Heart rate reduction by ivabradine reduces diastolic dysfunction and cardiac fibrosis.

OBJECTIVES: To determine if heart rate (HR) reduction with ivabradine (IVA), a selective inhibitor of the pacemaker I(f) current, prevents cardiac dysfunction associated with dyslipidemia. METHODS: New Zealand White rabbits received either a standard diet, a 0.5% cholesterol-enriched diet only (CD), or a 0.5% CD with IVA (17 mg/kg/day) for 12 weeks. HR, left ventricular (LV) systolic function, diastolic function and LV regional myocardial performance index (MPI) were studied using echocardiography. Histological analysis included cardiac interstitial fibrosis and collagen type I fibers. Plasma levels of angiotensin II and aldosterone were quantified by immunoassays. RESULTS: IVA reduced HR by approximately 11%. IVA improved MPI and attenuated LV diastolic dysfunction (DD) (92% mild and 8% moderate DD with IVA vs. 54% mild and 46% moderate DD in CD group). IVA also reduced atrial fibrosis (p = 0.027), ventricular fibrosis (p = 0.0002) and ventricular collagen type I (p = 0.0042). IVA decreased plasma angiotensin II levels (p = 0.042), and both angiotensin II and aldosterone levels were correlated with HR (p = 0.038 and 0.008). CONCLUSION: Selective HR reduction with IVA reduces DD and cardiac fibrosis in hypercholesterolemic rabbits. These beneficial effects of IVA support testing pure HR reduction in patients with diastolic heart failure.

Myocardial electrical alteration in canine preparations with combined chronic rapid pacing and progressive coronary artery occlusion.

Our objective was to create an animal preparation displaying long-term electrical alterations after chronic regional energetic stress without myocardial scarring. An Ameroid (AM) constrictor was implanted around the left circumflex coronary artery (LCx) 2 wk before chronic rapid ventricular pacing (CRP) was initiated at 240 beats/min for 4 wk (CRP-AM). Comparisons were made with healthy canines and canines with either AM or CRP. Unipolar electrograms were recorded from 191 sites in the LCx territory in open-chest, anesthetized animals during sinus rhythm and while pacing at 120-150 beats/min, with bouts of transient rapid pacing (TRP; 240/min). In CRP-AM and AM, ST segment elevation was identified at central sites and ST depression at peripheral sites, both increasing with TRP. In CRP-AM and CRP, the maximum negative slope of unipolar activation complexes was significantly depressed and activation-recovery intervals prolonged. Areas of inexcitability as well as irregular isocontour patterns displaying localized activation-recovery intervals shortening and gradients >20 ms between neighboring sites were identified in one-third of CRP-AM at slow rate, with increasing incidence and magnitude in response to TRP. In CRP-AM, programmed stimulation-induced marked conduction delay and block as well as polymorphic ventricular tachycardias, which stabilized into monomorphic tachycardias with the use of lidocaine or procainamide. Whole cell Na(+) current and channel protein expression were reduced in CRP-AM and CRP. Despite complete constrictor closure, small areas of necrosis were detected in a minority of CRP-AM. Long-term electrical alterations and their exacerbation by TRP contribute to arrhythmia formation in collateral-dependent myocardium subjected to chronic tachycardic stress.

Concurrent exercise prevents high-fat-diet-induced macrovesicular hepatic steatosis.

The purpose of the present study was to assess the effect of an exercise training program conducted concurrently with a high-fat (HF)-diet regimen on the induction of hepatic steatosis. Two groups of rats were fed either a standard (SD) or a HF (40% kcal) diet for 8 wk and were additionally assigned either to a sedentary (Sed) or a treadmill-trained (TR) group. Training (5 days/wk) was initiated at the same time as the HF diet and was progressively increased, reaching 60 min at 26 m/min, 10% grade, for the last 4 wk. At the end of the 8-wk period, HF-Sed rats exhibited approximately 72% higher liver triacylglycerol concentration than SD-Sed rats (means +/- SE: 17.15 +/- 1.5 vs. 9.98 +/- 1.0 mg/g; P < 0.01). Histological quantification of lipid infiltration, with the use of an image analysis computing system, revealed that, although fat was mainly stored as microvesicles (<1 microm(2)), the HF-diet-induced hepatic steatosis occurred via the accumulation of macrovesicles (>1 microm(2)). Concurrent exercise training completely prevented the HF-diet-induced hepatic steatosis. The surface area of liver parenchyma infiltrated by lipid vacuoles was similar in HF-TR as in SD-Sed rats (26.4 +/- 1.8 vs. 29.3 +/- 5.9 x 10(3) microm(2)/200,000 microm(2) of liver parenchyma, respectively; P > 0.05). The different states of liver lipid infiltration after the HF diet in Sed and TR rats were associated with similar changes in plasma free fatty acids and glycerol, as well as with similar changes in fat pad weights, but not with plasma triacylglycerol levels. It is concluded that, after a HF-diet regimen of 8 wk in rats, hepatic steatosis occurs primarily via the accumulation of lipid as macrovesicles. Exercise training pursued at the same time completely prevents the HF-diet-induced macrovesicular hepatic steatosis.