic-reperfused myocardium when compared to the uncontrolled reperfusion state. These data suggest that the magnitude of flow at an early stage of reperfusion is one of the important determinants in the outcome of ischemic myocardium.

This study shows significant changes occurring in systolic time intervals in an experimental animal model of aortic outflow obstruction with cardiac hypertrophy. The left ventricular ejection time is markedly prolonged and the preejection period/left ventricular ejection time ratio shortened. These changes are in the opposite direction of those usually observed with left ventricular dysfunction in man but similar to those described in man with aortic stenosis. Furthermore, the changes observed in systolic time intervals after digoxin in this experimental model are not comparable to those reported in man with normal or abnormal left ventricular function. Hence, the use of systolic time intervals, including digitalis effect, to evaluate the functional state of the left ventricle in aortic outflow obstruction are probably unreliable.

It is generally accepted that certain cardiac rhythm disturbances are due to imbalances between the sympathetic and parasympathetic nervous systems. We have provided evidence that digoxin is concentrated in the peripheral nervous system of the heart as well as in the central nervous system. Previous findings have indicated that cardiac glycosides may directly or indirectly affect autonomic neurotransmitters. Therefore the uptake of digoxin into the peripheral cardiac nervous system may play an important role in both the antiarrhythmic and toxic electrophysiologic actions of digoxin.

Transient myocardial ischemia in postoperative hypertension is relatively common with coronary artery bypass surgery. This study examines the effect of hypertension during reperfusion of transiently ischemic myocardium. The animal model was open chest pigs with myocardial ischemia induced by the occlusion of the left anterior descending coronary artery for 30 min followed by 2 hr of reperfusion. A normotensive control group was compared with animals rendered hypertensive with phenylephrine during the ischemic and reperfusion times. In the hypertensive group, systolic blood pressure was raised from 106 to 161 mm Hg and peripheral vascular resistance from normal to 3600 dyn-sec-cm −5 . Regional left ventricular wall thickness, mitochondrial function, sarcoplasmic reticulum Ca 2+ uptake, tissue calcium, water content, and hemorrhage were evaluated. Compared to controls the hypertensive group had (1) loss of systolic wall thickening with increased diastolic wall thickness in the reperfused zone, (2) intramyocardial hemorrhage in the area of reperfusion, (3) significant impairment of oxidative phosphorylation by mitochondria isolated from the reperfused zone, (4) a marked reduction in the rate of Ca 2+ uptake by sarcoplasmic reticulum vesicles, and (5) an increase in ischemic tissue calcium. Thus, hypertension associated with revascularization of acutely ischemic myocardium may accentuate myocardial damage.

Coronary artery reperfusion following acute myocardial ischemia may salvage ischemic jeopardized cells. We studied the effects of early brief reperfusion on totally ischemic and on partially ischemic myocardium of open-chest pigs. In 10 animals, coronary flow was reduced to 0% for 30 minutes and was followed by 10 minutes reperfusion (group A). In another 10 animals, coronary flow was reduced to 25% of the baseline value for 30 minutes followed by 10 minutes of reperfusion (group B). In another eight animals coronary flow was reduced to 25% of the baseline value for 60 minutes and followed by 10 minutes of reperfusion (group C). Results showed that a brief 10-minute period of reperfusion of ischemic myocardium after total occlusion caused abnormal diastolic wall thickening with only partial return of systolic wall thickening. However, reperfusion of ischemic myocardium after partial occlusion, whether 30 or 60 minutes, caused little diastolic wall thickening and a partial return of systolic thickening. A marked elevation of myocardial Ca2+, a decrease in mitochondrial adenosine triphosphate (ATP) production and cellular ATP concentration, and a reduction in the rate of Ca2+ uptake by sarcoplasmic reticulum vesicles occurred in the totally ischemic myocardium but not in the partially ischemic myocardium. These results demonstrate that reperfusion of ischemic myocardium after 1 hour of coronary flow reduction to 25% of baseline is less damaging than reperfusion after a 30-minute total coronary occlusion, and suggest that preexisting states affecting coronary flow need to be evaluated in assessing the outcome of reperfusion.

Reperfusion of acutely ischemic myocardium may cause profound alterations in left ventricular wall performance and metabolism. This study evaluates regional left ventricular wall thickness, analyzes metabolic and biochemical alterations, and examines tissue hemorrhage during 15, 30, and 120 minutes of myocardial ischemia, each followed by 120 minutes of reperfusion. Reperfusion after 15 minutes of ischemia showed nearly normal ventricular wall thickening and motion, intact metabolic and biochemical function, and no tissue hemorrhage. However, reperfusion after 30 and 120 minutes of ischemia was associated with ventricular wall thickening and failure to resume systolic and diastolic wall motion. Furthermore, adverse metabolic and biochemical alterations and reperfusion zone hemorrhaging increased proportionally with the duration of ischemia. These findings suggest critical myocardial damage occurring between 15 and 30 minutes of ischemia in an animal model without preexisting coronary collateral circulation. The observed metabolic and biochemical changes are consistent with irreversible cell membrane defects, allowing calcium ion accumulation and thus adversely affecting diastolic relaxation and systolic thickening.

Digoxin is often used as an antiarrhythmic and inotropic agent. It produces significant neuroexcitatory responses that influence both its therapeutic and toxic effects. Patients receiving digoxin can be separated into 2 groups: those who receive it acutely and those who receive it chronically. The therapeutic and toxic responses to digoxin vary between these groups. The neural tissue distribution of digoxin was compared in dogs after both acute and chronic injections. Acute administration of digitalis in this study was associated with preferential uptake of digoxin into peripheral sympathetic nerves. Chronic administration was associated with continued selective uptake into the central nervous system despite decreasing serum levels. Therefore, acute (experimental or suicidal) or chronic (maintenance) digoxin administration produces different neural responses. The peripheral sympathetic nervous system will be the primary area of interaction with acute digoxin administration and the central nervous system will have a greater involvement with chronic digoxin administration. Our results indicate that the uptake of digoxin into the peripheral nervous system and central nervous system depends upon the duration of digoxin administration. The time course of digoxin accumulation influences both its therapeutic and toxic actions.

The effects of afterload reduction with and without calcium blockade on reperfusion injury were studied in the pig. Reversible occlusion of the left anterior descending coronary artery was performed for 60 minutes followed by 120 minutes of reperfusion. For 15 minutes prior to and throughout reperfusion, treatment was administered with a calcium blocker (nifedipine or verapamil), a metallic organic dye and Ca2+ antagonist (ruthenium red), a vasodilator (nitroprusside), or saline. Biochemical functions, i.e., mitochondrial oxidative phosphorylation, myocardial ATP and Ca2+ content, and sarcoplasmic reticulum Ca2+ uptake were determined. Regional left ventricular wall motion was measured echocardiographically. Nifedipine and ruthenium red improved biochemical indices of ischemic myocardium in part by reducing afterload and thereby reducing oxygen demand and in part by reducing calcium entry into cells and mitochondria. Verapamil in the doses used failed to reduce afterload and demonstrated no salutary effect on biochemical parameters in ischemic myocardium. Nitroprusside reduced afterload, improved mitochondrial ATP production and increased percent wall thickening. Our findings suggest that afterload reduction with and without calcium blockade during the early reperfusion phase improves ischemic myocardium. These changes are predominantly biochemical in nature.

Experiments were conducted in open-chest pigs in which experimental myocardial ischemia was produced. Two groups of animals were evaluated: (1) those with short episodes of coronary occlusion and reperfusion, and (2) those with an initially longer period of occlusion (equal to the sum of the short multiple occlusions) and reperfusion. Indices of myocardial wall motion as determined by echocardiogram, of energy production as measured by mitochondrial oxidative phosphorylation, and of cellular membrane integrity as measured by calcium uptake by sarcoplasmic reticulum vesicles and calcium content of tissue and mitochondria were obtained. Our observation revealed better myocardial preservation in the group with brief periods of occlusion and reperfusion than those with a sustained period of ischemia followed by reperfusion. The concept that myocardium is less well preserved due to reperfusion damage by intermittent aortic cross-clamping or intermittent coronary perfusion during open heart surgery compared to uninterrupted cardiac arrest needs to be reexamined in light of the data presented and investigated in the hypothermic, cardioplegia model.

Coronary reperfusion of ischemic myocardium may be beneficial but is highly dependent upon occlusion and reperfusion times. To study the effects of early reperfusion on ischemic myocardium, 24 open chest pigs underwent coronary occlusion; one group was occluded for 40 min, and the other was occluded for 30 min followed by 10 min of reperfusion. Left ventricular wall thickness during systole and diastole was determined by ultrasound. Mitochondrial energy production and calcium content were evaluated from ischemic and nonischemic areas. Results showed: (1) There was an absence of systolic thickness, a slight decrease of diastolic thickness from baseline, and a decrease in energy production in the ischemic myocardium. (2) Reperfusion resulted in a diverse pattern of systolic and diastolic wall thickness in the ischemic area and a variable Ca 2+ accumulation and mitochondrial ATP production. (3) The variability of myocardial Ca 2+ accumulation in the ischemic reperfused group correlated inversely with mitochondrial ATP production ( r = −0.94) and directly with diastolic wall thickness ( r = 0.65). (4) Similarly, calcium accumulation, ATP production, and diastolic wall thickness correlated with mean blood pressure during reperfusion. These results suggest that many factors including individual characteristics of the animal and experimental conditions such as the level of blood pressure and the degree of calcium accumulation may determine outcome of reperfusion even in as brief a period as 10 min.

To the Editor.— In their article on the pharmacokinetics of digoxin after a single dose of quinidine sulfate, Chen and Friedman (1980;244:669) found that quinidine given 24 hours after the last dose of digoxin causes no change in serum digoxin levels. The authors interpreted the lack of effect of quinidine on serum digoxin levels 24 hours after the last dose of digoxin as an indication that the observed elevations of serum digoxin after simultaneous administration of quinidine is probably not caused by displacement of digoxin-binding sites by quinidine. The authors refer to an abstract published by our laboratory reporting "that quinidine displaces ouabain from beef heart membrane sodiumpotassium adenosine triphosphatase." We did, indeed, report that quinidine alters ouabain binding in the beef heart sodium potassium adenosine triphosphatase preparations but not by displacing already bound ouabain. Quinidine eliminates binding sites that are unoccupied by ouabain; it does not change the equilibrium

Polyuria and polydipsia developed in two cases during amphotericin B therapy for deep mycoses. Neither patient could concentrate his urine in response to water deprivation or exogenous vasopressin. Other causes of vasopressin-resistant nephrogenic diabetes insipidus were not present. Three months after amphotericin B therapy had been discontinued, concentrating ability improved toward normal. A third patient was further observed and demonstrated normal diluting capacity but impaired free-water reabsorption, suggesting a distal tubular defect consistent with nephrogenic diabetes insipidus. Four months after discontinuing therapy, renal concentrating ability was normal. Amphotericin B can induce a reversible form of nephrogenic diabetes insipidus. ( Arch Intern Med 139:86-88, 1979)