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.

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.

Temporal changes in ventricular function assessed echocardiographically in conscious and anesthetized mice.

The mouse is an important model system for cardiovascular biology, with echocardiography a critical tool for noninvasive measurement of cardiac morphology and function. The feasibility and short-term temporal consistency of repeated echocardiographic measurements in conscious mice has not been previously evaluated. We performed serial 2-dimensional guided M-mode transthoracic echocardiographic measurements at 5- to 10-minute intervals over 60 minutes in conscious mice and in mice treated with 1 of 3 anesthetic regimens: ketamine and acepromazine (n = 14); pentobarbital (n = 14); and ketamine and xylazine (n = 13). Unanesthetized mice received intraperitoneal saline (n = 6) or no injection (n = 7). In sequentially repeated measurements over 1 hour in conscious mice, none of the measured or derived echocardiographic parameters differed from baseline, whereas all 3 anesthetic regimens produced significant, prolonged, and temporally variable decreases in heart rate and fractional shortening. The relationship between heart rate and fractional shortening was not altered by anesthetic choice. Serial echocardiographic assessments of cardiac function, dimension, and mass can be performed with high reproducibility in conscious mice.

Improving cardiovascular disease prevention and management in Africa: issues to consider for the 21st century.

There is substantial evidence that cardiovascular diseases, and their associated risk factors, are becoming an increasing threat to the health of a large portion of the populace in many areas of Africa, particularly sub-Saharan Africa. If not adequately addressed, this epidemic will place an even greater burden on the poor economies and weak public health infrastructures of this continent. Important strategies for curtailing this epidemic will include primordial, primary, and secondary prevention, population-based prevention programs, improved research and surveillance, and increased governmental accountability for the adequate appropriation of public health.

Myocardial Contrast Echocardiography in the Evaluation of Hypertensive Heart Disease.

Myocardial contrast echocardiography (MCE) has an established role in left ventricular assessment by improving the ventricular opacification and endocardial border definition especially in patients with sub-optimal echocardiographic images. With advances in cardiac ultrasound imaging technology and the development of new contrast agents, the clinical utility of this technique has greatly expanded to include assessment of coronary reperfusion in the setting of acute myocardial infarction, determination of myocardial viability within infarct zones as well as assessment of coronary microcirculation and flow reserve in patients with microvascular coronary disease. Improvements in image quality with intravenous contrast agents can facilitate image acquisition and enhance delineation of regional wall motion abnormalities at peak levels of exercise. Numerous studies have confirmed the clinical utility of contrast enhancement during echocardiographic studies, particularly in patients undergoing stress testing. In this paper, we explore the evidence in support of MCE and its potential clinical applications. Our review aims to summarize (1) the basic principles of myocardial contrast echocardiography including recent advances in the ultrasound technology and contrast agents (2) its clinical applications in the diagnosis of cardiovascular diseases and finally, (3) its potential role in risk stratification and assessment of microvascular perfusion in patients with hypertensive heart disease.