Attenuation of conducted vasodilation in skeletal muscle arterioles during hyperhomocysteinemia.

BACKGROUND: Vasomotor responses conducted from terminal arterioles to proximal vessels may contribute to match tissue demands and blood supply during skeletal muscle contraction. Conduction of vasodilatation (CVD) from distal resistance arterioles to the proximal arterioles and feeding arteries during metabolic demand is mediated by intercellular gap junctions in the vascular endothelium. The role of hyperhomocysteinemia (HHcy) in the musculoskeletal system during CVD is unclear. We hypothesize that during HHcy, there is impaired CVD due to decreased expression of endothelial-associated connexins and thus decreased tissue perfusion to the contracting skeletal muscles. METHODS: CVD studies were performed in a gluteus maximus muscle preparation of wild-type (C57BL6/J) and CBS-/+ (HHcy) mice using intravital microscopy. Expression of connexins and myostatin protein (an antiskeletal muscle statin) was studied by Western blot and immunohistochemistry methods. Tissue perfusion to acetylcholine was assessed by the laser Doppler technique. RESULTS: There was decreased CVD and tissue perfusion in response to acetylcholine in CBS-/+ mice compared to wild-type controls. There was decreased expression of connexins 37, 40 and 43 and increased expression of myostatin in CBS-/+ mice compared to wild-type controls. CONCLUSION: Our findings suggest that CVD in skeletal muscle is decreased during HHcy due to decreased expression of gap junction connexins.

TIMP-2 mutant decreases MMP-2 activity and augments pressure overload induced LV dysfunction and heart failure.

Pressure overload induces cardiac extracellular matrix (ECM) remodelling and results in heart failure. ECM remodelling by matrix metalloproteinases (MMPs) is primarily regulated by their target inhibitors, tissue inhibitor of matrix metalloproteinases (TIMPs). It is known that TIMP-2 is highly expressed in myocardium and is required for cell surface activation of pro-MMP-2. We and others have reported that imbalance between angiogenic growth factors and anti-angiogenic factors results in transition from compensatory cardiac hypertrophy to heart failure. We previously reported the pro-angiogenic role of MMP-2 in cardiac compensation, however, the specific role of TIMP-2 during pressure overload is yet unclear. We hypothesize that genetic ablation of TIMP-2 exacerbates the adverse cardiac matrix remodelling due to lack of pro-angiogenic MMP-2 and increase in anti-angiogenic factors during pressure overload stress and results in severe heart failure. To verify this, ascending aortic banding (AB) was created to mimic pressure overload, in wild type C57BL6/J and TIMP-2-/- (model of MMP-2 deficiency) mice. Left ventricular (LV) function assessed by echocardiography and pressure-volume loop studies showed severe LV dysfunction in TIMP-2-/- AB mice compared to controls. Expression of MMP-2, vascular endothelial growth factor (VEGF) was decreased and expression of MMP-9, anti-angiogenic factors endostatin and angiostatin was increased in TIMP-2-/- AB mice compared with wild type AB mice. Connexins (Cx) are the gap junction proteins that are widely present in the myocardium and play an important role in endothelial-myocyte coupling. Our results showed that expression of Cx 37 and 43 was decreased in TIMP-2-/- AB mice compared with corresponding wild type controls. These results suggest that genetic ablation of TIMP-2 decrease the expression of pro-angiogenic MMP-2, VEGF and increases anti-angiogenic factors that results in exacerbated abnormal ventricular remodelling leading to severe heart failure.

A correlative study comparing current different methods of calculating left ventricular ejection fraction.

BACKGROUND: Left ventricular ejection fraction (EF) is a major determinant of survival in patients with coronary artery disease (CAD). Comparative accuracy of numerous modalities in calculating EF is not well investigated. METHOD: We compared EF as calculated by rest and post-stress Cedars automated quantitative gated SPECT (AQGS), rest and post-stress semi-automatically processed gated SPECT (MQGS), echocardiography and contrast ventriculography (LVG) to those determined by rest and post-stress cavity-to-myocardium ratio (CMR) in 109 patients. Gated SPECT was performed based on a 2-day protocol using Tc-MIBI. RESULTS: Mean EF in LVG, echo, post-stress CMR, rest CMR, post-stress AQGS, rest AQGS, post-stress MQGS and rest MQGS were 41.8%+/-12.1, 44.8%+/-11.8, 38.1%+/-10.7, 35.7%+/-12.1, 44.5%+/-15.1, 46.9%+/-14.7, 40.1%+/-14.3 and 43.5%+/-14.3 respectively. Although significant differences were observed between some of these methods, good and excellent linear correlations were present among values (all Pearson correlations >0.63). Considering LVG as the 'gold standard', we defined two groups: EF <35% (class 1) and >35% (class 2). Discriminant analysis showed that SPECT has the ability to predict patients' classes. In 4/18 of patients with normal SPECT (on both visual and quantitative analyses, SSS <4), EF on QGS showed a significant decrease on post-stress compared with rest. CONCLUSION: There is a good correlation in calculating EF by LVG, QGS and echocardiography, regardless of EF value. Whenever QGS is impossible, CMR is a reliable indirect indicator of EF. Gating of both phases (and when impossible, CMR of both phases) has an additional value in diagnosis of CAD.