Gender and age differences in cardiovascular complications in anorexia nervosa patients.

BACKGROUND: Anorexia nervosa (AN) is characterized by severe malnutrition and electrolyte imbalances. Differences in cardiovascular complications between males and females with AN have not been studied. Additionally, coronary artery disease (CAD) prevalence and cardiovascular complications in patients with AN >65years have not been reported. METHODS: AN patients>18years were identified in the Nationwide Inpatient Sample 2009-2010 database using the Ninth Revision of International Classification of Disease code 307.1. Demographics, risk factors, and cardiovascular event rates were compared to general population data. RESULTS: CAD incidence was lower in all AN patients compared to the general population (4.4% vs 18.4%, p<0.001). Despite AN males having higher prevalences of hypertension and diabetes than AN females, there was no difference in CAD. AN males had higher rates of cardiac arrests, arrhythmias, and heart failure. Interestingly, 4.3% of patients with AN were >65years old. When compared to the general population>65years, older AN patients had lower rates of CAD (35% vs 16%; p<0.001). Older AN patients still had higher CAD rates compared to the general population under 65 (8.6%) and AN patients under 65 (4%; p<0.001). Older AN patients had a lower incidence of heart failure (24% vs 16%; p=0.04), and a trend towards less arrhythmias (30% vs 21%; p=0.08). CONCLUSIONS: Our data suggests that male AN patients experienced more cardiac arrests, arrhythmias, and heart failure than female AN patients. Additionally, older AN patients have a decreased incidence of CAD and heart failure compared to the general population>65years old.

Primary hyperparathyroidism predicts hypertension: Results from the National Inpatient Sample.

INTRODUCTION: Primary hyperparathyroidism (pHPT), most commonly caused by solitary parathyroid adenomas, leads to mobilization of calcium and is known to result in nephrolithiasis and osteoporosis. To date, studies of pHPT and cardiovascular risk factors and events have produced discrepant findings, likely due to small sample sizes and enrolling populations with varying disease severity. HYPOTHESIS: We utilized a national registry, hypothesizing an association between pHPT and cardiovascular risk factors and events. METHODS: Patients >18years with a diagnosis of pHPT were identified in the Nationwide Inpatient Sample 2009-2010 database using the Ninth Revision of International Classification of Diseases code 252.01. Demographics, risk factors, and cardiovascular event rates were collected and compared to general population data. RESULTS: pHPT was present in 0.1% (n=37,922) of hospital admissions. There was a significant increase in the prevalence of most cardiac risk factors including hypertension (HTN), diabetes mellitus, hyperlipidemia, obesity, and chronic kidney disease. The rates of heart failure (HF) and coronary artery disease (CAD) were higher in the pHPT population. However, after performing multivariate regression for age and cardiac risk factors, pHPT did not independently predict HF or CAD. The risk of HTN, however, was independently predicted by pHPT (OR 1.3; p<0.001). CONCLUSIONS: Primary hyperparathyroidism independently predicted the risk of hypertension in a patient population from a large national database. Despite significant differences in univariate analysis of cardiac risk factors and events, pHPT did not independently predict risk of HF or CAD after multivariate regression analysis. Future studies should explore potential mechanisms relating hypertension to pHPT.

Statins in non-ischaemic cardiomyopathy: an update on our current clinical and pathophysiological understanding.

Statins are a cornerstone in reducing cardiovascular events. Studies show that statins are beneficial even in patients with normal or low cholesterol levels, indicating pleiotropic mechanisms of therapeutic benefit apart from their antihyperlipidemic effect. Non-randomised, observational and retrospective studies suggest that statins are associated with better outcomes in patients with heart failure (HF) of both ischaemic and non-ischaemic aetiologies. While cholesterol reduction and plaque stabilisation likely play a role in reducing cardiovascular events in ischaemic HF patients, the mechanisms underlying the benefit in non-ischaemic HF patients is less clear. This review suggests the pleiotropic effects of statin therapy can beneficially alter the pathophysiological mechanisms underlying the clinical benefit observed in non-ischaemic HF patients.

Natriuretic peptides and heart failure in the patient with chronic kidney disease: a review of current evidence.

Natriuretic peptides such as brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are commonly used in the diagnosis and evaluation of heart failure. However, their utility in patients with chronic kidney disease (CKD) is less clear as renal dysfunction itself can be associated with elevated concentrations of these biomarkers. Given the high prevalence of left ventricular hypertrophy and left ventricular systolic dysfunction in patients with CKD, diagnosis or exclusion of heart failure becomes important in this population. Most studies to date indicate that upward adjustment of diagnostic cut points preserves the usefulness of both BNP and NT-proBNP in the CKD patient, with similar clinical performance of each biomarker. We review the role of natriuretic peptide in heart failure in the setting of chronic renal disease.

Lipomatus hypertrophy of the atrial septum and prominent crista terminalis appearing as a right atrial mass.

In these case reports, transthoracic echocardiography suggested the presence of a right atrial mass. However, subsequent transoesophageal echocardiography revealed that the 'right atrial mass' was actually a lipomatous hypertrophied atrial septum in combination with a prominent crista terminalis. An understanding of the anatomy and the echocardiographic appearance of a lipomatous hypertrophied atrial septum appearing with a prominent crista terminalis will minimize the misdiagnosis of these structures.

Chronic dipyridamole therapy produces sustained protection against cardiac ischemia-reperfusion injury.

Sustained protection against ischemia-reperfusion injury is not available for patients at risk for myocardial infarction who may require emergent reperfusion therapy. Whereas ischemic preconditioning and adenosinergic agents reduce myocardial injury, they are only effective when given immediately before ischemia or reperfusion. We recently found chronic ethanol exposure, an adenosine uptake inhibitor, produced sustained cardioprotection against ischemia-reperfusion injury. We now ask whether chronic dipyridamole therapy, a clinically usable nucleoside transport inhibitor, induces similar cardioprotection. Perfused hearts from guinea pigs, given dipyridamole (4 mg. kg(-1). day(-1)) in their water for 2-6 wk (n = 10 for each group), underwent ischemia-reperfusion. Injury was assessed by recovery of left ventricular developed (LVDP) and end-diastolic (LVEDP) pressures and creatine kinase release. During reperfusion, hearts from dipyridamole-treated animals (6 wk) had 74% higher LVDP, 28% lower LVEDP, and 61% lower creatine kinase release versus controls. Adenosine A(1)-receptor antagonism (8-cyclopentyl-1, 3-dipropylxanthine; 200 nM) abolished the protection of dipyridamole but A(2) antagonism (3,7-dimethyl-1-propargylxanthine; 10 mM) did not. Dipyridamole therapy produces sustained protection against ischemia-reperfusion injury in guinea pigs. This cardioprotection requires adenosine A(1) receptor signaling at the time of ischemia.

Role of slowed Ca(2+) transient decline in slowed relaxation during myocardial ischemia.

The goal of this study was to test the hypothesis that during myocardial ischemia, slowing of the Ca(2+) transient decline causes slowed relaxation. Our approach was to monitor pressure and Ca(2+) transients in isovolumic rat hearts during control and low flow ischemia conditions. In addition, we experimentally slowed the decline of the Ca(2+) transient using cyclopiazonic acid (CPA) to inhibit the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA, the most important pump for rapidly transporting Ca(2+) out of the cytosol). Using 9 microm CPA during normoxia, we were able to reproduce the slowed Ca(2+) transient decline and slowed relaxation found during low flow ischemia. The time constants of cytosolic [Ca(2+)] decline and pressure decline (tau(Ca) and tau(P) respectively) with CPA (78+/-5 ms and 64+/-3 ms) were similar to those found with ischemia (89+/-12 ms and 72+/-10 ms, mean+/-SEM, n=7) and were considerably greater than for controls (41+/-3 and 25+/-2 ms, mean+/-SEM, n=14, P<0.01). Furthermore, the relationship of tau(P) v tau(Ca) with CPA was similar to that found with ischemia. These findings are consistent with the hypothesis that the slowed Ca(2+) transient decline with both CPA and ischemia causes slowed relaxation. Consistent with this conclusion, a simple mathematical model to relate cytosolic [Ca(2+)] and pressure also suggests that slowed pressure relaxation can be explained by slowing of the Ca(2+) transient decline. This study suggests that impaired Ca(2+) uptake is a major injury causing slowed relaxation during ischemia.

Thermodynamic limitation for Ca2+ handling contributes to decreased contractile reserve in rat hearts.

The free energy release from ATP hydrolysis (|DeltaG approximately p|) is decreased by inhibiting the creatine kinase (CK) reaction, which may limit the thermodynamic driving force for the sarcoplasmic reticulum (SR) Ca2+ pumps and thereby cause a decrease in contractile reserve. To determine whether a decrease in |DeltaG approximately p| results in decreased contractile reserve by impairing Ca2+ handling, we measured left ventricular pressure and cytosolic Ca2+concentration ([Ca2+]c; by indo 1 fluorescence) in isolated perfused rat hearts, with >95% inhibition of CK with 90 micromol iodoacetamide. Iodoacetamide did not directly alter SR Ca2+-ATPase activity, baseline left ventricular developed pressure, or baseline [Ca2+]c. When perfusate Ca2+ concentration was increased from 1.2 to 3.3 mM, LV developed pressure increased from 67 +/- 6 to 119 +/- 8 mmHg in control hearts (P < 0.05) but did not significantly increase in CK-inhibited hearts. Similarly, the amplitude of the [Ca2+]c transient increased from 548 +/- 54 to 852 +/- 140 nM in control hearts (P < 0.05) but did not significantly increase in CK-inhibited hearts. We conclude that decreased |DeltaG approximately p| limits intracellular Ca2+ handling and thereby limits contractile reserve.

Benzocaine-induced methemoglobinemia--two case reports related to transesophageal echocardiography premedication.

Benzocaine-induced methemoglobinemia is a potentially life-threatening complication. We report two cases of methemoglobinemia due to topical benzocaine spray used as premedication for transesophageal echocardiography. A high index of suspicion is needed for this readily treatable condition.

Ca2+ regulates the kinetics of tension development in intact cardiac muscle.

The goal of this study was to determine whether Ca2+ plays a role in regulating tension development kinetics in intact cardiac muscle. In cardiac muscle, this fundamental issue of Ca2+ regulation has been controversial. The approach was to induce steady-state tetanic contractions of intact right ventricular trabeculae from rat hearts at varying external Ca2+ concentrations ([Ca2+]) at 22 degreesC. During tetani, cross bridges were mechanically disrupted and the kinetics of tension redevelopment were assessed from the rate constant of exponential tension redevelopment (ktr). There was a relationship between ktr and external [Ca2+] that was similar in form to the relationship between tension and [Ca2+]. Thus a close relationship also existed between ktr and tension (r = 0.88; P < 0. 001); whereas at maximal tetanic tension (saturating cytosolic [Ca2+]), ktr was 16.4 +/- 2.2 s-1 (mean +/- SE, n = 7), at zero tension (low cytosolic [Ca2+]), ktr extrapolated to 20% of maximum (3.3 +/- 0.7 s-1). Qualitatively similar results were obtained using different mechanical protocols to disrupt cross bridges. These data demonstrate that tension redevelopment kinetics in intact cardiac muscle are influenced by the level of Ca2+ activation. These findings contrast with the findings of one previous study of intact cardiac muscle. Activation dependence of tension development kinetics may play an important role in determining the rate and extent of myocardial tension rise during the cardiac cycle in vivo.

Alcohol consumption reduces ischemia-reperfusion injury by species-specific signaling in guinea pigs and rats.

We recently discovered that regular alcohol consumption reduces ischemia-reperfusion injury to the same degree as ischemic preconditioning in guinea pig hearts. Ischemic preconditioning, like this cardioprotective effect of alcohol, is mediated by adenosine signaling in guinea pigs. In rats, ischemic preconditioning may be mediated predominantly by alpha1-adrenergic signaling. To be certain that this protective effect of alcohol is a general biological response, we searched for alcohol's cardioprotection in rat and identified a potential signaling mechanism. Hearts isolated from alcohol-fed guinea pigs and rats were subjected to ischemia-reperfusion. Hearts from alcohol-fed animals showed greater recovery of left ventricular developed pressure than controls (guinea pigs, 46 vs. 29%; rats, 50 vs. 31%) and decreased myocyte necrosis assessed by creatine kinase release (guinea pigs, 204 +/- 42 vs. 440 +/- 70 U . ml-1 . g dry wt-1; rats 158 +/- 13 vs. 328 +/- 31 U . ml-1 . g dry wt-1). Adenosine receptor blockade [8-(p-sulfophenyl)theophylline] abolished alcohol's protection in guinea pig but not rat hearts. By contrast, alpha1-adrenergic blockade (prazosin) abolished alcohol's protection in rat but not guinea pig hearts. We conclude that regular alcohol consumption reduces ischemia-reperfusion injury and is mediated by species-specific signaling mechanisms. A major goal of cardiovascular research is to find a pharmacologically induced chronic state of preconditioning. Understanding the mechanisms of alcohol's cardioprotection against ischemia-reperfusion injury may aid in reaching this goal.

Chronic alcohol-induced changes in cardiac contractility are not due to changes in the cytosolic Ca2+ transient.

Long-standing heavy alcohol consumption acts as a chronic stress on the heart. It is thought that alcohol-induced changes of contractility are due to altered Ca2+ handling, but no measurements of cytosolic Ca2+ ([Ca2+]c) after chronic alcohol exposure have been made. Therefore experiments were performed to determine whether alcohol-induced changes in contractility are due to altered Ca2+ handling by measuring [Ca2+]c (indo 1) in hearts from rats drinking 36% ethanol for 7 mo and age-matched controls. Peak left ventricular pressure was depressed (-16%), whereas rates of contraction (12%) and relaxation (14-20%) were faster in alcohol-exposed hearts. Systolic [Ca2+]c (808 +/- 45 vs. 813 +/- 45 nM), diastolic [Ca2+]c (195 +/- 11 vs. 193 +/- 10 nM), and rates of [Ca2+]c rise and decline were the same in alcohol-exposed and control hearts. Protein levels of Ca2+-handling proteins, sarcoplasmic reticulum Ca2+-ATPase and phospholamban, were the same in myocytes isolated from alcohol-exposed and control hearts (SDS-polyacrylamide gel). These data suggest that chronic alcohol-induced contractile changes are not due to altered Ca2+ handling but may be due to changes at the level of the myofilament. As a first step in elucidating the mechanism(s) of alcohol-induced changes at the myofilament, we assessed myosin heavy chain (MHC) isoform content (SDS-polyacrylamide gel). alpha-MHC was decreased relative to beta-MHC (a/a + b = 0.55 +/- 0.03 vs. 0.66 +/- 0.02; P < 0.02) in alcohol-exposed hearts, which cannot account for the observed alcohol-induced contractile changes. In conclusion, changes of myocardial contractility due to chronic alcohol exposure do not result from altered Ca2+ handling but from changes at the level of the myofilament that do not involve MHC isoform shifts.

Activation of epsilon protein kinase C correlates with a cardioprotective effect of regular ethanol consumption.

In addition to decreasing the incidence of myocardial infarction, recent epidemiological data suggest that regular alcohol consumption improves survival after myocardial infarction. We recently found that chronic ethanol exposure induces long-term protection against cardiac ischemia-reperfusion injury, which improves myocardial recovery after infarction. Furthermore, this cardioprotection by ethanol is mediated through myocyte adenosine A1 receptors. We now determine the role of protein kinase C (PKC) in ethanol's protective effect against ischemia-reperfusion injury. Using perfused hearts of ethanol-fed guinea pigs, we find that improved contractile recovery and creatine kinase release after ischemia-reperfusion are abolished by PKC inhibition with chelerythrine. Western blot analysis and immunofluorescence localization demonstrate that regular ethanol consumption causes sustained translocation (activation) of epsilonPKC, but not delta or alphaPKC. This same isozyme is directly implicated in ischemic preconditioning's protection against ischemia-reperfusion injury. Our findings suggest (i) that regular ethanol consumption induces long-term cardioprotection through sustained translocation of epsilonPKC and (ii) that PKC activity is necessary at the time of ischemia to mediate ethanol's protective effect against ischemia-reperfusion injury. Studying this selective effect of ethanol on epsilonPKC activation may lead to new therapies to protect against ischemia-reperfusion injury in the heart and other organ systems.

Thyroid hormone improves function and Ca2+ handling in pressure overload hypertrophy. Association with increased sarcoplasmic reticulum Ca2+-ATPase and alpha-myosin heavy chain in rat hearts.

We asked whether thyroid hormone (T4) would improve heart function in left ventricular hypertrophy (LVH) induced by pressure overload (aortic banding). After banding for 10-22 wk, rats were treated with T4 or saline for 10-14 d. Isovolumic LV pressure and cytosolic [Ca2+] (indo-1) were assessed in perfused hearts. Sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, and alpha- and beta-myosin heavy chain (MHC) proteins were assayed in homogenates of myocytes isolated from the same hearts. Of 14 banded hearts treated with saline, 8 had compensated LVH with normal function (LVHcomp), whereas 6 had abnormal contraction, relaxation, and calcium handling (LVHdecomp). In contrast, banded animals treated with T4 had no myocardial dysfunction; these hearts had increased contractility, and faster relaxation and cytosolic [Ca2+] decline compared with LVHcomp and LVHdecomp. Myocytes from banded hearts treated with T4 were hypertrophied but had increased concentrations of alpha-MHC and SERCA proteins, similar to physiological hypertrophy induced by exercise. Thus thyroid hormone improves LV function and calcium handling in pressure overload hypertrophy, and these beneficial effects are related to changes in myocyte gene expression. Induction of physiological hypertrophy by thyroid hormone-like signaling might be a therapeutic strategy for treating cardiac dysfunction in pathological hypertrophy and heart failure.

Inorganic phosphate and coronary perfusion pressure mediate contractile dysfunction during mild ischemia.

During mild graded ischemia in perfused rat hearts, we (V.M. Figueredo, R. Brandes, M. W. Weiner, B. M. Massie, and S. A. Camacho. J. Clin. Invest 90: 1794-1802, 1992) previously found a relationship between decreased left ventricular developed pressure (LVDP) and increased Pi, in which intracellular pH, cytosolic Ca2+ concentration ([Ca2+]i), ATP, and free-energy change of ATP hydrolysis were not altered enough to affect contractility. However, the contribution of decreased coronary perfusion pressure (CPP) to decreased LVDP could not be determined. Thus, in the present study, graded hypoxia in perfused rat hearts (95-37.5% O2) was used to increase Pi to similar levels produced during mild ischemia without altering CPP and minimizing changes of other potential mediators of contractile dysfunction. 31P-magnetic resonance spectroscopy and indo 1 fluorescence were used to assess energy metabolites and [Ca2+]i, respectively. The relationship between LVDP and Pi during graded hypoxia was fit to a monoexponential (LVDP = 105 x e-0.04Pi). These data were compared with the relationship of LVDP and Pi during mild ischemia (LVDP = 106 x e-0.08Pi) (V. M. Figueredo, R. Brandes, M. W. Weiner, B. M. Massie, and S. A. Camacho. J. Clin. Invest 90: 1794-1802, 1992). The exponential constant, which describes the effect of Pi on LVDP, was 50% lower during graded hypoxia relative to mild ischemia. This suggests that another mediator, which accounted for approximately 50% of the decrease of LVDP during mild ischemia, was not present during hypoxia. Because CPP decreased during ischemia but not hypoxia, these data suggest that CPP and Pi contribute similarly in mediating contractile dysfunction during mild ischemia.

Regular alcohol consumption mimics cardiac preconditioning by protecting against ischemia-reperfusion injury.

Epidemiologic studies indicate that long-term alcohol consumption decreases the incidence of coronary disease and may improve outcome after myocardial infarction. Attenuation of ischemia-reperfusion injury after myocardial infarction improves survival. This study investigates the possibility that alcohol consumption can improve survival after myocardial infarction by reducing ischemia-reperfusion injury. Hearts were isolated from guinea pigs after drinking ethanol for 3-12 weeks and subjected to global ischemia and reperfusion. Hearts from animals drinking ethanol showed improved functional recovery and decreased myocyte damage when compared with controls. Adenosine A1 receptor blockade abolished the protection provided by ethanol consumption. These findings indicate that long-term alcohol consumption reduces myocardial ischemia-reperfusion injury and that adenosine A1 receptors are required for this protective effect of ethanol. This cardioprotective effect of long-term alcohol consumption mimics preconditioning and may, in part, account for the beneficial effect of moderate drinking on cardiac health.

The effects of alcohol on the heart: detrimental or beneficial?

Alcohol abuse is a substantial public health problem, resulting in staggering financial costs and other burdens. Prolonged alcohol abuse leads to cardiomyopathy in a minority of alcohol abusers, but because alcoholism is so widespread, alcohol is the major cause of nonischemic cardiomyopathy in Western society. In contrast, substantial evidence now suggests that moderate alcohol consumption has cardioprotective effects. It not only reduces the incidence of fatal ischemic heart disease, but it improves outcome in patients who have other risks for coronary events and go on to have myocardial infarctions. Therefore, physicians' recommendations about alcohol consumption should be as individualized as their patients.