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BackgroundHIV and HCV have been linked to an increased risk of cardiovascular disease (CVD). Their impact on long-term outcomes following ST-segment myocardial infarction (STEMI) has not been previously studied.MethodsWe leveraged data from a STEMI registry (n=1208) at an inner-city health system to assess the influence of HIV and HCV on post-STEMI outcomes. Cox regression was used to compare HIV-monoinfected (n=22), HCV-monoinfected (n=26) and HIV-HCV-coinfected patients (n=8) with the neither-infected group (n=1152) with regard to death, death or any readmission, and death or CVD readmission.ResultsThe cohort was majority black or Hispanic. Median follow-up was 4.3 years. Compared to the neither-infected group, the HIV-monoinfected group showed near-significantly higher risks of death or any readmission (HR=1.62, 95% CI=0.96, 2.74) and death or CVD readmission (HR=1.82, 95% CI=0.98, 3.39) after full adjustment. On similar comparison, the HCV-monoinfected group exhibited significantly higher risks of death (HR=2.09, 95% CI=1.05, 4.15) and death or any readmission (HR=1.68, 95% CI=1.07, 2.65), whereas the HIV-HCV-coinfected group showed higher risk of death (HR=6.51, 95% CI=2.28, 18.61).ConclusionsIn this cohort composed mostly of race-ethnic minorities, HIV monoinfection tended to be associated with 1.6-to-1.8-fold higher risk of death or readmission for any cause or CVD over long-term follow-up compared to neither infection, whereas HCV monoinfection was associated with 1.7-to-2.1-fold higher risk of death and death or any readmission, and HIV-HCV coinfection with 6.5-fold higher risk of death. These associations require further study in larger populations, but highlight the importance of identifying and treating HIV and HCV in patients presenting with STEMI.

Objectives To compare outcomes by age and sex in race/ethnic minorities presenting with ST‐elevation myocardial infarction (STEMI), as studies are limited. Methods We studied sociodemographics, management, and outcomes in 1208 STEMI patients evaluated for primary percutaneous coronary intervention between 2008 and 2014 at Montefiore Health System (Bronx, NY). A majority of patients self‐identified as nonwhite, and nearly two‐thirds were young (

Background Hyperglycaemia occurs frequently in ST‐elevation myocardial infarction (STEMI) and is associated with poor outcomes, for which continuous insulin infusion therapy (CIIT) may be beneficial. Information is limited regarding hyperglycaemia in acute STEMI affecting urban minority populations, or how CIIT fares in such real‐world settings. Methods and results We assembled an acute STEMI registry at an inner‐city health system, focusing on patients with initial blood glucose ≥180 mg/dL to determine the impact of CIIT vs usual care. Clinical and outcomes data were added through linkage to electronic records. Inverse‐probability‐of‐treatment weighting using propensity scores (PS) was used to compare CIIT vs no CIIT. The 1067 patients included were mostly Hispanic or African American; 356 had blood glucose ≥180 mg/dL. Such pronounced hyperglycaemia was related to female sex, minority race‐ethnicity and lower socioeconomic score, and associated with increased death and death or CVD readmission. CIIT was preferentially used in patients with marked hyperglycaemia and was associated with in‐hospital hypoglycaemia (21% vs 11%, P = .019) and, after PS weighting, with increased in‐hospital (RR 3.23, 95% CI 0.94, 11.06) and 1‐year (RR 2.26, 95% CI 1.02, 4.98) mortality. No significant differences were observed for death at 30 days or throughout follow‐up, or death and readmission at any time point. Conclusions Pronounced hyperglycaemia was common and associated with adverse prognosis in this urban population. CIIT met with selective use and was associated with hypoglycaemia, together with increased mortality at specific time points. Given the burden of metabolic disease, particularly among race‐ethnic minorities, assessing the benefits of CIIT is a prerogative that requires evaluation in large‐scale randomized trials., Weighted risk estimates (with 95% confidence intervals) for the main outcomes at different time points for CIIT versus no CIIT (no CIIT is the referent) additionally adjusting for smoking status. All risk estimates are risk ratios except for those corresponding to comparisons through follow‐up (labelled overall), which are hazard ratios. CIIT=Continuous insulin infusion therapy, CVD=Cardiovascular disease.

Although cocaine is a well-recognized risk factor for coronary disease, detailed information is lacking regarding related behavioral and clinical features of cocaine-associated ST-segment elevation myocardial infarction (STEMI), particularly in socioeconomically disadvantaged urban settings. Nor are systematic or extended follow-up data available on outcomes for cocaine-associated STEMI in the contemporary era of percutaneous coronary intervention. We leveraged a prospective STEMI registry from a large health system serving an inner-city community to characterize the clinical features, acute management, and middle-term outcomes of cocaine-related versus cocaine-unrelated STEMI. Of the 1,003 patients included, 60% were black or Hispanic. Compared with cocaine-unrelated STEMI, cocaine-related STEMI (n = 58) was associated with younger age, male gender, lower socioeconomic score, current smoking, high alcohol consumption, and human immunodeficiency virus seropositivity but less commonly with diabetes or hypertension. Cocaine users less often received drug-eluting stents or β blockers at discharge. During median follow-up of 2.7 years, rates of death, death or any rehospitalization, and death or cardiovascular rehospitalization did not differ significantly between cocaine users and nonusers but were especially high for death or any hospitalization in the 2 groups (31.4 vs 32.4 per 100 person-years, p = 0.887). Adjusted hazard ratios for outcomes were likewise not significantly different. In conclusion, in this low-income community, cocaine use occurred in a substantial fraction of STEMI cases, who were younger than their nonuser counterparts but had more prevalent high-risk habits and exhibited similarly high rates of adverse outcomes. These data suggest that programs targeting cocaine abuse and related behaviors could contribute importantly to disease prevention in disadvantaged communities.

Mutations in cardiac troponin T (cTnT) are linked to a severe form of Familial Hypertrophic Cardiomyopathy. Patients carrying mutations flanking the tropomyosin-binding domain of cTnT (R92L and Delta160E) develop distinct clinical syndromes. In order to better understand the cellular pathophysiology underlying these clinically relevant differences, we studied isolated adult left ventricular myocytes from independent transgenic cTnT mouse lines carrying either a 35% (Delta160E) or 50% (R92L) replacement of the endogenous cTnT with the mutant forms. Measurement of baseline myocellular contraction revealed that the Delta160E cells had significant decreases in the peak rate of contraction and percent shortening as compared to either R92L or Non-TG myocytes. In addition, while both Delta160E and R92L myocytes demonstrated a decrease in the peak rate of relaxation as compared to Non-TG, the magnitude of the difference was significantly greater in Delta160E cells. Concurrent myocyte [Ca2+](i) transient measurements revealed that while the alterations in the peak rates and times of the rise and decline of the [Ca2+](i) transient were similar to the changes in the respective measures of sarcomeric mechanics, R92L cells also exhibited reduced rates of the rise and decline of the [Ca2+](i) transient but did not exhibit these reductions in terms of sarcomeric mechanics. Of note, only Delta160E, and not R92L myocytes, demonstrated significant reductions in SR Ca2+ load and uptake, corresponding to the impairments seen in the [Ca2+](i) and mechanical transients. Finally, Western analysis revealed a significant Delta160E-specific reduction in the SERCA2a/PLB ratio, which may well underlie the observed alterations in Ca2+ homeostasis. Therefore, independent cTnT mutations result in significant mutation-specific effects in Ca2+ handling that may, in part, contribute to the observed clinical variability in cTnT-related FHC.

There has been intense interest in the roles catecholamines may play in compensatory myocardial hypertrophy. This article reviews the following: (1) chronic infusions of catecholamines in experimental animals result in cardiac hypertrophy, but in many of the studies mechanical factors have played a role; (2) experiments using isolated papillary muscles and isolated hearts, stretched isolated myocytes, and denervated hearts in vivo demonstrate that mechanical activity is sufficient to cause increased protein synthesis and cell growth; (3) in neonatal myocyte cell cultures, alpha-adrenergic agonists are powerful stimulants for protein synthesis and cell growth. Beta-adrenergic stimulation of nonmyocyte myocardial cells causes release of a factor that promotes protein synthesis in neonatal myocytes. Either alpha or beta stimulation, probably through different mechanisms, appears to have growth-promoting effects on isolated adult myocytes in culture; (4) alpha stimulation is transduced through the Gq pathway and its activation of phospholipase C, cleavage of phosphatidylinositol (4,5)-bisphosphate, and then further through the ras/raf, mitogen-activated protein (MAP) kinase system; (5) transgenic mice with upregulation of catecholamine-related systems have not clarified the independent role of either the alpha- or beta-adrenergic pathway; and (6) observations in humans suggest that mechanical factors predominate in the development and regression of cardiac hypertrophy. Humoral mechanisms, including catecholamines, may play a role, but their quantitative importance has not been determined. It is hypothesized that catecholamines may play a role in transition from the adaptive to the maladaptive state.

Beginning in 1977, the leaders at the Albert Einstein College of Medicine (AECOM) and Montefiore Medical Center (MMC) began to develop unifieddepartments combining the strengths at both campuses under a single department chair. The unification of the Department of Medicine was carried out under the leadership of Dr. Louis M. Sherwood in 1980. This step built upon the strength of the two Departments that had developed separately at MMC and AECOM during the previous era. During the 1980s and the 1990s, the subspecialty divisions, along with their training and research programs, were merged. Other changes evolved though that period, so that by the turn of the century many aspects of the Department of Medicine differed from its structure and function in 1980.

The medicine we knew at the school’s beginning in 1955 was almost unrecognizable at the end of the twentieth century. The science, the knowledge base, the organization, and the funding of health care had all undergone dramatic changes. Fifty years ago, we thought we might be able to conquer infectious diseases. Now we are facing rampant ‘new’ diseases such as Human Immunodeficiency Virus (HIV) and Severe AcuteRespiratory Syndrome (SARS), and are witnessing the development of resistance to antibiotics by many microorganisms, including the previously highly sensitive pneumococcus. Fifty years ago, cardiac surgery was still in its youth, and mitral commissurotomies were highpoints of surgical endeavor. Now, rheumatic heart disease is very uncommon in the United States (although still common in parts of the third world). Fifty years ago, we had only primitive antihypertensive drugs, which were difficult for patients to tolerate. Now, antihypertensivedrugs are far more effective and better tolerated by patients. Fifty years ago, the structure and mechanism of replication of DNA had just been described by Watson and Crick. Now, we are using therapeutic agents manufactured by recombinant techniques, and are beginning to see clinical applications of gene transfer therapy.

Dr James A. Shaver, our friend and colleague, died of pneumonia on April 13, 2012, after a long history of chronic renal disease. At the time of his death, he was professor of medicine and the former chief of the division of cardiology at the University of Pittsburgh School of Medicine. Born in Ridgway, Pennsylvania, he was elected to Phi Beta Kappa at the University of Pennsylvania and to Alpha Omega Alpha at the Hahnemann Medical College, from which he graduated in 1959. Dr Shaver trained in internal medicine at the University of Pennsylvania and the University of Pittsburgh, where he also completed his cardiology fellowship. He joined the Pitt faculty in 1965 and rose through the ranks to become a full professor in 1977. He was director of the cardiac diagnostic laboratories and then became director of the division from 1971 to 1994. Dr Shaver also served as director of the Cardiovascular Fellowship Program from 1971 to 2006, training more than 325 fellows, many of whom went on to assume leadership positions of their own. Since he left the division directorship, he led the medical school second-year course in physical diagnosis and continued to play an active role as a consulting cardiologist and a charismatic teacher at all levels of medical education. Dr …

To the Editor: I write about the excellent article describing studies of patients with dilated cardiomyopathy who were treated with Trimetazidine.1 The apparent beneficial effect of this agent on left ventricular ejection fraction in patients with congestive heart failure has been demonstrated previously.2 The current report describes metabolic and hormonally related factors that may in part …

Edmund H. Sonnenblick, the Edmond J. Safra Distinguished University Professor of Medicine and Chief Emeritus the Division of Cardiology at the Albert Einstein College of Medicine, died on September 22, 2007, after a long struggle with esophageal cancer. Born in New Haven, Conn, he graduated from Wesleyan University summa cum laude and Phi Beta Kappa in 1954, and from Harvard Medical School cum laude and Alpha Omega Alpha in 1958. He then entered the residency program in internal medicine at Columbia-Presbyterian in New York City. In 1960, he joined the laboratory of Dr Stanley Sarnoff at the National Heart Institute and began his seminal work on cardiac function and myocardial muscle mechanics. From that laboratory in 1962, at the age of 30, he was the sole author of the pioneering paper “Force-Velocity Relations in Mammalian Heart Muscle,” published in the American Journal of Physiology . Up until that time there had been little focus on the fundamental physiological properties of the myocardium. This article, drawing on concepts of muscle mechanics as studied by A.V. Hill and others, led the development of a new field focusing on myocardial function as it relates to normal and abnormal heart performance. In 1963, Dr Sonnenblick joined the cardiology branch of the National Institutes of Health and published …

To assess the role of intermittent beta-adrenergic stimulation on alpha-myosin heavy chain expression and cellular hypertrophy, we studied the effect of intermittent dobutamine on myosin heavy chain isoform distribution and protein synthesis in the heterotopic rat heart preparation. This model allows the analysis of a pharmocologic stimulus in isolation from the mechanical load on the myocardium induced by the drug. Intermittent administration of dobutamine resulted in elevated alpha-MHC levels (75 +/- 12%) compared to control (55 +/- 10%; X +/- s.e.; P0.05) transplanted hearts. This effect was not altered by alpha-receptor blockade with terazosin (72 +/- 8%). Intermittently pacing the transplanted hearts at the same rate as observed with dobutamine alone, also elevated alpha-MHC levels (70 +/- 5%). In contrast, total protein synthesis in the transplanted hearts was not altered with any of the drug or pacing interventions compared to control hearts. These data suggest that intermittent beta-receptor stimulation and/or intermittent increased heart rate contribute to altered patterns of myosin heavy chain expression. However, increases in cardiac mass and protein synthesis are probably mediated by hemodynamic factors rather than catecholamine stimulation.

Multiple closely related, yet distinct, isoforms exist for each of the cardiac contractile proteins. The isoform composition of the heart changes in response to developmental and physiologic cues. This paper reviews the molecular basis for cardiac contractile protein isoform diversity and the functional consequences of isoform shifts.

Substrate utilization by heart muscle provides the fuel for both maintenance of structure and function of the myocardium and for ample reserve capacity to meet sudden surges in cardiac energy requirements. Many factors influence the balance of substrate uptake by the myocardium, but in general, utilization of lipids versus carbohydrates correlates to their concentration in the arterial blood. There is evidence in humans that severe cardiomyopathy and heart failure are accompanied by alterations in the balance of substrates used and of energy reserves, and these may limit myocardial function.1 However, myocardial metabolic changes have not been well described in human hearts with compensated hypertrophy. Compensated cardiac hypertrophy due to systolic overload in experimental animals is associated with a recapitulation of a fetal genetic pattern.2,3 This is most dramatically demonstrated in the hearts of rodents in which their contractile proteins switch from a predominance of α-myosin to a more energy conserving β-myosin pattern,4 but also involves enzymes in metabolic pathways of energy transfer.2 Many of these genetic alterations affect reactions that influence the balance between carbohydrate and lipid use by the heart. GLUT-4 protein, the main insulin sensitive glucose transporter may be normal or its mRNA reduced.5,6 GLUT-4 deletion leads to hypertrophy and upregulation of GLUT-1, a glucose independent transporter, and to enhanced insulin independent glucose transport.7 However, selective GLUT-1upregulation protects heart function, but may also promote cardiac hypertrophy.8 On the lipid side, transcription of PPAR-α and other genes related to fatty acid oxidation is also reduced. …

Adaptive cardiac hypertrophy in the rat has been characterized as pathological or physiological reflecting the nature of the inciting stimulus. These two adaptations are distinguished by alterations in contractility and in the myosin ATPase composition of the affected muscle. We investigated the relative amounts of the mRNAs encoding cardiac sarcoplasmic reticular calcium ATPase (SERCA2), cardiac and skeletal troponin I (TnI), atrial natriuretic factor (ANF). and myosin light chain 1 (MLCI) in the hearts of rats that had been subjected to either conditioning by swimming (Sw), to renovascular hypertension (H) or to the combined stimulus (H-Sw) for 6 weeks. Compared to control animals, the mRNA levels for SERCA2 and cardiac TnI were slightly increased with Sw and moderately depressed with H. H-Sw animals showed a trend towards normalized mRNA levels for both genes. ANF mRNA levels were slightly elevated with Sw and markedly elevated with both H and H-Sw. MLC1 mRNA levels did not change with either or both stimuli. These data confirm that these two types of adaptive hypertrophy can be distinguished at the level of gene expression and suggest that the mechanical alterations seen in adaptive hypertrophy reflect a spectrum of pre-translational alterations which are not limited to changes in myosin heavy chain gene expression.

Study objective – The aim was to determine whether surviving myocardium in the infarcted rat heart retains the ability to respond to sustained increases in afterload. Design – Cardiac mass, ventricular function, and actomyosin ATPase activity were compared in animals subjected to coronary artery ligation to produce infarction, superimposed renal artery constriction 4 weeks after infarction, and in sham operated animals. Experimental material – Female Wistar rats obtained at 10 weeks of age (200-225 g) were used for the studies. Measurements and main results – Four weeks after coronary artery ligation, infarcted hearts showed a 22% increase in heart weight and a significant reduction in peak systolic pressure and +/- dP/dt during acute volume infusion and aortic occlusion compared to sham operated hearts. Eight weeks after the initial surgical intervention, the infarct group showed significant impairment in ventricular performance compared to the sham operated group but no further decrement was observed between hearts with infarction and those with infarct and superimposed renal artery constriction for peak systolic pressure and +/- dP/dt during volume infusion and aortic occlusion. Actomyosin ATPase activity, however, was depressed and the shift to V3myosin isoenzyme was greater in infarct and renal artery constriction compared to infarct alone. Conclusions – Left ventricular myocardium following infarction does not retain the ability to increase cardiac mass and shows depressed levels of actomyosin ATPase activity when exposed to a superimposed chronic afterload from renal artery constriction. However, cardiac function in situ is maintained.

Left ventricular papillary muscle function, transmembrane action potentials, myosin adenosinetriphosphatase (ATPase) and isoenzyme distribution, and myocardial pathology were studied in hypertensive (H), diabetic (D), hypertensive-diabetic (HD), and control (C) rats. There was approximately 50% relative left ventricular hypertrophy in H and HD rats. Relative lung and liver weights were greater in HD rats. Peak velocity of shortening tended to decrease progressively in H, D, and HD rats. The duration of contraction and relaxation was markedly prolonged in Ds and HDs. The length-developed tension relation was blunted in HDs. The negative inotropic effect of verapamil was similar in all groups. Resting membrane potential and amplitude were decreased in D and HD rats. Action potential duration was increased in H, D, and especially HD rats. The shortening of action potential duration with increased stimulus frequency was greater in H, D, and especially HD rats than in Cs. Left ventricular myosin ATPase and V1 isoenzyme content decreased progressively in H, D, and HD rats. Right ventricular V1 isoenzyme content was not affected in H rats but was markedly decreased in D and HD rats. Left (and right) ventricular pathology was unchanged in rats with diabetes but was increased in rats with hypertension. These data suggest that the combination of myocardial pathology (due to hypertension) and cellular dysfunction (caused mainly by diabetes) may result in cardiomyopathy and congestive heart failure in the HD rat.

To evaluate the combined effects of cardiac overload imposed by hypertension and chronic swim training on coronary vascularity, female rats were made hypertensive by unilateral renal artery stenoses and were exercised in an 8- to 10-wk swimming program. Maximal coronary flow was assessed in isolated retrograde buffer-perfused hearts under conditions of minimal coronary resistance (15 microM adenosine or anoxia). Sedentary normotensive animals, sedentary hypertensive animals, and normotensive animals exposed to a swimming program were also studied. Swimming was associated with an 18% increase in heart weight and with increases in both absolute (ml/min) and relative (ml X g-1 X min-1) maximal coronary flow. Hypertension was associated with a 32% increase in heart weight but with a decrease in absolute and relative coronary flow compared with controls. The combined stimuli resulted in a 63% myocardial hypertrophy and a 19% increase in absolute flow. Relative coronary flow (g tissue-1) was similar in hearts from hypertensive sedentary animals and hypertensive swimmers. These data indicate that the coronary vascular deficit that accompanies the cardiac hypertrophy of hypertension is not worsened by the superimposition of an exercise load that exaggerates the hypertrophy.

To explore the effect of physiologic hypertrophy superimposed on pathologic hypertrophy, hearts from female control rats (C), renal hypertensive rats (H), rats conditioned with a 10-12 wk swimming program (Sw), and hypertensive rats trained by the swimming program (H-Sw) were perfused in an isolated working rat-heart apparatus. Systolic blood pressure was approximately 100 mmHg in C and Sw and was 160 mmHg in H and H-Sw. The swimming program had no effect on blood pressure. Compared with C, heart weight was increased by 30% in Sw, 47% in H, and 77% in H-Sw. At high preload and afterload, cardiac output (milliliters per gram dry LV weight) was decreased in H, increased in Sw, and partially restored towards normal in H-Sw. Ejection fraction, percent fractional shortening, and mean velocity of circumferential fiber shortening were enhanced in Sw, depressed in H, and normalized in H-Sw when compared with C. Coronary flow and myocardial oxygen consumption in this series of hearts were depressed in H, with no restoration in H-Sw, but coronary effluent lactate/pyruvate ratios were only elevated in the hearts of H-Sw. Coronary vascular responses were examined in a second series of experiments which used microspheres. In this series, the depressed coronary flow observed in H was partially restored towards normal in H-Sw and the inner/outer myocardial flow ratio was normal when hearts were perfused at 140 cm aortic pressure but was somewhat depressed in both H and H-Sw when the hearts were perfused at 80 cm aortic pressure. These studies demonstrate that hypertrophic hearts from renal hypertensive rats have diminished coronary flow and depressed cardiac function when they are studied in the isolated working heart apparatus, yet there is no evidence of myocardial ischemia. Superimposition of a chronic swimming program results in increased hypertrophy but restoration of cardiac function partially or completely to normal. Thus, pathologic and physiologic hypertrophy are biologically distinct entities. Physiologic hypertrophy may partially ameliorate the defects associated with pathologic hypertrophy.

In rats, chronic diabetes is associated with depressed cardiac myosin ATPase activity and a shift from the predominant V1 isoenzyme to V3, correlating with depressed contractility. Rabbit myocardium consists mostly of the V3 isoenzyme, and therefore a switch to even more V3 isoenzyme in diabetes might not be possible and therefore not explain the mechanical abnormalities observed. To explore this, rabbits were made diabetic with 140-150 mg/kg of alloxan, and their hearts were studied 3 days, 1 mo, 3 mo, and 6 mo later. Ca2+-myosin-ATPase activity was decreased in the diabetic rabbit at 1, 3, and 6 mo, correlating with increased percent V3. Actin-activated Mg2+-ATPase activity was not significantly decreased in diabetics, but myofibrillar ATPase activity was decreased in 6-mo diabetic animals. When 3- to 4-mo diabetic animals were administered insulin for 3-4 additional months, myosin-ATPase activity and isoenzyme distribution normalized. These results correlate well with mechanical changes in papillary muscle from these same hearts. They suggest that in rabbit, as in rat, changes in cardiac contractile function are at least partially mediated by changes in myosin isoenzyme composition and are reversible with insulin.

The effects of renovascular hypertension on the biochemical, contractile, and electrical performance of myocardial tissue from rats of various ages has been examined. Male Fischer rats, 2, 7, 12, and 17 months old, were made hypertensive by constriction of the left renal artery. Ten weeks after the onset of hypertension, left ventricular papillary muscles were isolated from those four groups when 5, 10, 15, and 20 months old, respectively. Mechanical performance and transmembrane electrical events were recorded simultaneously. Contractile protein enzyme activity was determined in the same hearts from which papillary muscles were used for acquisition of mechanical and electrical information. There was a slight increase in blood pressure in control groups as a function of age while blood pressure maintained a range of approximately 179-188 mm Hg for all hypertensive groups. Heart weight of control animals increased significantly from 5 months to 20 months of age from 539 +/- 26 to 1088 +/- 56 mg, representing an increase of 101%. In hypertensive animals, heart weight increased 50% in 5-month-, 15% in 10-month-, 50% in 15-month-, and 11.7% in 20-month-old animals. Although control groups revealed alterations in mechanical, electrical, and biochemical parameters that increased as a function of age, the magnitude of the biochemical, contractile, and electrical response to hypertension varied monotonically with the extent of myocardial hypertrophy, rather than age per se. Adaptation to the stress of hypertension was observed in each age group, and was revealed as prolongation of mechanical and electrical timing parameters, depression of the load-velocity relation, and contractile protein enzyme activity. Thus, the stress of hypertension, which was tolerated by the 10- and 20-month-old animals with lesser relative hypertrophy and lesser changes in measured parameters, may represent a differential adaptation to the stress of hypertension.

Previous studies have demonstrated impaired contractile performance and delayed relaxation of hearts of diabetic rats. Male and female rats were made diabetic with intravenous streptozotocin and their hearts were studied 4 to 5 or 9 weeks later. Plasma glucose in female diabetics averaged 453 mg100 ml and in male diabetics 615 mg100 ml. Calcium uptake by isolated sarcoplasmic reticulum in the absence of oxalate were significantly lower in preparations from hearts of diabetic males and females than from controls. Rats pretreated with 3-0-methyl glucose before streptozotocin also had normal calcium binding by SR in the absence of oxalate. Sarcoplasmic reticulum Mg2+ ATPase and Ca2+Mg2+ (total) ATPase activities were significantly depressed in preparations from the diabetic animals. The results may partially explain the abnormalities in contraction and relaxation previously observed in hearts of diabetic animals.

Physiological cardiac hypertrophy was produced in female rats by subjecting them to a swimming program for 8 wk. Conditioned rats (C) had body weights similar to sedentary control rats (S), but hearts from C weighed 33% more than hearts from S. Heart function was assessed in an isolated working-heart apparatus at similar heart rates and aortic diastolic pressures and over a range of 5-20 cmH2O left atrial filling pressure (LAP). At any given LAP, absolute values for cardiac output and coronary flow were greater (p less than 0.001) in C than S, but when these values were normalized for dry left ventricular (LV) weight, no differences were observed. Peak LV systolic pressure and ejection fraction were greater (p less than 0.01) in C than S at all LAP. Derived measures of contractility calculated at the midwall demonstrated greater (p less than 0.01) velocity and extent of circumferential fiber shortening in C compared with S. Therefore, chronic swimming in female rats leads to enhanced contractile performance of the left ventricle despite a marked degree of hypertrophy. These results contrast with our earlier observations in female rats trained by running where neither hypertrophy nor enhanced function were observed.

Hearts of rats conditioned by a moderate swimming program for 8 weeks were compared with hearts of sedentary animals. Hearts of conditioned rats had greater mechanical responses to tachycardia and to increases in preload and afterload, in part because of improved coronary blood flow and oxygen delivery. Energy stores and intermediary metabolism could not account for improved performance of conditioned hearts. Changes in the properties of myocardial contractile proteins with conditioning were characterized by increased adenosine triphosphatase (ATPase) activity and rates of superprecipitation of actomyosin and by alterations in the availability of sulfhydryl groups at the active site of myosin. Hearts of conditioned rats were partially resistant to hypoxia. During hypoxia they converted chemical energy to external work with greater efficiency than hearts of sedentary rats. The studies indicate that a moderate conditioning program in rats improves potential aerobic cardiac performance. Factors in this improvement include increased capacity for coronary flow and oxygen delivery and higher levels of actomyosin and myosin ATPase activity. Conditioning also confers partial resistance to hypoxia, apparently as a result of improved mechanisms of energy utilization.

Left ventricular (LV) performance was studied in 30 rats conditioned by swimming and in 27 sedentary controls. Hearts were studied in the open chest both during sinus rhythm and during atrial pacing. Afterload was increased by occlusion of the aorta. Sinus rates were 328 beats/min in sedentary and 300 in conditioned animals (P less than 0.01). During ejection (E), peak left ventricular systolic pressure (PLVSP) and maximum LV dP/dt were significantly higher in conditioned than in sedentary animals. When data from hearts matched for similar heart rates were compared, increased LV performance was still seen during aortic obstruction in conditioned animals. Performance at pacing rates up to 400 beats/min was similar in hearts from conditioned and sedentary animals. At pacing rates above 400 beats/min cardiac performance was less in sedentary than in the conditioned animals. These data illustrate that although base-line cardiac performance may be the same in rats conditioned by a moderate swimming program and in sedentary animals, cardiac reserve is improved by the swimming program.

To study cardiac carbohydrate metabolism in acute or chronic uremic conditions, hearts from animals were studied at 24 h after bilateral nephrectomy (acute uremia) or 2 weeks after 5 6 nephrectomy (chronic uremia). Studies performed in isolated perfused hearts, using glucose-U-14C and 5 m m glucose as a substrate, showed that glucose uptake and glycogen turnover were depressed in hearts from acute uremic animals. The residual glycogen content remained higher in uremic than sham hearts. These abnormalities were correctable with insulin. Although chronic uremic animals had less cardiac glycogen content than chronic sham-operated animals, there were no differences in glucose or glycogen metabolism or in response to insulin in these isolated perfused hearts. Glycolysis and oxidative metabolism appeared to be normal in acute and chronic uremic hearts. Normal hearts perfused in the presence of urea 2.5, 10, or 20 m m , guanidinosuccinic acid 0.31 m m , creatinine 0.88 m m and methylguanidine 0.46 m m alone or in combination showed normal carbohydrate metabolism in the absence and presence of insulin. Thus, abnormal carbohydrate metabolism can only be demonstrated in acute uremic rat hearts, and this resulted from the impairment of glucose transport, a diminution of the hexokinase activity, and abnormal glycogen metabolism.

SummaryIn isolated working rat hearts, the washout of 3H sorbitol as well as the exchange of 45Ca2+ could be described as the sum of three processes, two of which were found to be exponential in nature. The volume of distribution of 45Ca2+ was greater than that of the sorbitol. This greater volume of distribution was clearest for the compartment with the longest time constant. Addition of quinidine in doses which produced a 32% decline in maximum dP/dt had no effect on the rate constants for the washout of sorbitol or the exchange of 45Ca2+. The difference between the volume of distribution of calcium and sorbitol was also not measurably changed by the negative inotropic intervention.The results suggest that the kinetics of 45Ca2+ exchange are determined by those processes which limit the washout of the extracellular space. The studies with quinidine further suggest that if this agent displaces Ca2+ from binding or storage sites, the amount affected is too small to be detected by kinetic analysis of calci...

To study effects of physiologic hypertrophy on contractile protein ATPases and sarcoplasmic reticulum, hypertrophy was caused in female Wistar rats by a chronic swimming program. Nonhypertrophied hearts of female control sedentary rats and rats made to run on a treadmill program were also examined. The swimming program, but not the running program, resulted in a significant increase in heart weight. Actomyosin ATPase activity was also increased by 15% in the hearts of swimmers but not runners. Similar increases were observed for Ca2+-activated myosin ATPase activity and actin-activated ATPase of myosin. Sarcoplasmic reticulum from the hearts of swimmers showed increased calcium binding and calcium uptake as a function of time and of calcium concentration. Sarcoplasmic reticulum ATPase activities were not altered by hypertrophy. These findings in physiologic hypertrophy contrast with those of pathologic hypertrophy in which ATPase activity of contractile proteins and calcium binding and uptake of sarcoplasmic reticulum have generally been found to be depressed.

To evaluate the combined effects of cardiac overload imposed by hypertension and by chronic exercise, male and female rats were made hypertensive by unilateral renal artery stenoses and made to exercise in an 8-10-wk swimming program. Sedentary normotensive animals, sedentary hypertensive animals and normotensive animals exposed to the swimming program were also studied. Hypertension was associated with the development of cardiac hypertrophy, and this was exaggerated in hypertensive swimmers. Actomyosin, Ca2+-myosin, and actin-activated Mg2+-myosin ATPase activities were enhanced in normotensive swimmers, depressed in hypertensives and were normal or increased in hypertensive swimmers. Myosin isoenzyme analysis showed a predominant V1 pattern in normals; an increase in percent V1 isoenzyme is swimmers; a predominant V3 pattern in hypertensives; and a return to the predominant V1 pattern in hypertensive swimmers. These findings suggest that the hypertrophy imposed by hypertension and hypertrophy imposed by physical training using a chronic swimming program are distinctly different biological phenomena. Physical training by swimming prevents the changes in cardiac myosin induced by hypertension despite the exaggeration of hypertrophy.

To evaluate the effects of sex hormones on heart function and biochemistry, gonadectomy (GX) was performed in postpubertal male (M) and female (F) rats and compared with sham-operated controls (SH). The groups were MSH; MGX; MGX replaced with testosterone 3 mg/day s.c. (MGX + T), FSH, and FGX replaced with estrogen 2 mg/day (FGX + E), progesterone 0.4 mg/day (FGX + P), estrogen and progesterone (FGX + EP), or testosterone 2 mg/day (FGX + T). Body weight was decreased in MGX and was decreased further in MGX + T. Heart weight was decreased in both MGX and MGX + T. Body weights were increased in FGX and FTX + P and were increased further in FGX + T but were normal in FGX + E and FGX + EP. Heart weights were unchanged in F groups except in FGX + T, where it was increased. Cardiac performance in perfused hearts, as measured by stroke work, ejection fraction, fractional shortening and mean velocity of circumferential fiber shortening, was decreased in MGX but was slightly increased in MGX + T. Papillary muscle studies showed increases in time to peak tension and one-half relaxation in MGX, but these were decreased in MGX + T. Isotonic shortening studies showed decreased velocity of shortening in MGX and increased velocity in MGX + T. Heart function was significantly decreased in FGX and FGX + P compared with FSH but was similar to FSH in FGX + E and FGX + EP. FGX + T had greater stroke work and ejection fraction than FSH and FGX.(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously shown that swim conditioning corrects the depressed mechanical function and myosin adenosinetriphosphatase (ATPase) activities associated with renovascular hypertension (HTN) in the rat. The present study was designed to assess the effects of swim conditioning on another form of systolic overload, subdiaphragmatic suprarenal aortic stenosis. Cardiac mechanics in an isolated working heart apparatus and myosin enzymology were studied in four groups of rats: controls (C), animals with chronic systolic overload secondary to aortic constriction (St), swim-conditioning animals (Sw), and animals exposed to a combined load (St-Sw). Heart weight was increased by 23% in St, 27% in Sw, and 36% in St-Sw. In contrast to HTN, cardiac pump and muscle function were not depressed in St. Sw was associated with improved cardiac output, stroke work, and velocity of circumferential fiber shortening. St-Sw showed improved mechanical cardiac performance relative to both C and St. The percent of ventricular myosin of the V1 type and Ca2+-activated myosin ATPase activity relative to C was unchanged in Sw but was depressed in St and St-Sw. These data demonstrate that the salutory mechanical effects of Sw can be superimposed on the systolic overload of St. However, the dissociation between mechanics and myosin enzymology suggests that factors in excitation-contraction coupling other than myosin isoenzyme shifts are responsible for this finding.

The purpose of this study was to evaluate peak pressure systolic volume ratio as a detector of cardiac disease. To validate that tracings obtained through fluid-filled catheters were accurate for this purpose, in 35 patients left ventricular pressure-volume loops were constructed from tracings recorded with a micromanometer-tipped angiographic catheter. Comparisons were made between the peak ratio of left ventricular pressure to volume (Emax) using the micromanometer-tipped angiographic catheter and the ratio between peak left ventricular pressure before angiography and end-systolic volume during angiography ( peak pressure systolic volume ratio) using the fluid-filled lumen of the same catheter. The relations of Emax and that of peak pressure systolic volume ratio to ejection fraction were similar and curvilinear. Peak pressure systolic volume ratio was approximately 10 percent higher than Emax, with a correlation coefficient between 0.99 of the two ratios. Therefore, peak pressure systolic volume ratio, which is easily obtained in clinical practice, can be used instead of Emax. Retrospective analysis of the peak pressure systolic volume ratio and ejection fraction was made from routine diagnostic catheterization data obtained using fluid-filled catheters in 115 subjects, of whom 17 were normal, 60 had coronary artery disease without asynergy, 23 had aortic valve disease and 15 had mitral valve disease. In subjects with a normal ejection fraction (more than 60 percent) the peak pressure systolic volume ratio separated those groups with a diseased heart from those with a normal heart. Those with a diseased heart had a greater end-systolic volume than normal subjects. Thus, the peak pressure systolic volume ratio is more sensitive than ejection fraction in detecting subtle changes in myocardial function in human beings.

Myosin was isolated from the hearts of 210-day-old genetically myopathic Syrian hamsters (Bio 53:58) and its properties compared to the myosin from random bred controls of the same age. The Ca2+ ATPase was depressed in the myosin from the hearts of myopathic animals. The K+-EDTA ATPase and the total-SH content did not differ significantly in the two groups. Myosin from myopathic animals showed a loss of LC2. Analyses of myofibrils and actomyosin revealed that the LC2 was present in these preparations from the myopathic animals and the loss of LC2 was taking place during the purification of myosin. Despite the presence of LC2 in the myofibrils and actomyosin, the corresponding ATPase activities were depressed in the myopathic hearts. The loss of LC2 in myopathic cardiac myosin was found to be due to high levels of neutral protease activity co-purifying with myosin. The protease fraction from myopathic hearts degraded the cardiac LC2 of control hamster and dog cardiac myosin, however, the Ca2+ ATPase remained unchanged.

Rats were trained with two running protocols previously demonstrated to result in enhanced cardiac performance. Control groups included free-eating sedentary animals and food-restricted animals in which the body weights were the same as the runners. Calcium binding by isolated sarcoplasmic reticulum (SR) was slightly but significantly increased in SR from runners at low but not high calcium concentrations at 15 s and 1 min. Calcium uptake in the presence of 1 mM oxalate was increased in SR from runners. Actomyosin ATPase activity was increased by 10% (P less than 0.001) with one running protocol but not with the other. Myosin Ca2+ ATPase activity and actin-activated ATPase activity were also slightly increased in hearts of runners. In food-restricted cardiac actomyosin ATPase was significantly decreased. Actomyosin ATPase activity was found to be normal in hearts of sedentary animals subjected to water immersion without exercise. Therefore, physical training of rats by running, which produces a cardiac mechanical advantage similar to training by swimming, is not accompanied by cardiac biochemical changes of the same magnitude as in the hearts of swimmers.

Although more studies need to be done, particularly using sensitive nuclear techniques in humans, the data available demonstrate that conditioning has multiple salutary effects on the heart and suggest that exercise training may be an important adjuvant therapy for a variety of clinical disorders

Previous reports have documented a cardiomyopathy in rats resulting from streptozotocin-induced diabetes. In order to determine the reversibility of streptozotocin-induced cardiomyopathy to insulin therapy, hearts from rats made diabetic by streptozotocin for 6 weeks and then treated with insulin for 3 weeks were compared with untreated diabetic rats and control rats not injected with streptozotocin. When perfused in an isolated working heart apparatus with 5.5 m m glucose as substrate, hearts from untreated diabetic rats when compared to hearts from either streptozotocin-injected rats treated with insulin or control rats showed significant depressions in peak left ventricular pressure, maximal positive and negative d P d t , oxygen extraction, lactate production and effluent lactate; pyruvate ratio. Ca2+-actomyosin ATPase was also depressed in untreated diabetics. As left atrial pressure was raised in untreated diabetic rats, a decline in cardiac output was observed, whereas in insulin-treated or control groups there was no such negative response. Indices of cardiac performance were significantly greater in insulin-treated rats when compared to control rats suggesting overcorrection with insulin therapy. To explore whether insulin treatment may have a beneficial effect on the myocardium control rats were made hyperinsulinemic for 6 to 7 weeks. Shorter isovolumic relaxation times and elevated values for Ca2+-actomyosin ATPase were observed in hearts from hyperinsulinemic animals when compared to hearts from control animals. These results demonstrate complete reversibility of streptozotocin-induced cardiomyopathy and confirm that this condition is due to insulin deficiency and not to a primary cardiotoxic effect of streptozotocin.

Coronary artery disease causing myocardial ischemia and infarction is the leading cause of death in America. Methods that can be used to diagnose and follow the response to therapy of coronary artery disease or its effect on myocardial ischemia should help control the morbidity and mortality of ischemic heart disease. The use of ECG monitoring is less sensitive and specific for ischemia than thallium (TI) imaging or the use of radionuclide angiography (RNA). In large patient populations, the findings of a positive ECG and TI or RNA study will be highly predictive for the presence of coronary artery disease, while negative test results make the disease unlikely. A combined approach to the patient with possible ischemic heart disease is presented.

The objective of this investigation was to compare intrinsic cardiac function in male and female rats. The first series of experiments (Series I) compared hearts from age-matched males and females at 18 weeks of age. Since body and heart weight were 65 and 51 per cent greater respectively in male rats in this study, a second series of experiments was performed (Series II) where heart mass was matched in males and females by studying males at 10 weeks of age and females at 18 weeks of age. Cardiac function was studied in an isolated working heart apparatus at similar heart rates and at controlled levels of end-diastolic pressure and aortic diastolic pressure (ADP). In Series I coronary flow and end-diastolic volume (both per g LV) were the same in male and female hearts, while stroke work (per g LV), ejection fraction and fractional shortening were significantly greater in male hearts but only as the ADP was increased. In Series II all of these measurements were significantly greater in male hearts at all loading conditions. The magnitude of the differences between male and female hearts was greater in Series II than in Series I which may have been due to a Frank-Starling effect in male hearts from Series II. The results indicate that intrinsic cardiac function is moderately greater in male rats compared to female rats. Studies employing similar size male and female hearts suggest that differences in heart mass may have accounted for the differential response to ADP in Series I.

The hemodynamic effects of nitroglycerin taken sublingually were studied during cardiac catheterization in 10 patients with valvular aortic stenosis. Hemodynamics and cineangiographic left ventricular volumes were determined before administration of nitroglycerin and at peak nitroglycerin effect. Diastolic pressure-time and ejection pressure-time product were used to evaluate left ventricular energy supply and demand. Pressurevolume loops and left ventricular wall tension were calculated. There was a decrease ( P P It is concluded that sublingual nitroglycerin in aortic valve stenosis: (1) improves indirect indexes of left ventricular energy supply/demand ratio, (2) decreases left ventricular preload and afterload, and (3) does not change left ventricular contractility.

Morphologically intact muscle cells were prepared by perfusing adult rat hearts with a balanced salt medium containing 0.1% collagenase and 0.2% hyaluronidase. Yields of intact cells representing up to 25% of the weight of the heart were obtained. The cells separated along the line of the intercalated discs, with cleavage of desmosomes but with tearing of the plasma membrane in the region of the gap junction, so that when two contiguous cells were parted, the gap junction was retained intact attached to one of the cells. The fine structure of undamaged cells was indistinguishable from that of normal myocardial cells in situ, whereas damaged cells characteristically revealed numerous cytoplasmic vacuoles, clumping of myofilaments, and blebbing of the cell membrane, but morphologically normal mitochondria. The earliest lesion detected was a dilatation of the T (transverse tubular) system. Respiration in the intact cells was linear for 30 to 60 minutes and approximately two to three times the rate observed with heart muscle slices or the arrested isolated perfused heart. Oxygen uptake was stimulated by pyruvate but not by lactate. These observations demonstrate the feasibility of preparing intact isolated cells from adult rat heart and their potential value in histologic, pharmacologic, and metabolic studies.

SummaryRat hearts were perfused in an apparatus in which coronary flow, cardiac output, left ventricular pressure, rate of rise of left ventricular pressure (dp/dt) and external cardiac work could be measured. The effects of the presence and absence of exogenous glucose were compared. In the presence of glucose stable performance lasted longer than without substrate. When the heart failed cardiac output, left ventricular pressure, maximal dp/dt and cardiac work declined simultaneously. At the time of failure endogenous cardiac glycogen stores had declined to the same level whether or not exogenous glucose had been furnished. The hexose cost of cardiac work was greater when glucose was furnished, suggesting whatever hexose was available was more completely metabolized in the absence of exogenous substrate.