Angiotensin-Converting Enzyme Inhibitor Therapy Affects Left Ventricular Mass in Patients With Ejection Fraction >40% After Acute Myocardial Infarction

AbstractObjectives. We tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitor therapy decreases left ventricular (LV) mass in patients with a left ventricular ejection fraction (LVEF) >40% and no evidence of heart failure after their first acute Q wave myocardial infarction (MI).Background. Recently, ACE inhibitor therapy has been shown to have an early mortality benefit in unselected patients with acute MI, including patients without heart failure and a LVEF >35%. However, the effects on LV mass and volume in this patient population have not been studied.Methods. Thirty-five patients with a LVEF >40% after their first acute Q wave MI were randomized to titrated oral ramipril (n = 20) or conventional therapy (control, n = 15). Magnetic resonance imaging (MRI) performed an average of 7 days and 3 months after MI provided LV volumes and mass from summated serial short-axis slices.Results. Left ventricular end-diastolic volume index did not change in ramipril-treated patients (62 ± 16 [SD] to 66 ± 17 ml/m2) or in control patients (62 ± 16 to 68 ± 17 ml/m2), and stroke volume index increased significantly in both groups. However, LV mass index decreased in ramipril-treated patients (82 ± 18 to 73 ± 19 g/m2, p = 0.0002) but not in the control patients (77 ± 15 to 79 ± 23 g/m2). Systolic arterial pressure did not change in either group at 3-month follow-up.Conclusions. In patients with a LVEF >40% after acute MI, ramipril decreased LV mass, and blood pressure and LV function were unchanged after 3 months of therapy. Whether the decrease in mass represents a sustained effect that is associated with a decrease in morbid events requires further investigation.(J Am Coll Cardiol 1997;29:49–54)

Mitochondrial Genetic Background Modulates Bioenergetics and Susceptibility to Acute Cardiac Volume Overload

Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial–nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the ‘mitochondrial paradigm’ for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress

Hospitalizations Due to Unstable Angina Pectoris in Diastolic and Systolic Heart Failure

Patients with diastolic heart failure (HF) i.e. clinical HF with normal or near normal left ventricular ejection fraction (LVEF) may experience unstable angina pectoris (UAP) due to epicardial atherosclerotic coronary artery disease (CAD) and/or to subendocardial ischemia, even in the absence of CAD. However, the risk of UAP among ambulatory diastolic HF patients has not been well studied. We examined incident hospitalizations due to UAP among 916 diastolic HF (LVEF >45%) patients without significant valvular heart disease and 6800 systolic HF (LVEF ≤45%) patients in the Digitalis Investigation Group trial. During a 38-month median follow-up, 12% (797/6,800) of systolic HF patients (incidence rate, 435/10,000 person-years) and 15% (138/916) of diastolic HF patients (incidence rate, 536/10,000 person-years) were hospitalized for UAP (adjusted hazard ratio for diastolic HF, 1.22; 95% confidence interval, 1.02–1.47; p=0.032). There was a graded increase in incident hospital admissions for UAP with increasing LVEF. Hospitalizations for UAP occurred in 11% (520/4,808; incidence rate, 407/10,000 person-years), 14% (355/2556; incidence rate, 496/10,000 person-years) and 17% (60/352; incidence rate, 613/10,000 person-years) of HF patients, respectively, with LVEF 55%. Compared with HF patients with LVEF 55% were respectively 1.17 (1.02–1.34; p=0.028) and 1.57 (1.20–2.07; p=0.026). In conclusion, in ambulatory chronic HF patients, higher LVEF was associated with increased risk of hospitalizations due to UAP. As in patients with systolic HF, those with diastolic HF should be routinely evaluated for myocardial ischemia and managed accordingly

AKT-independent activation of p38 MAP kinase promotes vascular calcification

Vascular calcification is prevalent in patients with atherosclerosis, and oxidative stress promotes pathogenesis of atherosclerosis. We have previously reported that activation of AKT by oxidative stress induces vascular calcification. Using sodium dichloroacetate (DCA), a previously reported small molecule inhibitor of AKT, the present studies uncovered an AKT-independent mechanism in regulating vascular calcification.We found that DCA dose-dependently induced calcification of vascular smooth muscle cells (VSMC) in vitro and aortic rings ex vivo. Furthermore, DCA markedly enhanced vascular calcification in atherosclerotic ApoE knockout mice in vivo. DCA-induced VSMC calcification was associated with increased Runx2, but not via activation of AKT, a key upstream signal that upregulates Runx2 during VSMC calcification. In contrast, DCA inhibited AKT activation and induced activation of p38 MAPK in calcified atherosclerotic lesions in vivo and calcified VSMC in vitro. Using a pharmacological inhibitor and shRNA for p38 MAPK, we demonstrated that inhibition of p38 MAPK blocked DCA-induced Runx2 upregulation and VSMC calcification. Furthermore, Runx2 deletion attenuated DCA-induced VSMC calcification. Immunoprecipitation analysis revealed association of p38 MAPK with Runx2, which was enhanced by DCA treatment. Knockdown p38 MAPK inhibited DCA-induced Runx2 transactivity, supporting the function of p38 MAPK in regulating Runx2 transactivity.Our studies have uncovered a new function of DCA in regulating vascular calcification, via AKT-independent activation of p38 MAPK. Furthermore, we have identified novel interaction between p38 MAPK and Runx2 enhances Runx2 transactivity, thus promoting VSMC calcification. These results revealed a novel signaling mechanism underlying DCA-induced vascular calcification, and offer opportunities to identify new therapeutic targets. Keywords: Oxidative stress, Vascular calcification, P38 MAPK, AKT, Runx