Cardiomyocyte Proliferation from Fetal- to Adult- and from Normal- to Hypertrophy and Failing Hearts.

The cardiomyocyte undergoes dramatic changes in structure, metabolism, and function from the early fetal stage of hyperplastic cell growth, through birth and the conversion to hypertrophic cell growth, continuing to the adult stage and responding to various forms of stress on the myocardium, often leading to myocardial failure. The fetal cell with incompletely formed sarcomeres and other cellular and extracellular components is actively undergoing mitosis, organelle dispersion, and formation of daughter cells. In the first few days of neonatal life, the heart is able to repair fully from injury, but not after conversion to hypertrophic growth.

Turning back the clock: A concise viewpoint of cardiomyocyte cell cycle activation for myocardial regeneration and repair.

Patients with acute myocardial infarction (MI) could progress to end-stage congestive heart failure, which is one of the most significant problems in public health. From the molecular and cellular perspective, heart failure often results from the loss of cardiomyocytes-the fundamental contractile unit of the heart-and the damage caused by myocardial injury in adult mammals cannot be repaired, in part because mammalian cardiomyocytes undergo cell-cycle arrest during the early perinatal period. However, recent studies in the hearts of neonatal small and large mammals suggest that the onset of cardiomyocyte cell-cycle arrest can be reversed, which may lead to the development of entirely new strategies for the treatment of heart failure.

Changes in Cardiomyocyte Cell Cycle and Hypertrophic Growth During Fetal to Adult in Mammals.

The failure of adult cardiomyocytes to reproduce themselves to repair an injury results in the development of severe cardiac disability leading to death in many cases. The quest for an understanding of the inability of cardiac myocytes to repair an injury has been ongoing for decades with the identification of various factors which have a temporary effect on cell-cycle activity. Fetal cardiac myocytes are continuously replicating until the time that the developing fetus reaches a stage of maturity sufficient for postnatal life around the time of birth.

Mechanisms of increased vascular stiffness down the aortic tree in aging, premenopausal female monkeys.

Protection against increased vascular stiffness in young women is lost after menopause. However, little is known about vascular stiffness in older, premenopausal females, because most of the prior work has been conducted in rodents, which live for only 1-3 yr and do not go through menopause. The goal of the current investigation was to quantitate differences in stiffness down the aortic tree and the mechanisms mediating those differences in older, premenopausal (24 ± 0.

Extracellular Matrix Disarray as a Mechanism for Greater Abdominal Versus Thoracic Aortic Stiffness With Aging in Primates.

Objective: Increased vascular stiffness is central to the pathophysiology of aging, hypertension, diabetes mellitus, and atherosclerosis. However, relatively few studies have examined vascular stiffness in both the thoracic and the abdominal aorta with aging, despite major differences in anatomy, embryological origin, and relation to aortic aneurysm.

Approach And Results: The 2 other unique features of this study were (1) to study young (9±1 years) and old (26±1 years) male monkeys and (2) to study direct and continuous measurements of aortic pressure and thoracic and abdominal aortic diameters in conscious monkeys.

'Reduced malignancy as a mechanism for longevity in mice with adenylyl cyclase type 5 disruption'.

Disruption of adenylyl cyclase type 5 (AC5) knockout (KO) is a novel model for longevity. Because malignancy is a major cause of death and reduced lifespan in mice, the goal of this investigation was to examine the role of AC5KO in protecting against cancer. There have been numerous discoveries in genetically engineered mice over the past several decades, but few have been translated to the bedside.

Interaction between bradykinin subtype 2 and angiotensin II type 2 receptors during post-MI left ventricular remodeling.

Angiotensin II type 2 receptor (AT(2)R) overexpression (AT(2)TG) attenuates left ventricular remodeling in a mouse model of anterior myocardial infarction (MI). We hypothesized that the beneficial effects of cardiac AT(2)TG are mediated via the bradykinin subtype 2 receptor (B(2)R). Fourteen transgenic mice overexpressing the AT(2)R (AT(2)TG mice), 10 mice with a B(2)R deletion (B(2)KO mice), 13 AT(2)TG mice with B(2)R deletion (AT(2)TG/B(2)KO mice), and 11 wild-type (WT) mice were studied.

Interaction between AT1 and AT2 receptors during postinfarction left ventricular remodeling.

The relative contribution of the angiotensin II type 1 and 2 receptors (AT1-R and AT2-R) in postmyocardial infarction (MI) remodeling remains incompletely understood. We studied five groups of C57Bl/6 mice after 1 h of left anterior descending artery occlusion-reperfusion: 1) wild type, untreated (n = 12); 2) wild type, treated with the AT1-R blocker losartan (10-20 mg.kg(-1).

Contributions of Purkinje-myocardial coupling to suppression and facilitation of early afterdepolarization-induced triggered activity.

Electrical loading by ventricular myocardium modulates conduction system repolarization near Purkinje-ventricular junctions (PVJs). We investigated how that loading suppresses and facilitates early afterdepolarizations (EADs) under conditions where there is a high degree of functional coupling between tissue types, which is consistent with the anatomic arrangement at the peripheral conduction system-myocardial interface. Experiments were completed in eight rabbit right ventricular (RV) free wall preparations.

The angiotensin II type 2 receptor and improved adjacent region function post-MI.

Angiotensin II type 2 receptor (AT2-R) overexpression in the mouse heart preserves left ventricular (LV) size and global LV function during post-MI remodeling. We hypothesized that CMR tagging would localize regional improvements in myocardial function during post-MI remodeling in AT2-R cardiac overexpressed transgenic mice (TG), which could explain the preservation of global LV function post-MI. Six male wild-type (WT) C57BL/6 mice and 10 TG mice were studied by CMR at baseline (day 0) and days 1, 7, and 28 post-MI.

Nitric oxide mediates benefits of angiotensin II type 2 receptor overexpression during post-infarct remodeling.

We hypothesized that nitric oxide (NO) mediates the benefits of cardiac angiotensin II type 2 (AT(2)-R) overexpression during postmyocardial infarction (post-MI) remodeling. Eleven wild-type (WT) C57BL/6 mice and 28 transgenic (TG) mice with AT(2)-R overexpression were studied by cardiac magnetic resonance imaging (CMR) at baseline and days 1 and 28 post-MI induced by left anterior descending artery occlusion and reperfusion. Sixteen TG mice were treated from day 1 through 28 post-MI with the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester in drinking water at 1 mg/mL (TG-Rx).

Adding angiotensin II type 1 receptor blockade to angiotensin-converting enzyme inhibition limits myocyte remodeling after myocardial infarction.

Background: Adding angiotensin II type 1 receptor blockade (ARB) to angiotensin-converting enzyme inhibition (ACEI) further attenuates left ventricular (LV) remodeling in an ovine model of myocardial infarction (MI). We hypothesized that combined therapy with ACEI and ARB (CT) would be additive in the limitation of the myocyte hypertrophy and dysfunction that occurs in untreated adjacent noninfarcted regions during remodeling.

Methods And Results: Nineteen sheep underwent coronary ligation to create a moderate-sized anteroapical infarction.

Accelerated cardiomyopathy in mice with overexpression of cardiac G(s)alpha and a missense mutation in the alpha-myosin heavy chain.

Background: To understand further the pathogenesis of familial hypertrophic cardiomyopathy, we determined how the cardiomyopathy induced by an Arg403-->Gln missense mutation in the alpha-myosin heavy chain (403) is affected by chronically enhancing sympathetic drive by mating the mice with those overexpressing G(s)alpha (G(s)alpha x403).

Methods And Results: Heart rate in 3-month-old conscious mice was elevated similarly (P<0.05) in mice overexpressing G(s)alpha (G(s)alpha mice; 746 +/- 14 bpm) and G(s)alpha x403 mice (718+/- 19 bpm) compared with littermate wild-type mice (WT; 623+/- 18 bpm) and 403 mice (594+/- 16 bpm).

Altered excitation-contraction coupling in myocytes from remodeled myocardium after chronic myocardial infarction.

Following myocardial infarction (MI), the left ventricle undergoes progressive dilatation and eccentric hypertrophy, i.e., remodeling, which is greater in the adjacent than the remote region.

Downregulation of ANG II receptor is associated with compensated pressure-overload hypertrophy in the young dog.

We studied the gradual onset of pressure overload (PO) induced by a mildly constricting aortic band in 8-wk-old puppies (n = 8) that increased to 98 +/- 11 mmHg at 9 mo. Left ventricular (LV) weight/body weight was increased in PO versus sham-operated littermate controls [8.11 +/- 0.