Myocyte cellular hypertrophy is responsible for ventricular remodelling in the hypertrophied heart of middle aged individuals in the absence of cardiac failure.

Objective: The aim was to measure changes in the numbers and size of ventricular myocytes in human hearts with marked ventricular hypertrophy and no clear signs of cardiac failure, to determine whether myocyte cellular hypertrophy is the only factor involved in the increase in cardiac mass.

Methods: Morphometric techniques were applied to estimate the number of myocyte nuclei per unit volume of myocardium which, in combination with the determination of the volume percent of myocytes, allowed the computation of the average myocyte cell volume per nucleus and total number of myocyte nuclei in the ventricles. Subsequently, the volume fraction of replacement fibrosis in the tissue was assessed and absolute component volumes in the ventricles obtained.

Acute myocardial infarction leads to upregulation of the IGF-1 autocrine system, DNA replication, and nuclear mitotic division in the remaining viable cardiac myocytes.

Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are required for cell proliferation in vitro, raising the possibility that an autocrine IGF-1-IGF-1R system may be present in vivo and become activated in the viable ventricular myocytes shortly after infarction. Therefore, following the in vivo documentation of left ventricular failure in rats subjected to occlusion of the left coronary artery, the unaffected myocytes of the left ventricle were enzymatically dissociated and the expression of IGF-1R and IGF-1 mRNAs were measured at 12 h and at 1, 2-3, and 7 days after surgery. The level of expression of IGF-1R mRNA increased at 12 h and remained elevated at 1 and 2-3 days following coronary ligation.

Myocyte nuclear and possible cellular hyperplasia contribute to ventricular remodeling in the hypertrophic senescent heart in humans.

Objectives: The present investigation was designed to evaluate the growth reserve capacity of the aged and senescent myocardium.

Background: Aging affects the ability of the heart to sustain alterations in ventricular loading, and this phenomenon may be coupled with attenuation of the hypertrophic reaction of the myocardium. However, because myocyte cellular hyperplasia has been documented experimentally in the old heart, a similar adaptation may also occur in humans and play a role in this process.

Coronary artery constriction in rats affects the activation of alpha 1 adrenergic receptors in cardiac myocytes.

Objective: To determine whether alpha 1 adrenergic receptor mediated myocyte contractility and growth are depressed acutely after non-occlusive coronary artery narrowing, the left coronary artery was constricted in rats and mechanical behaviour, cytosolic calcium, and regulation of alpha 1 adrenergic receptors were examined in myocytes seven days later.

Methods: Coronary artery stenosis was surgically induced in rats and following the estimation of global cardiac performance myocytes were enzymatically dissociated and radioligand binding studies were performed. In addition, the isotonic contractile performance, cytosolic calcium transients and noradrenaline stimulated inositol phosphate generation in myocytes were measured in the presence of WB 4101 or after chlorethylclonidine treatment.

Efficacy of angiotensin-converting enzyme inhibition and AT1 receptor blockade on cardiac pump performance after myocardial infarction in rats.

To determine whether cardiac unloading by inhibition of angiotensin I (AI) to AII conversion by captopril or blockade of the AII receptor (AT1) by losartan was more effective in prevention of the detrimental hemodynamic consequences of myocardial infarction (MI), inhibition of metabolic production of AII by captopril was compared with blockade of AT1 with losartan in Sprague-Dawley rats with large MI. Infarcts were created by surgical occlusion of the left main coronary artery and oral drug therapy initiated immediately and continued until hemodynamic evaluation seven days later. Heart weight was unchanged in untreated infarcted animals, whereas captopril reduced heart weight in control animals and losartan increased heart weight in infarcted animals.

Myocyte cellular hyperplasia and myocyte cellular hypertrophy contribute to chronic ventricular remodeling in coronary artery narrowing-induced cardiomyopathy in rats.

To determine whether cardiac failure produced by chronic coronary artery stenosis was associated with the activation of myocyte cellular hyperplasia in the myocardium, the changes in number and size of left ventricular myocytes were measured in rats 3 months after surgery. The hypertrophied left ventricle was found to possess 44%, 32%, 49%, and 48% fewer mononucleated, binucleated, trinucleated, and tetranucleated myocytes, respectively. In contrast, the hypertrophied right ventricle contained 1.

Length-dependent modulation of ANG II inotropism in rat myocardium: effects of myocardial infarction.

To determine whether changes in sarcomere length affect the inotropic response of the heart to angiotensin II (ANG II) differently in dilated and failing myocardium, papillary muscles were removed 2 days after infarction, and the effects of ANG II were studied at various muscle lengths. Myocardial infarction, which averaged 52% of the left ventricle inclusive of the interventricular septum, was characterized hemodynamically by left ventricular failure and right ventricular dysfunction. ANG II administration at 100% the muscle length where force development is maximal (Lmax) produced a 12% depression of developed tension in papillary muscles from noninfarcted ventricles and a 37% decrease in developed tension in the viable myocardium of infarcted rats.

Structural basis of end-stage failure in ischemic cardiomyopathy in humans.

Background: Ischemic cardiomyopathy is characterized by myocyte loss, reactive cellular hypertrophy, and ventricular scarring. However, the relative contribution of these tissue and cellular processes to late failure remains to be determined.

Methods And Results: Ten hearts were obtained from individuals undergoing cardiac transplantation as a result of chronic coronary artery disease in its terminal stage.

Upregulation of IGF1, IGF1-receptor, and late growth related genes in ventricular myocytes acutely after infarction in rats.

To determine the effects of acute myocardial infarction on the expression of insulin-like growth factor1 (IGF1) and insulin-like growth factor1 receptors (IGF-1R) on the surviving myocytes of the left and right ventricles, large infarcts were produced in rats and the animals sacrificed 2 days later. Hemodynamic measurements of left and right ventricular pressures, +dP/dt and -dP/dt, and central venous pressure documented that coronary occlusion was associated with a severe impairment of cardiac function. By employing reverse transcriptase polymerase chain reaction (RTPCR), a low level of expression of IGF-1R mRNA was detected in myocytes from sham-operated rats.

Cytosolic calcium transients in myocytes isolated from rats with ischemic heart failure.

Mechanical performance and cytosolic Ca2+ dynamics were characterized in myocytes isolated from left and right ventricles of rats with ischemic heart failure. Seven days after coronary artery narrowing (CAN) in rats filling pressures were elevated, whereas systolic pressures and ejection of blood were depressed. Left ventricular myocytes increased 18% in length and 19% in width, whereas right myocytes expanded longitudinally by 23% and transversely by 24%.

Effects of hypertension and coronary constriction on cardiac function, morphology, and contractile proteins in rats.

In an attempt to elucidate the effects of two major risk factors of heart failure in humans, high blood pressure and coronary artery disease, renal hypertension and coronary artery constriction were induced singularly and in combination in rats, and the functional, structural, and biochemical alterations of the myocardium were examined 12-13 wk later. Renal hypertension (RH), coronary narrowing (CN), and their association (NH) resulted in left ventricular failure demonstrated by a significant increase in left ventricular end-diastolic pressure, a decrease in +dP/dt and -dP/dt, and a reduction in stroke volume and cardiac output. Measurements of ventricular loading documented that RH was characterized by elevations in systolic and diastolic wall stress of 42 and 160%, respectively.

Impairment of myocyte contractility following coronary artery narrowing is associated with activation of the myocyte IGF1 autocrine system, enhanced expression of late growth related genes, DNA synthesis, and myocyte nuclear mitotic division in rats.

To determine whether the alterations in ventricular loading and myocyte cellular contractile performance produced by short-term coronary artery constriction were associated with the activation of genes implicated in myocyte DNA synthesis including changes in the expression of insulin-like growth factor-1 (IGF1) and insulin-like growth factor-1 receptors (IGF1-R), nonocclusive coronary artery narrowing (CAN) was induced in rats. Animals were examined 2 and 7 days after coronary constriction. Following the in vivo documentation of severe impairment of ventricular performance, estimations of single-cell mechanics in vitro showed that peak shortening was decreased in left and right myocytes of coronary stenosed rats.

Effects of genetic hypertension and nutritional anaemia on ventricular remodelling and myocardial damage in rats.

Objective: In order to determine whether alterations in cardiac function and structure occur early in life in spontaneously hypertensive rats (SHR) and whether the addition of a volume load would affect myocardial growth and haemodynamic performance, SHR were exposed to an iron and copper deficient diet for 12 weeks (SHR-A) and compared with untreated SHR and Wistar Kyoto controls (WKY).

Results: Systolic arterial blood pressure increased in SHR, whereas nutritional anaemia prevented the rise of blood pressure in SHR-A. The diet employed provoked a severe hypochromic microcytic anaemia with a marked reduction in blood viscosity and increased volume load on the heart in SHR-A.

Regulation of angiotensin II receptors on ventricular myocytes after myocardial infarction in rats.

To determine the effects of acute myocardial infarction on the regulation of angiotensin II (Ang II) receptors and contractile performance of left and right ventricular myocytes, coronary artery ligation was surgically induced in rats, and Ang II receptor density and affinity and the mechanical properties of surviving muscle cells were examined 1 week later. Physiological determinations of cardiac pump function revealed the presence of ventricular failure, which was associated at the cellular level with a depression in the velocity of myocyte shortening and relengthening, a prolongation of time to peak shortening, and a reduction in the extent of cell shortening. These abnormalities in single-cell function were more prominent in left than in right ventricular myocytes.

Myocyte DNA synthesis with aging: correlation with ventricular loading in rats.

To determine whether the detrimental mechanical and anatomical changes that occur biventricularly with aging are associated with activation of DNA synthesis, flow cytometric analysis was performed on myocyte nuclei prepared from the left and right ventricles of rats at 4, 12, 20, and 29 months of age. Heart weight increased significantly with age, and this growth adaptation was associated with the development of left ventricular failure and right ventricular dysfunction. These phenomena were coupled with marked elevations in diastolic wall stress and increases in the percentage of myocyte nuclei in S+G2M in both ventricles.

Myocardial infarction, cardiac anatomy and ventricular loading.

To see whether the hypertrophic response of the surviving myocardium after infarction leads to a complete reconstitution of ventricular mass, the left coronary artery was ligated in rats and the animals killed one month later. In infarcts affecting an average of 38% of the free wall of the left ventricle, the ratio of wall thickness to chamber radius remained essentially constant. On the other hand, the ratio decreased significantly in the presence of infarcts involving an average of 60% of the ventricular wall.

Alterations in ANG II responsiveness in left and right myocardium after infarction-induced heart failure in rats.

To determine the effects of coronary arterial occlusion on the contractile response of the heart to angiotensin II (ANG II) administration, large infarcts were surgically induced in Sprague-Dawley rats at 2 mo of age. Forty-eight hours later, hearts from experimental animals presented a hemodynamic profile indicative of left ventricular failure and right ventricular dysfunction and revealed a loss of mass of 49.3 +/- 10.

Myocyte loss and left ventricular failure characterise the long term effects of coronary artery narrowing or renal hypertension in rats.

Objective: The aim was to determine the effects of chronic coronary artery narrowing and two kidney, one clip renal hypertension alone and in combination on ventricular function and myocardial morphology.

Methods: Left coronary stenosis and renal artery clipping were surgically induced in rats and pump dynamics, systolic and diastolic wall stress, cardiac anatomy, and the changes in number and size of left ventricular myocytes were examined 11-13 weeks later.

Results: Ventricular failure evolved with each intervention: left ventricular end diastolic pressure was raised, whereas +dP/dt, -dP/dt, stroke volume, cardiac output, and cardiac index were reduced.

Segmental calculation of left ventricular wall stresses.

A procedure for calculating left ventricular wall stresses segmentally was devised. Rectangular coordinates of the wall surfaces as seen in longitudinal section were plotted with the long axis as the x-axis. For each cavity point, a third-order polynomial (cubic spline) was fitted to the point together with several adjacent points on either side of it; the cavity radius (normal to cavity surface) at the point was found algebraically from the spline's coefficients.

Propionyl-L-carnitine limits chronic ventricular dilation after myocardial infarction in rats.

To determine whether propionyl-L-carnitine (PLC) administration ameliorates ventricular remodeling after myocardial infarction, we performed coronary occlusion in rats and examined the long-term effects of the drug 19-24 wk after surgery. In view of the well-established role of angiotensin-converting enzyme (ACE) inhibitors in the reduction of ventricular dilation after infarction, the therapeutic impact of oral PLC (60 mg/kg) was compared with that of enalapril (1 mg/kg). Infarct size measured planimetrically was found to be comparable in untreated, PLC-treated, and enalapril-treated rats, averaging 40-46% of the left ventricular free wall.

ANG II receptors, c-myc, and c-jun in myocytes after myocardial infarction and ventricular failure.

To determine the relationship between reactive cardiac hypertrophy and the expression of angiotensin II (ANG II) receptors in surviving myocytes after infarction, large infarcts were produced in rats that were killed 2-3 days later. Measurements of global ventricular dynamics indicated that left ventricular failure and right ventricular dysfunction occurred in experimental animals. These alterations in ventricular pump function were associated with increases in ventricular weight-to-body weight ratio, indicative of developing cardiac hypertrophy.

Ventricular loading is coupled with DNA synthesis in adult cardiac myocytes after acute and chronic myocardial infarction in rats.

To determine whether the overload associated with myocardial infarction and ventricular failure in rats is coupled with activation of DNA synthesis in the remaining left and right ventricular myocytes, flow cytometric analysis was performed on myocyte nuclei prepared from both ventricles 7 and 30 days after coronary occlusion. In addition, oral captopril was administered in separate groups of control and experimental rats to establish whether a relation existed between attenuation of ventricular loading and magnitude of DNA synthesis in myocytes. Results demonstrated that left ventricular failure and right ventricular dysfunction at 7 days after infarction were biventricularly associated with marked increases in the number of myocyte nuclei in the G2M phase of the cell cycle.

Cellular basis of ventricular remodeling in hypertensive cardiomyopathy.

This review summarizes the effects of long-term pressure overload hypertrophy on the right and left ventricular myocardium. In particular, the role that the fundamental processes of myocyte growth plays in the remodeling of the wall is analyzed quantitatively. Moreover, emphasis is placed on the observation that the duration of the overload is an important component of the onset, development, and progression of time-dependent myocardial dysfunction associated with hypertensive cardiomyopathy.