Valsartan in the Treatment of Heart Attack Survivors

Survivors of myocardial infarction (MI) are at high risk of disability and death. This is due to infarct-related complications such as heart failure, cardiac remodeling with progressive ventricular dilation, dysfunction, and hypertrophy, and arrhythmias including ventricular and atrial fibrillation. Angiotensin (Ang) II, the major effector molecule of the renin–angiotensin–aldosterone system (RAAS) is a major contributor to these complications. RAAS inhibition, with angiotensin-converting enzyme (ACE) inhibitors were first shown to reduce mortality and morbidity after MI. Subsequently, angiotensin receptor blockers (ARBs), that produce more complete blockade of the effects of Ang II at the Ang II type 1 (AT1) receptor, were introduced and the ARB valsartan was shown to be as effective as an ACE inhibitor in reducing mortality and morbidity in high-risk post-MI suvivors with left ventricular (LV) systolic dysfunction and and/or heart failure and in heart failure patients, respectively, in two major trials (VALIANT and Val-HeFT). Both these trials used an ACE inhibitor as comparator on top of background therapy. Evidence favoring the use of valsartan for secondary prevention in post-MI survivors is reviewed

Clinical effectiveness of telmisartan alone or in combination therapy for controlling blood pressure and vascular risk in the elderly

Elderly patients (age ≥65 years) with hypertension are at high risk for vascular complications, especially when diabetes is present. Antihypertensive drugs that inhibit the renin-angiotensin system have been shown to be effective for controlling blood pressure in adult and elderly patients. Importantly, renin-angiotensin system inhibitors were shown to have benefits beyond their classic cardioprotective and vasculoprotective effects, including reducing the risk of new-onset diabetes and associated cardiovascular effects. The discovery that the renin-angiotensin system inhibitor and angiotensin II type 1 (AT1) receptor blocker (ARB), telmisartan, can selectively activate the peroxisome proliferator-activated receptor-γ (PPARγ, an established antidiabetic drug target) provides the unique opportunity to prevent and treat cardiovascular complications in high-risk elderly patients with hypertension and new-onset diabetes. Two large clinical trials, ONTARGET (Ongoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE-I iNtolerant subjects with cardiovascular disease) have assessed the cardioprotective and antidiabetic effects of telmisartan. The collective data suggest that telmisartan is a promising drug for controlling hypertension and reducing vascular risk in high-risk elderly patients with new-onset diabetes

Modification of left ventricular geometry and function during healing after acute myocardial infarction

Increased left ventricular (LV) size and deformation of LV geometry are associated with LV dysfunction. Regional shape distortion (RSD), detected on two-dimensional echocardiography (2D-Echo) after acute myocardial infarction (MI), is associated with poor outcome. Two hypotheses were tested: i) early RSD of the asynergic infarct zone after MI is followed by progressive global LV dilatation, remodelling towards a spheroidal shape, and more LV dysfunction; and ii) the progressive remodelling of LV geometry spans the phases of early infarction and healing and may be modified by early and prolonged therapies applied over the phases of infarction and healing. A bench to bedside approach was used, with concurrent studies in a dog model of healing over 6 weeks after MI and patients with first MI's. Computer- assisted analysis of the 2D-Echo images with 3D reconstruction was used to quantify LV asynergy (akinesis + dyskinesis), LV volumes, LV ejection fraction, RSD bulge and global LV shape. The animal studies showed that collagen deposition during healing after MI increases progressively, reaching a plateau around 2 weeks, and deposition of collagen in already dilated infarct zones is followed by late thinning and further RSD associated with LV aneurysms. Importantly, serial 2D-Echo tracked the in- vivo changes in LV geometry and function and showed greater RSD and LV dysfunction with anterior than inferior MI, and with transmural MI than nontransmural MI. Other studies showed: i) lower LV resistance to distension and rupture in infarcted hearts; ii) marked extracellular matrix (ECM) disruption and RSD in transmural MI; ill) delayed effects on LV remodelling after infarct-limiting therapies given during acute MI; iv) loss of beneficial effects of the vasodilator nitroglycerin (NTG) with hypotension induced by high doses during acute MI; v) decreased wall stress by prolonged LV unloading after MI, with nitrates (eccentric dosing) and angiotensin-converting enzyme (ACE) inhibitors, limited early RSD and progressive LV remodelling and dysfunction; this effect was greater with therapy over 6-weeks than just over the first 2 weeks; vi) late reperfusion limited early RSD and adverse LV remodelling, and preserved ECM in the epicardial rim; vii) the resistance of the healed left ventricle to distension and rupture was further reduced by prolonged anti-inflammatory therapy (ibuprofen); viii) prolonged ACE inhibitor therapy decreases infarct collagen, which may be harmful under certain conditions. The clinical studies with serial 2D-Echo showed that systematic tomographic imaging could provide quantitative data on regional and global LV geometry and function including the degree of RSD (depth, area, and volume). An early 2D-Echo not only provided diagnostic data on LV thrombi and complications of MI, but the extent of LV asynergy on the initial 2D-Echo predicted outcome at 3 months and 1 year. Importantly, the degree of RSD on the initial 2D-Echo predicted patients at high risk of adverse remodelling with infarct expansion, greater LV dysfunction, progressive LV dilatation, and poor outcome at 1 year. Survivors of MI with > 18% LV asynergy and significant RSD on a baseline 2D Echo were at increased risk of topographic deterioration on exercise programs. Anti-inflammatory therapy after MI resulted in more RSD and adverse remodelling. Short-term LV unloading with low-dose intravenous NTG therapy during the acute MI, as well as prolonged nitrate (eccentric dosing) and captopril therapy during healing over 6 weeks after MI, improved 2D-Echo indexes of LV geometry and function, decreased complications and improved outcome. Acute thrombolytic therapy also limited LV remodelling after MI. In all these studies, the degree of RSD and severity of LV dysfunction were greater with anterior than inferior MI, and with Q-wave than non-Q wave MI. In Conclusion, the overall results indicate that early RSD in the infarct zone leads to progressive global LV dilatation, LV dysfunction and poor outcome and the changes in LV geometry and function can be quantified by serial quantitative 2D-Echo imaging. Marked RSD is associated with early ECM disruption and aneurysm formation after transmural MI. During healing, infarct zones may be thinned and dilated before the collagen plateau, and collagen deposition into these zones result in further RSD and chronic aneurysms. Prolonged anti-remodelling therapy during healing, with agents that decrease wall stress without damaging the ECM, or decreasing infarct collagen, or causing infarct thinning, or impairing healing, might be more effective for reducing RSD, LV aneurysm, global dilatation and poor outcome. The 2D-Echo measurement of RSD early after MI might be potentially important for stratifying patients according to their topographic status and for the objective assessment of the effects of anti-remodelling strategies during healing after MI

Healing after myocardial infarction in the dog: Changes in infarct hydroxyproline and topography

Temporal changes in infarct collagen and left ventricular topography during healing after myocardial infarction were studied in 132 dogs with coronary artery ligation: 8 sham dogs and 13 with no infarction (controls) and 111 with infarction (3 at 1 day, 54 at 2 days, 25 at 7 days, 3 at 2 weeks, 9 at 4 weeks and 17 at 6 weeks). Myocardial hydroxyproline (a marker of collagen) was measured by spectrophotometry and pathologic infarct size, arteriographic occluded bed size and topography by computerized planimetry of weighed left ventricular rings. Over 6 weeks, hydroxyproline was unchanged in normal regions (average 4.20 mg/g dry weight) but increased progressively between 7 days and 6 weeks (9.94 versus 55.55 mg/g, p < 0.001) in infarct zones. Progressive infarct contraction occurred over 6 weeks, with infarct size at 6 weeks being 40% less than at 2 days (9.7 versus 16.3% of the left ventricle, p < 0.001), although total infarct hydroxyproline was directly related to infarct size at each time period (r = 0.73 to 0.81, p ≤ 0.05).Significant (p ≤ 0.05) left ventricular topographic changes in infarct hearts compared with control hearts included: 1) increase in cavity area (5.0 versus 3.9 cm2), endocardial circumference (8.8 versus 7.4 cm) and expansion index (infarct/normal endocardial segment length, 1.21 versus 1.02) by 7 days; and 2) decrease in thinning ratio (infarct/normal wall thickness, 0.71 versus 0.98) by 6 weeks. Also, compared with 2 day infarcts, by 6 weeks infarct area was decreased (1.8 versus 3.4 cm2) and the noninfarcted segment length increased (6.9 versus 5.4 cm). Changes in hydroxyproline and topography were similar for anterior (n = 54) and posterior (n = 57) infarcts.Thus, healing in canine infarcts is associated with cavity dilation and infarct expansion within 7 days followed by infarct contraction and thinning by 6 weeks, whereas collagen increases between 7 days and 6 weeks. Collagen deposition in expanded and thinned infarct segments explains the permanent regional shape distortion associated with ventricular aneurysms

Different Relations Between Infarct Size and Occluded Bed Size in Barbiturate-Anesthetized Versus Conscious Dogs

The relation between infarct size and occluded bed size in barbiturate-anesthetized (n = 32) and conscious (n = 34) dogs was compared using models of the left anterior descending (n = 43) and circumflex (n = 23) coronary arteries with 2 day old infarcts. Infarct and occluded bed (postmortem coronary arteriography) masses were measured by computerized planimetry of weighed left ventricular rings. For either type of occlusion, infarcts were larger in anesthetized than in conscious dogs (56 versus 33% occluded bed, p < 0.001), with greater slopes of the linear regressions between infarct size and occluded bed size (p < 0,001) and less epicardial sparing (p < 0.05) on topographic mapping. Although arterial and left atrial pressures were similar in the two groups, heart rates were higher in the anesthetized dogs, both before (127 versus 88 beats/min, p < 0.001) and after (151 versus 109 beats/min, p < 0.001) occlusion. Myocardial blood flow distribution (radioactive microspheres, n = 33) favored the epicardium in anesthetized dogs, with lower endocardial-epicardial flow ratios pre- and postocclusion. Also, the level of total plasma catecholamines (radioenzymatic assay) was higher in barbiturate-anesthetized (n = 5) than in conscious (n = 5) dogs. Increasing the heart rate in conscious dogs (n = 18) to that of the anesthetized group (139 beats/min) by pacing produced larger infarcts and greater linear regression slopes, as seen in anesthetized dogs. Decreasing the heart rate in anesthetized dogs (n = 7) to that of the conscious group (98 beats/min) by sinoatrial node destruction and pacing resulted in smaller infarcts and lower linear regression slope, as seen in conscious dogs. Thus, the larger infarcts in barbiturate-anesthetized dogs appeared to be related mainly to the tachycardia, although transmural maldistribution of flow and increased circulating catecholamines might have contributed

Functional impact of remodeling during healing after non-Q wave versus Q wave anterior myocardial infarction in the dog

AbstractObjectives. This study was undertaken to compare changes in left ventricular remodeling and function during healing after a first anterior non-Q wave versus a Q wave myocardial infarction in the dog.Background. Whether ventricular remodeling is more severe after anterior Q wave than after anterior non-Q wave infarction has not been studied systematically.Methods. Serial remodeling and functional variables (two-dimensional echocardiography), electrocardiography and hemodynamic data were recorded over 6 weeks in 58 instrumented dogs subjected to left anterior descending coronary artery ligation or ligation plus collateral obliteration. Postmortem topography and transmurality (by planimetry) and infarct collagen (hydroxyproline) were measured at 6 weeks.Results. At 6 weeks, infarct collagen was similarly increased in both groups, but the Q wave group had greater infarct size (7.2% vs. 4.5%, p < 0.025) and greater transmurality (88% vs. 58%, p < 0.001), higher left atrial pressures, more infarct expansion (expansion index 2.62 vs. 2.31, p < 0.001), more thinning (thinning ratio 0.62 vs. 0.72, p < 0.001), greater cavity dilation (diastolic volume 88 vs. 72 ml, p < 0.001), more regional bulging in the short-axis view (depth 4.9 vs. 1.9 mm, p < 0.001), more regional asynergy (18% vs. 7%, p < 0.001), lower global ejection fraction (40% vs. 48%, p < 0.001), more endocardial and epicardial bulging in the long-axis view and greater incidence of aneurysm (82% vs. 36%, p < 0.005), left ventricular thrombus (64% vs. 0%, p < 0.0005) and ventricular arrhythmias. Echocardiograms obtained during a 6-week period indicated that left ventricular topographic deterioration and dysfunction were present in the earliest postinfarction study at 2 days in both groups but were more frequent in the Q wave group. Regional myocardial blood flow (24 dogs) was lower in the Q wave than in the non-Q wave group. Scanning electron microscopy (10 dogs) revealed preservation of the epicardial collagen matrix in the non-Q wave but not the Q wave group.Conclusions. Anterior Q wave infarction is associated with greater transmurality and more postinfarction left ventricular remodeling and dysfunction than is non-Q wave infarction