Bodh I. Jugdutt

Ventricular remodeling after infarction and the extracellular collagen matrix: when is enough enough?

Left ventricular (LV) remodeling after myocardial infarction (MI) contributes significantly to LV dilation and dysfunction, and disability and death. Two paradigms, pertinent to antiremodeling therapy after MI (Figure 1), have evolved over the last 3 decades. Paradigm 1, LV remodeling is a major mechanism for disability and death,1,2 has received a great deal of attention. In contrast, paradigm 2, remodeling of the extracellular collagen matrix (ECCM) plays a major role in LV remodeling,3–7 whereby decrease, disruption, and/or defective composition of the ECCM promote LV dilation and rupture,4–7 has received little attention. A host of clinical trials showed that angiotensin-converting enzyme (ACE) inhibitors (ACE-Is) with or without aldosterone antagonists, angiotensin II (AngII) type 1 (AT1) receptor blockers (ARBs), β-adrenergic blockers or reperfusion improve outcome in survivors of MI.8–10 Concurrent evidence has underscored the importance of preserving the ECCM during healing after MI.2–7 However, the antifibrotic action of ACE-Is, aldosterone antagonists and ARBs on ECCM in the infarct zone (IZ) and noninfarct zone (NIZ),6,7,9,11 and the reperfusion-induced damage to the ECCM in the IZ,5,7,12 remain unreconciled with the benefits.8–10,13 Nevertheless, excessive ECCM, as in dilated ischemic cardiomyopathy after remote MI,14,15 can contribute to LV diastolic dysfunction and poor outcome,6 suggesting that antifibrotic drugs that target excess ECCM might be a logical therapeutic approach. This review focuses on the role of the ECCM in the evolution of LV remodeling after MI and the potential impact of therapies that target the ECCM. Figure 1. Role of ECCM in ventricular remodeling; shown are 2 paradigms for adverse outcome after MI. Top, Cascade from acute transmural MI to heart failure and death. Left, Diagrams of short- and long-axis sections of the heart after anterior MI. Middle, Diagrams showing topographic changes in short-axis sections during healing …

Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion, and complications. Effect of timing, dosage, and infarct location.

To determine 1) whether the effect of intravenous nitroglycerin (NG) therapy during acute myocardial infarction on creatine kinase infarct size is influenced by infarct location (anterior vs. inferior), timing (therapy less than 4 hours vs. greater than or equal to 4 hours after onset of pain), and dose response (mean blood pressure greater than or equal to 80 mm Hg vs. less than 80 mm Hg during the first 12 hours) and 2) whether NG therapy modifies infarct expansion, 310 patients were randomly allocated to NG (n = 154) and control (n = 156) groups. NG infusion was titrated to lower mean blood pressure by 10% in normotensive and 30% in hypertensive patients, but not below 80 mm Hg, and was maintained for 39 hours. Measurements included clinical variables, creatine kinase infarct size (geq) as well as left ventricular (LV) asynergy, LV ejection fraction, expansion index, and thinning ratio on serial two-dimensional echocardiography. Compared with controls, creatine kinase infarct size was less in the NG group (41 vs. 55 geq, p less than 0.001), in anterior (44 vs. 58 geq, p less than 0.05), and inferior (39 vs. 53 geq, p less than 0.025) NG subgroups, and in early than late NG subgroups (43% vs. 22% decrease). Other indexes of infarct size also improved (p less than or equal to 0.05) with NG compared with controls. Thus, by 10 days, LV asynergy was 40% less, LV ejection fraction was 22% more, and Killip class score was 41% less. A negative effect of mean blood pressure less than 80 mm Hg with NG was reflected in these indexes. In addition, expansion index increased (p less than 0.001) by 31% and thinning ratio decreased (p less than 0.001) by 17% in controls by 10 days but remained unchanged with NG. Infarct-related major complications were less frequent in the NG than the control groups: infarct expansion syndrome (2% vs. 15%, p less than 0.0005), LV thrombus (5% vs. 22%, p less than 0.0005), cardiogenic shock (5% vs. 15%, p less than 0.005), and infarct extension (11% vs. 22%, p less than 0.025). Mortality was less in NG than in control groups in-hospital (14% vs. 26%, p less than 0.01), at 3 months (16% vs. 28%, p less than 0.025) and 12 months (21% vs. 31%, p less than 0.05), but this advantage was only found in the anterior subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)

Apoptosis and oxidants in the heart

Cardiomyocyte (CM) apoptosis has been reported in a variety of cardiovascular diseases, including myocardial infarction, ischemia/reperfusion, end-stage heart failure, arrhythmogenic right ventricular dysplasia, and adriamycin-induced cardiomyopathy. The role of CM apoptosis in the development and progression of cardiac diseases merits further investigation. Cumulative evidence suggests that reactive oxygen species (ROS), which have been implicated in cardiac pathophysiology, can trigger myocyte apoptosis by up-regulating proapoptotic proteins, such as Bax and caspases, and the mitochondria-dependent pathway. These apoptotic proteins and pathways are inhibited by various antioxidants, as well as by overexpression of the antiapoptotic protein Bcl-2 by way of the antioxidant pathway. Detection of CM apoptosis with the terminal transferase-mediated DNA nick-end labeling assay alone has recently been questioned because of technical concerns regarding its sensitivity and specificity. Because CMs are mononuclear or binuclear, if only one nucleus or a certain percentage of fragmented nuclei is stained with TUNEL assay at the early stage of apoptotic cell death, it remains unknown whether this particular early apoptotic CM is still functionally active. The issue of TUNEL specificity further questions reports of high percentages of apoptotic CM nuclei (0.02%-35%) in the heart. Nevertheless, oxidative stress is a major apoptotic stimulus in many cardiovascular diseases and the process can be inhibited by antioxidants both in vitro and in vivo.

Exercise training after anterior Q wave myocardial infarction: Importance of regional left ventricular function and topography☆☆☆

To determine whether the extent of left ventricular dysfunction and the degree of shape distortion can predict outcome in survivors of moderate-sized anterior Q wave myocardial infarction who are undergoing exercise training, these variables were measured by two-dimensional echocardiography before and after 12 weeks of a low level exercise training program starting 15 weeks after infarction in 13 patients (7 in group 1 and 6 in group 2) and 12 weeks apart in 24 matched control patients without training. By the end of training, the functional class score had increased in group 2 (from 2.25 to 2.67, p less than 0.005) but had not changed in group 1. Further discrimination of groups 1 and 2 was provided by an initial asynergy (akinesia or dyskinesia, or both) less than 18% or greater than or equal to 18%. Compared with group 1, group 2 had greater initial asynergy (32 versus 6%, p less than 0.001), expansion index (asynergic/normal endocardial segment length: 1.8 versus 1.6, p less than 0.025) and peak shape distortion index (12.2 versus 1.0 mm, p less than 0.005) but lower ejection fraction (43 versus 59%, p less than 0.05) and thinning ratio (asynergic/normal wall thickness: 0.61 versus 0.74, p less than 0.05). These variables did not change with training in group 1. However, in group 2, training caused significant increase in asynergy (from 32 to 40%, p less than 0.05), expansion index (from 1.8 to 2.0, p less than 0.01) and peak shape distortion (from 12.2 to 20.9 mm, p less than 0.05) associated with a decrease in thinning ratio (from 0.61 to 0.51, p less than 0.001) and ejection fraction (from 43 to 30%, p less than 0.005). Initial values for these variables were similar for corresponding control groups but did not change over the 12 weeks. Thus, patients with greater than or equal to 18% left ventricular asynergy on the initial echocardiogram showed more shape distortion, expansion and thinning before exercise training and developed further functional and topographic deterioration with training.

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 less than 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 less than 0.001), although total infarct hydroxyproline was directly related to infarct size at each time period (r = 0.73 to 0.81, p less than or equal to 0.05). Significant (p less than or equal to 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.

Opposite Effects of Angiotensin AT1 and AT2 Receptor Antagonists on Recovery of Mechanical Function After Ischemia-Reperfusion in Isolated Working Rat Hearts

BACKGROUND Angiotensin II type 1 (AT1) receptor antagonists, when given over the long term, reduce the deleterious consequences of ischemia-reperfusion injury. Whether short-term administration of AT1 or angiotensin II type 2 (AT2) receptor antagonists is cardioprotective has not been investigated. METHODS AND RESULTS The effects of short-term administration of selective AT1 and AT2 receptor antagonists on the recovery of mechanical function during reperfusion after 30 minutes of global, no-flow ischemia were studied in left atrium-perfused isolated working rat hearts. Control hearts (n = 8) showed incomplete recovery of left ventricular minute work (LV work) and cardiac efficiency during reperfusion to 51 +/- 15% and 61 +/- 19% of preischemic levels, respectively. Compared with control hearts, the selective AT2 receptor antagonist PD123,319 (0.3 mumol/L) given before ischemia (n = 7) improved the recovery of LV work and efficiency to 82 +/- 4% and 98 +/- 7% of preischemic levels, respectively (P < .01). In contrast, the selective AT1 antagonist losartan (1 mumol/L) blocked the recovery of LV work and depressed efficiency to 0 +/- 0% and 1 +/- 0% (n = 7) of preischemic levels, respectively (P < .01; n = 7). Neither antagonist altered coronary vascular conductance. CONCLUSIONS This is the first demonstration that short-term treatment with a selective AT1 versus AT2 antagonist exerts different effects on recovery of mechanical function after ischemia-reperfusion: the AT2 antagonist was cardioprotective, whereas the AT1 antagonist was not. These data suggest that AT2 antagonists and AT1 agonists may offer novel approaches for the treatment of mechanical dysfunction after ischemia-reperfusion.

Prospective two-dimensional echocardiographic evaluation of left ventricular thrombus and embolism after acute myocardial infarction

To determine whether two-dimensional echocardiography can identify patients with left ventricular thrombus after myocardial infarction who are prone to embolism, clinical and echocardiographic variables in 541 patients with a first infarction between 1979 and 1983 were studied prospectively. The first echocardiogram showed definite thrombus in 115 patients (Group 1, 21%) and no thrombus in 426 (Group 2, control). In Group 1, 27 patients (23%) had clinical evidence of systemic embolism related to the thrombus before referral (Group 1a) and 88 did not (Group 1b); these two groups were similar in age, gender and infarct location, but more Group 1a patients were within 1 month of the acute infarction. In both Groups 1a and 1b, the thrombus was found in apical views over asynergic zones, with no difference (p greater than 0.05) between the two groups in the size (average area from two views being 5.3 versus 4.5 cm2), type (protruding in apical views 30% versus 27%), location (apical 83% versus 86%; septal 11% versus 11%; posterior 4% versus 2%), extent of asynergy (31% versus 33%) and ejection fraction (33% versus 34%). However, the frequency of anticoagulant therapy was less (26% versus 63%, p less than 0.005), adjacent hyperkinesia greater (100% versus 49%, p less than 0.005) and thrombus mobility greater (81% versus 19%, p less than 0.005) in Group 1a than in Group 1b. Serial echocardiograms revealed a decreased size of the thrombus by 6 months in both Groups 1a and 1b, and little or no trace in 85% by 24 months. Thus, ventricular thrombus size, location and protrusion in apical views on echocardiography did not correlate with embolism. In contrast, thrombus mobility, the presence of adjacent hyperkinesia and thrombus protrusion assessed in multiple views appeared to be strong discriminators of thrombus prone to embolism. These echocardiographic features might provide a guide for the duration of anticoagulant therapy.

Effect of prolonged nitrate therapy on left ventricular remodeling after canine acute myocardial infarction.

BACKGROUND Prolonged nitrate therapy during healing between 2 days and 6 weeks after anterior myocardial infarction has the potential for limiting further left ventricular remodeling (or changes in topography) and preserving function. Longterm therapy throughout healing over 6 weeks might be more beneficial than short-term therapy over the first 2 weeks after infarction. METHODS AND RESULTS The effect of prolonged nitrate therapy between 2 days and 6 weeks during healing after infarction on serial parameters of ventricular remodeling (scar expansion, scar thinning, ventricular dilation, and hypertrophy) and function (asynergy or akinesis plus dyskinesis and ejection fraction) by serial two-dimensional echocardiography, hemodynamics, postmortem topography (computerized planimetry, geometric maps, and radiographs), and collagen content (hydroxyproline) was studied in 64 instrumented dogs randomized 2 days after left anterior descending coronary artery ligation to various nitrate regimens (n = 32) over the first 2 weeks (subgroup 1: 2% transdermal nitroglycerin at 8 AM and 4 PM, n = 6; subgroup 2: 2% transdermal nitroglycerin plus 2.6 mg of sustained-release oral nitroglycerin at 8 AM, 3 PM, and 10 PM, n = 5; subgroup 3: oral isosorbide dinitrate, 30 mg at 8 AM and 4 PM, n = 11) or 6 weeks (subgroup 4: isosorbide dinitrate, n = 10) and in matching controls (n = 32). Nitrate therapy reduced left atrial pressure, mean arterial pressure, and the rate-pressure product compared with controls over the 6 weeks. Postmortem scar mass and hydroxyproline were similar in control and nitrate groups. However, scar stretching and thinning, cavity dilation, noninfarct wall hypertrophy, and apical bulging were less with nitrates, especially in the long-term subgroup 4. In vivo remodeling parameters between 2 days and 6 weeks after ligation showed that, compared with controls, nitrate therapy prevented further stretching of the asynergic segment, decreased the expansion index, decreased further scar thinning, prevented the increase in ventricular volumes, reduced the frequency of ventricular aneurysm, prevented the increase in ventricular mass, reduced the extent of asynergy, and improved ejection fraction. Although the beneficial effect on topography and function was seen in all nitrate subgroups, the overall benefit was greater with long-term therapy over 6 weeks (subgroup 4) than short-term therapy confined to the first 2 weeks (subgroups 1, 2, and 3). CONCLUSIONS Prolonged nitrate therapy, in various regimens during healing after infarction, effectively reduced left ventricular loading and prevented infarct thinning, further infarct expansion, progressive ventricular dilation, and the increase in mass. These effects were associated with decreased asynergy and improved ejection fraction. The beneficial effects were greater with long-term therapy over 6 weeks than short-term therapy over the first 2 weeks.

Effect of long-term captopril therapy on left ventricular remodeling and function during healing of canine myocardial infarction

To determine whether the long-term reduction of preload and afterload by captopril during healing after acute anterior myocardial infarction might attenuate left ventricular remodeling and improve function, 30 chronically instrumented dogs with infarction produced by left anterior descending coronary artery ligation were randomized 2 days later to oral therapy with placebo (n = 15) or captopril, 50 mg twice daily (n = 15), for 6 weeks. Serial hemodynamic as well as topographic and functional variables (two-dimensional echocardiography) were measured over 6 weeks. Scar topography (planimetry), occluded bed size (coronary arteriography) and collagen (hydroxyproline) content were measured at 6 weeks. Between 2 days and 6 weeks, captopril decreased (p less than 0.001) mean arterial pressure and mean left atrial pressure more than did placebo, but it did not influence heart rate. Infarct scar mass, transmurality and collagen content at 6 weeks were similar in the two groups but scars showed less (p less than 0.001) thinning and expansion with captopril than with placebo. Echocardiograms showed similar infarct expansion and thinning in the two groups at 2 days but less aneurysm with captopril at 6 weeks. Between 2 days and 6 weeks, expansion index (infarct-/noninfarct-containing segment length) decreased (p less than 0.001) with captopril but increased (p less than 0.001) with placebo. Also, thinning ratio (infarct/normal wall thickness) decreased (p less than 0.001) with placebo but did not change (p = NS) with captopril. By 6 weeks, left ventricular asynergy and volumes showed a greater decrease (p less than 0.01) and global ejection fraction a greater increase (p less than 0.05) with captopril.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased burden of coronary artery disease in South-Asians living in North America. Need for an aggressive management algorithm

Despite improvements in cardiovascular outcomes, coronary artery disease (CAD) continues to be a major cause of death worldwide. South-Asians (SAs) show an increased risk of atherosclerosis and have the highest mortality rates from CAD than any other ethnic group. The greater susceptibility of SAs to CAD cannot be explained entirely by conventional risk factors alone. Other factors are involved, such as genetic predisposition and high prevalence of the metabolic syndrome and type-2 diabetes. CAD is more severe, extensive and malignant among SAs. It is often unsuspected and associated with adverse outcome requiring a more aggressive management strategy. With the growing SA population in North America, physicians need to be aware of the epidemiology, conventional causes, associated contributors, and adverse outcomes of CAD in this group. Importantly, physicians need a structured approach and an aggressive management algorithm for the optimal care of the high-risk SA patient population.