Global longitudinal strain aids the detection of non-obstructive coronary artery disease in the resting echocardiogram.

AIMS: To evaluate the diagnostic power of abnormal global longitudinal strain (GLS) to detect non-obstructive coronary artery disease (CAD) in the resting echocardiogram. GLS using two-dimensional speckle-tracking echocardiography (2D STE) is a powerful tool for detecting advanced CAD. However, the diagnostic power of 2D STE for detecting moderate, clinically unapparent CAD from images obtained at rest is unknown. METHODS AND RESULTS: We retrospectively studied 2D STE characteristics in 123 consecutive patients who underwent stress echocardiography, and subsequently coronary angiography within 10 days. We compared the diagnostic power of GLS at rest to the conventional wall motion score index (WMSI) during stress for detecting stenosis ≥ 50% (CAD(>50)) in any major coronary artery. Studies with akinetic or dyskinetic segments and reduced left ventricular ejection fraction were excluded. In 56 patients with significant CAD(>50), GLS was -16.77 ± 3.18% compared with -19.05 ± 3.43% in the 67 patients without CAD(<50) (P = 0.0002). A GLS cutpoint of greater than -17.77% had the most optimal sensitivity and specificity (66/76%) for detecting CAD and was comparable to a WMSI ≥ 1.13 (68/70%) measured during stress. CONCLUSION: Non-obstructive CAD was identified by a reduced GLS measured by 2D STE in rest images with similar accuracy to the traditional WMSI measured in stress echocardiography.

Protein kinase C epsilon induces systolic cardiac failure marked by exhausted inotropic reserve and intact Frank-Starling mechanism.

Myofilament dysfunction is a common point of convergence for many forms of heart failure. Recently, we showed that cardiac overexpression of PKC epsilon initially depresses myofilament activity and then leads to a progression of changes characteristic of human heart failure. Here, we examined the effects of PKC epsilon on contractile reserve, Starling mechanism, and myofilament activation in this model of end-stage dilated cardiomyopathy. Pressure-volume loop analysis and echocardiography showed that the PKC epsilon mice have markedly compromised systolic function and increased end-diastolic volumes. Dobutamine challenge resulted in a small increase in contractility in PKC epsilon mice but failed to enhance cardiac output. The PKC epsilon mice showed a normal length-dependent tension development in skinned cardiac muscle preparations, although Frank-Starling mechanism appeared to be compromised in the intact animal. Simultaneous measurement of tension and ATPase demonstrated that the maximum tension and ATPase were markedly lower in the PKC epsilon mice at any length or Ca2+ concentration. However, the tension cost was also lower indicating less energy expenditure. We conclude 1) that prolonged overexpression of PKC epsilon ultimately leads to a dilated cardiomyopathy marked by exhausted contractile reserve, 2) that PKC epsilon does not compromise the Frank-Starling mechanism at the myofilament level, and 3) that the Starling curve excursion is limited by the inotropic state of the heart. These results reflect the significance of the primary myofilament contractilopathy induced by phosphorylation and imply a role for PKC epsilon-mediated phosphorylation in myofilament physiology and the pathophysiology of decompensated cardiac failure.

Protein kinase Cepsilon overexpression alters myofilament properties and composition during the progression of heart failure.

We report characterization of a transgenic mouse that overexpresses constitutively active protein kinase Cepsilon in the heart and slowly develops a dilated cardiomyopathy with failure. The hemodynamic, mechanical, and biochemical properties of these hearts demonstrate a series of temporal events that mark the progression of the disease. In the 3-month transgenic (TG) animals, contractile properties and gene expression measurements are normal, but an increase in myofibrillar Ca2+ sensitivity and thin filament protein phosphorylation is noted. At 6 months, there is a decrease in the myofibrillar Ca2+ sensitivity, a significant increase in beta-myosin heavy chain mRNA and protein, normal cardiac function, but a blunted response to an inotropic challenge. The transition at 9 months is especially interesting because age-related changes appear to contribute to the decline in function seen in the TG heart. At this point, there is a decline in baseline function and maximum tension produced by the myofibrils, which is coincident with the onset of atrial myosin light chain isoform re-expression in the ventricles. In the 12-month TG mice, there is clear hemodynamic and geometric evidence of failure. Alterations in the composition of the myofibrils persist but the phosphorylation of myosin light chain 2v is dramatically different at this age compared with all others. We interpret these data to implicate the disruption of the myofibrillar proteins and their interactions in the propagation of dilated cardiac disease.

alpha-Adrenergic response and myofilament activity in mouse hearts lacking PKC phosphorylation sites on cardiac TnI.

Protein kinase C (PKC)-mediated phosphorylation of cardiac myofilament (MF) proteins has been shown to depress the actomyosin interaction and may be important during heart failure. Biochemical studies indicate that phosphorylation of Ser(43) and Ser(45) of cardiac troponin I (cTnI) plays a substantial role in the PKC-mediated depression. We studied intact and detergent-extracted papillary muscles from nontransgenic (NTG) and transgenic (TG) mouse hearts that express a mutant cTnI (Ser43Ala, Ser45Ala) that lacks specific PKC-dependent phosphorylation sites. Treatment of NTG papillary muscles with phenylephrine (PE) resulted in a transient increase and a subsequent 62% reduction in peak twitch force. TG muscles showed no transient increase and only a 45% reduction in force. There was a similar difference in maximum tension between NTG and TG fiber bundles that had been treated with a phorbol ester and had received subsequent detergent extraction. Although levels of cTnI phosphorylation correlated with these differences, the TG fibers also demonstrated a decrease in phosphorylation of cardiac troponin T. The PKC-specific inhibitor chelerythrine inhibited these responses. Our data provide evidence that specific PKC-mediated phosphorylation of Ser(43) and Ser(45) of cTnI plays an important role in regulating force development in the intact myocardium.