Effect of obesity on cardiovascular disease risk factors in African American women.

Obesity is a growing health care concern with implications for cardiovascular disease (CVD). Obesity and CVD morbidity and mortality are highly prevalent among African American women. This pilot study examined the association between obesity and the traditional and emerging CVD risk factors in a sample of African American women. Participants comprised 48 women (27 obese, 21 normal weight) aged 18-45. with no known history of CVD. The women completed demographic and 7-day physical activity recall questionnaires. Height and weight were used to determine body mass index (BMI). Hypertension risk was assessed using the average of two resting blood pressure (BP) measurements. Lipid profile, blood glucose, fibrinogen, high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI-1), soluble intercellular adhesion molecule-1 (sICAM-1), and E-selectin (eSel) levels were assessed using fasting blood samples. Laboratory findings were interpreted using the American Diabetes Association (ADA) and Adult Treatment Panel (ATP) III reference guidelines as well as manufacturers' reference ranges for the novel CVD risk factors. The most common traditional risk factors were physical inactivity (72.9%), positive family history of CVD (58.3%), and obesity (56.3%). Obese individuals had elevated systolic BP (p = .0002), diastolic BP (p = .0007) and HDL-cholesterol (p = .01), triglyceride (p = .02), hs-CRP (p = .002), and fibrinogen (p = .01), when compared with normal-weight women. The findings suggest an association between obesity and higher prevalence of both traditional and emerging CVD risk factors in young African American women.

Ventricular tachycardia storm successfully treated with immunosuppression and catheter ablation in a patient with cardiac sarcoidosis.

We describe the case of a 43-year-old male with cardiac sarcoidosis and ventricular tachycardia storm successfully treated with catheter ablation and immunosuppression. Antiarrhythmics alone, and in combination with immusuppressive agents, failed to successfully manage the ventricular tachycardia episodes. Catheter ablation in conjunction with immunosuppression proved to be the most successful treatment strategy. The reported efficacy of catheter ablation for ventricular tachycardia in cardiac sarcoidosis is variable.

Calmodulin kinase II inhibition disrupts cardiomyopathic effects of enhanced green fluorescent protein.

Transgenic expression of enhanced green fluorescent protein (eGFP) in myocardium can result in cardiac dysfunction and cardiomyopathy, presumably through toxic effects that disrupt normal cellular signaling. The multifunctional Ca(2+)- and calmodulin-dependent protein kinase II (CaMKII) is widely expressed in myocardium and CaMKII activity is increased in human and animal models of cardiomyopathy, so we hypothesized that increased CaMKII activity is important for cardiomyopathy due to transgenic expression of eGFP. Here we report that cardiomyocyte-delimited eGFP over-expression causes increased CaMKII activity that predicts left ventricular dilation and dysfunction. On the other hand, transgenic co-expression of a CaMKII inhibitory peptide with eGFP prevents eGFP-mediated left ventricular dilation and dysfunction. These findings suggest that increased CaMKII activity is a critical pathological signal in transgenic cardiomyopathy due to eGFP over-expression.

Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy.

BACKGROUND: Activation of cellular Ca2+ signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca2+-dependent phosphatase calcineurin (CAN) causes severe cardiomyopathy marked by left ventricular (LV) dysfunction, arrhythmias, and increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk of death. METHODS AND RESULTS: We found that activity and expression of a second Ca2+-activated signaling molecule, calmodulin kinase II (CaMKII), were increased in hearts from CAN transgenic mice and that CaMKII-inhibitory drugs improved LV function and suppressed arrhythmias. We devised a genetic approach to "clamp" CaMKII activity in CAN mice to control levels by interbreeding CAN transgenic mice with mice expressing a specific CaMKII inhibitor in cardiomyocytes. We developed transgenic control mice by interbreeding CAN transgenic mice with mice expressing an inactive version of the CaMKII-inhibitory peptide. CAN mice with CaMKII inhibition had reduced risk of death and increased LV and ventricular myocyte function and were less susceptible to arrhythmias. CaMKII inhibition did not reduce transgenic overexpression of CAN or expression of endogenous CaMKII protein or significantly reduce most measures of cardiac hypertrophy. CONCLUSIONS: CaMKII is a downstream signal in CAN cardiomyopathy, and increased CaMKII activity contributes to cardiac dysfunction, arrhythmia susceptibility, and longevity during CAN overexpression.

Calmodulin kinase II activity is required for normal atrioventricular nodal conduction.

BACKGROUND: Multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is abundant in myocardium. CaMKII activity is augmented by catecholamine stimulation, which enhances AV nodal conduction, suggesting the hypothesis that CaMKII also contributes to AV nodal conduction properties. OBJECTIVES: The purpose of this study was to test the potential role of CaMKII in regulating AV nodal conduction in heart. METHODS: We developed a novel mouse with genetic CaMKII inhibition by cardiac-specific expression of autocamtide 3 inhibitory peptide (AC3-I) mimicking a conserved sequence of the CaMKII regulatory domain. We also engineered a control transgenic mouse with cardiac expression of an inactive, scrambled version of AC3-I (autocamtide 3 control peptide [AC3-C]) and performed electrophysiologic measurements in vivo and in Langendorff-perfused isolated hearts. RESULTS: AC3-I and AC3-C were abundantly expressed in AV nodal cells. AC3-I mice with implanted ECG telemeters showed enhanced Wenckebach-type AV conduction block after isoproterenol (present in 9/9 mice) compared with AC3-C mice (present in 1/5 mice, P = .005). Intracardiac recordings showed significant PR and AH interval prolongation in AC3-I mice at baseline and after isoproterenol compared with AC3-C mice. HV durations were not different. Langendorff-perfused AC3-I hearts had significantly prolonged Wenckebach cycle lengths and AV nodal effective refractory periods compared with AC3-C hearts, whereas sinus node recovery time and left ventricular effective refractory times were similar between these genotypes. CONCLUSIONS: These studies define CaMKII as a critical determinant of normal and catecholamine-stimulated AV nodal conduction responses.

Calmodulin kinase II inhibition protects against structural heart disease.

Beta-adrenergic receptor (betaAR) stimulation increases cytosolic Ca(2+) to physiologically augment cardiac contraction, whereas excessive betaAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a recently identified downstream element of the betaAR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in betaAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive betaAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and betaAR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to betaAR signaling.

Outcome and complications of intraoperative hemodialysis during cardiopulmonary bypass with potassium-rich cardioplegia.

BACKGROUND: Potassium-rich cardioplegia has advantages over other cardioplegic solutions in preserving the myocardium during cardiopulmonary bypass, but it is avoided in patients with renal failure because of hyperkalemia. METHODS: We first determined the ability of intraoperative hemodialysis (IHD) to remove potassium during cardiopulmonary bypass with potassium-rich cardioplegia in 9 patients by measuring potassium levels in all dialysate and urine. We then studied 24 patients with renal failure, grouped with the 9 previous patients, to assess safety, rebound hyperkalemia, and patient outcome with this technique. RESULTS: In the first phase, 9 patients were administered 128 +/- 11 mmol of potassium in potassium-rich cardioplegia, and IHD removed 157 +/- 23 mmol. Urinary potassium excretion was only 10 +/- 3 mmol. Potassium removal occurred at a rate of 1.25 mmol/min with 0-mEq/L (mmol/L) potassium dialysate and a rate of 0.75 mmol/min with 3.0-mEq/L (mmol/L) potassium dialysate. In all 33 patients, successful initiation of cardiac rhythm occurred after cardiopulmonary bypass, and 5 patients had cardiac arrhythmias possibly from hypokalemia. In the next 24 hours, 5 dialysis-dependent patients developed hyperkalemia (potassium > 5.2 mEq/L [mmol/L]) requiring hemodialysis. Postoperative hemodialysis was delayed 2 to 3 days in the other patients. The overall death rate was 24% at 30 days. CONCLUSION: IHD effectively and safely removes potassium administered during potassium-rich cardioplegia during cardiopulmonary bypass in patients with renal failure and prevents postoperative hyperkalemia in the majority of patients. Overall mortality in patients with acute and chronic renal failure undergoing cardiac surgery is high irrespective of control of potassium balance in these patients.

Migration and infection of a pace-sense lead from an abdominal defibrillator system.

A 47-year-old man had an ICD system with epicardial and endocardial components and an abdominal generator placed in 1990 following a cardiac arrest. Ten years later his BT10 lead was amputated due to an insulation defect, and he received a new pectoral generator with transvenous leads. A few months later he developed fevers, chills, and bacteremia. Evaluation demonstrated migration of the entire BT10 lead into the right atrium. Complete surgical explantation was required and the bacteremia resolved. This case illustrates the importance of solid anchoring of distal lead components following generator removal and the potential complication of intravascular lead migration.

Calmodulin inhibitor W-7 unmasks a novel electrocardiographic parameter that predicts initiation of torsade de pointes.

BACKGROUND: We have shown that the calmodulin inhibitor W-7 suppresses torsade de pointes (TdP) without shortening the QT interval, which is consistent with other findings that QT prolongation, per se, is insufficient to generate TdP. ECGs were analyzed from a well-characterized animal model of TdP to identify more reliable predictors of this life-threatening ventricular arrhythmia. METHODS AND RESULTS: TdP was induced using methoxamine and clofilium in 12 of 14 rabbits pretreated with vehicle control, whereas pretreatment with W-7 (50 micromol/kg), an inhibitor of the intracellular Ca2+-binding protein calmodulin, significantly suppressed TdP induction (1 of 11 rabbits with TdP, P<0.001). W-7 did not affect heart rate, increases in QT intervals, or dispersion compared with measurements in vehicle-treated control animals. However, a progressive and significant increase in the ratio of U-wave to T-wave amplitude (UTA) occurred before TdP onset in control animals, and this was prevented by W-7. CONCLUSIONS: Selective suppression of TdP inducibility by W-7, without shortening the duration of cardiac repolarization, allowed identification of the UTA ratio as a new electrocardiographic index for predicting TdP onset. These findings are consistent with the idea that prolonged repolarization is not the proximate cause of arrhythmia initiation, and they suggest that an increased UTA ratio reflects activation of intracellular Ca2+/calmodulin-dependent processes that are required for triggering TdP in this model.