Hypertrophy cardiac

PREDICTIVE CARDIAC HYPERTROPHY BIOMARKERS IN NONCLINICAL STUDIES 

Chronic hypertension, such as during obesity or in neurohormonal imbalances (Crowley et al., 2006), results in increased pressure in the aorta (pressure overload). The aortic valve opens at the start of systole and blood is forced from the LV into the aorta as the heart contracts as a result of higher pressure in the ventricle than the aorta. When the aortic valve closes at the end of systole, the remaining volume of blood in the LV is known as end-systolic volume (ESV). The resistance to blood flow from the LV is a result of pressure in the aorta and is known as afterload. When afterload is increased as a result of hypertension, the amount of blood ejected from the LV with each contraction, or stroke volume (S V=EDV - ESV), is reduced and ESV is increased, increasing wall stress and resulting in concentric hypertrophy of the LV. 

In both previously mentioned examples, a fundamental property of the myocardium, described by the Frank-Starting mechanism, comes into play. The Frank-Starling mechanism holds that the force of contraction generated by the heart is increased as the amount of blood filling the LV is increased and the myocardium is stretched (Moss and Fitzsimons, 2002 Vincent, 2008). In the example of valvular 

PURPOSE AND RATIONALE Measurement of cardiac function and morphology is a key part of the preclinical evaluation of experimental medicinal compounds. Blood pressure, heart rate, and electrocardiogram evaluation are part of the core portfolio of safety pharmacology studies carried out in conscious telemetry dogs. If results from the core battery of tests raise concern then supplemental studies are conducted to measure endpoints such as left ventricular pressure, pulmonary arterial pressure, heart rate variability, baroreflex, cardiac output, ventricular contractility and vascular resistance. However, many 

Frames corresponding to end diastole and end systole are identified from each cine sequence and regions-of-interest (ROI) drawn around the left ventricular (LV) epi- and endocardial borders using ParaVision software (Bruker). The area of the ROIs is summed and multiplied by the inter-slice distance (5 mm) to calculate the end diastolic and end systolic volumes (EDV and ESV) of the whole ventricle and lumen. Other cardiac parameters are calculated as follows  

Left ventricle myocardial mass at end systole is calculated as  

Left ventricle myocardial wall thickness in diastole is calculated from the epi- and endocardial areas at the slice where the epicardial area is maximum as follows  

Alternatives to MRI include echo cardiography to measure LV wall thickness, lumen volume and cardiac output (Coatney 2001 Collins et al. 2003 de Simone et al. 1990 Zhou et al. 2004), dye-dilution techniques such as bolus thermodilution to measure cardiac output (Siren et al. 1990), and implanted pressure transducers and flow probes to measure left ventricular pressure 

In general, the hypertrophied heart seems to be more susceptible to the deleterious effects of ischemia and reperfusion (reviewed by Friehs and Del Nido200). This may be attributed to alterations in myocardial energy metabolism and calcium handling or to anatomic and functional abnormalities of the coronary bed, such as reduced capillary density and coronary flow reserve. 

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ACE inhibitors inhibit the degradation of bradykinin and potentiate the effects of bradykinin by about 50-100-fold. The prevention of bradykinin degradation by ACE inhibitors is particularly protective for the heart. Increased bradykinin levels prevent postischemic reperfusion arrhythmia, delays manifestations of cardiac ischemia, prevents platelet aggregation, and probably also reduces the degree of arteriosclerosis and the development of cardiac hypertrophy. The role of bradykinin and bradykinin-induced NO release for the improvement of cardiac functions by converting enzyme inhibitors has been demonstrated convincingly with use of a specific bradykinin receptor antagonist and inhibitors of NO-synthase. 

ACE inhibitors are approved for the treatment of hypertension and cardiac failure [5]. For cardiac failure, many studies have demonstrated increased survival rates independently of the initial degree of failure. They effectively decrease work load of the heart as well as cardiac hypertrophy and relieve the patients symptoms. In contrast to previous assumptions, ACE inhibitors do not inhibit aldosterone production on a long-term scale sufficiently. Correspondingly, additional inhibition of aldosterone effects significantly reduces cardiac failure and increases survival even further in patients already receiving diuretics and ACE inhibitors. This can be achieved by coadministration of spironolactone, which inhibits binding of aldosterone to its receptor. 

Calcineurin is involved in cardiac hypertrophy and in cognitive and behavioral defects in the brain. Inhibitors of calcineurin such as cyclosporine A and FK 506 are used clinically in transplant rejection and autoimmune diseases. 

Cardiac hypertrophy appears to be mediated by HS proteins (Izumo et al., 1988). Cardiac myocytes exposed to a hemodynamic stress have been found to increase their levels of heat shock proteins (Delcayre et al., 1988). Although experiments involving interference with HS protein synthesis were not done in these studies. 

Calcineurin Cytosol A calmodulin-regulated protein phosphatase. May play important roles in cardiac hypertrophy and in regulating amounts of slow and fast twitch muscles. 

In the setting of a sustained loss of myocardium, a number of mechanisms aid the heart when faced with an increased hemodynamic burden and reduced CO. They include the following the Frank-Starling mechanism, tachycardia and increased afterload, and cardiac hypertrophy and remodeling (Table 3-2).5,7... 

Friddle CJ et al. Expression profiling reveals distinct sets of genes altered during induction and regression of cardiac hypertrophy. Proc Natl Acad Sci USA 2000 97 6745-6750. 

Arnott D et al. An integrated approach to proteome analysis identification of proteins associated with cardiac hypertrophy. Anal Biochem 1998 258 1-18. 

Perry GJ, Tatsuhiko M, Wei C-C, Xu XY, Chen Y-F, Oparil S, Lucchesi P, Dell Italia LJ. Genetic variation in angiotensin-converting enzyme does not prevent development of cardiac hypertrophy or upregulation of angiotensin 11 in response to aortocaval fistula. Circulation 2001 103 1012-1016. 

ACE inhibitors (Table 8-2) decrease angiotensin II and aldosterone, attenuating many of their deleterious effects, including reducing ventricular remodeling, myocardial fibrosis, myocyte apoptosis, cardiac hypertrophy, norepinephrine release, vasoconstriction, and sodium and water retention. 

ARNOTT, D., O CONNELL, K.L., KING, K.L., STULTS, J.T., An integrated approach to proteome analysis Identification of proteins associated with cardiac hypertrophy, Anal. Biochem., 1998,258, 1-18. 

Angiotensin-II AT, Human cDNA Artherosderosis, cardiac hypertrophy, congestive heart failure, hypertension, myocardial infarction, renal disease, cancer, diabetes, obesity, glaucoma, cystic fibrosis, Alzheimer s disease, Parkinson s disease Smooth muscle contraction, cell proliferation and migration, aldosterone and ADH release, central and peripheral sympathetic stimulation, extracellular matrix formation, tubular sodium retention, neuroprotection... 

Norepinephrine NE transporter Human cDNA Depression, Alzheimer s disease, epilepsy, anxiety, attention deficit hyperactivity, angina, asthma, cardiac arrhythmia, cardiac hypertrophy, congestive heart failure, myocardial ischemia, hypertension, artherosclerosis, narcolepsy, orthostatic hypotension, prostatic hyperplasia, rhinitis, diabetes, diarrhea, glaucoma, impotence, obesity, opiate withdrawal pain, Raynaud s disease, preterm labor pain Modulation of norepinephrine concentration in the neuronal synaptic clefts, neuroprotection... 

Aberrant acetylation levels of non histone proteins not only lead to the dysfunction of these proteins but also cause disturbances in cellular processes thereby leading to several diseases (Fig. 3). There are several reports of aberrant acetylation in diseases like cancer, diabetes, cardiac hypertrophy and viral diseases. 

Apart from this HDACs are also associated with a number of other epigenetic repression mechanisms including histone methylation, polycomb group of proteins and DNA methylation (discussed later). The class II HDACs have been found to be involved in muscle development, particularly HDAC 5 and 9 knockouts or mutants show evidence of cardiac hypertrophy in a age or stress dependent manner (Zhang et al, 2002 Chang et al, 2004). 

Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN (2002) Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110 479 88... 

OTHER DISEASES ASTHMA, CARDIAC HYPERTROPHY, HUNTINGTON S DISEASE etc. 

In patients with cardiac hypertrophy, this situation reverses to some extent. In the failing heart glucose oxidation increases, and p-oxidation falls. 

The observations above have led to speciilation that HDAC inhibitors may cause cardiac hypertrophy. Surprisingly however, it was observed that HDAC inhibitors may actually be beneficial in treating cardiac hypertrophy. TSA has... 

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