Pleiotropic effects of cardiac drugs on healing post-MI. The good, bad, and ugly

Healing after myocardial infarction (MI) is a well-orchestrated time-dependent process that involves inflammation, tissue repair with extracellular collagen matrix (ECCM) deposition and scar formation, and remodeling of myocardial structure, matrix, vasculature, and function. Rapid early ECCM degradation followed by slow ECCM replacement and maturation during post-MI healing results in a prolonged window of enhanced vulnerability to adverse remodeling. Decreased ECCM results in adverse ventricular remodeling, dysfunction, and rupture. Inflammation, a critical factor in normal healing, if impaired results in adverse remodeling and rupture. Several therapeutic drugs prescribed after MI exert pleiotropic effects that suppress ECCM and inflammation during healing and may have good, bad, or ugly consequences. This article reviews the potential impact of pleiotropic effects of some prototypic cardiac drugs such as renin-angiotensin-aldosterone system (RAAS) inhibitors, statins, and thrombolytics during healing post-ST-segment-elevation MI (STEMI), with special focus on inflammation, ECCM and remodeling, and implications in the elderly.     

Potential prevention of myocardial rupture resulting from acute myocardial infarction

The clinical characteristics of 30 cases of myocardial rupture resulting from acute myocardial infarction were analyzed. Predisposing factors of myocardial rupture appeared to be the following (1) age 60 years or older, (2) female, (3) no previous history of angina or myocardial infarction, (4) hypertension on admission, (5) persistent or recurrent chest pain, (6) physical activity and/or emotional unrest, (7) less than 10 days since the onset of myocardial infarction. From 1979 to 1982, we tried to eliminate these risk factors in the acute stage of myocardial infarction, of which hypertension appeared to be the most important and main correlating factor. The incidence of myocardial rupture before elimination of risk factors was 31.2% (26 of 84 patients) which was reduced to 8.8% after elimination. In the years 1981 and 1982, only two cases of myocardial rupture were found in each year, 4.3% and 5.6% of MI patients, respectively.     

Brain natriuretic peptide and cardiac rupture after acute myocardial infarction

Cardiac rupture is a fatal complication in the acute stage of myocardial infarction (MI). However, no measures have yet been established to predict it. Herein we describe three MI patients with cardiac rupture in whom plasma brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) concentrations had been serially monitored from the onset of MI to cardiac rupture. In these cases, plasma BNP levels increased without symptomatic and hemodynamic changes and reached their highest level immediately before cardiac rupture, while plasma ANP levels remained unchanged. These cases suggest that the increased plasma BNP concentrations without symptomatic and hemodynamic changes may be a useful marker for predicting cardiac rupture after acute MI.     

Acute myocardial infarction as the presenting symptom of acute myeloblastic leukemia with extreme hyperleukocytosis

This case report deals with an unusual leukostatic complication in a 56-year-old woman with acute myeloblastic leukemia (AML) and extreme hyperleukocytosis (316 x 10(9)/L) who presented with acute myocardial infarction (MI). After leukopheresis the patient achieved hemodynamic stabilization and rapid neurologic recovery of encephalopathy that had also developed after the infarction. Considering the central role of WBC in the remodeling of post MI myocardial tissue, it was obvious that administration of chemotherapy with its subsequent inevitable pancytopenia could impose an increased risk for further cardiac complications including myocardial rupture. Nevertheless, cytarabine-based induction chemotherapy was initiated 3 days after admission, and she achieved prolonged complete remission. Coronary angiography disclosed segmental atherosclerosis, but the only significant obstruction was in the right coronary artery. The patient died with relapsed leukemia 7 years later without recurrence of any cardiac symptoms or signs. Autopsy disclosed segmental coronary atherosclerosis involving the LAD (60% obstruction), suggesting that atherosclerosis was a predisposing risk factor. Additional compromise to blood perfusion due to leukostasis had led to this unusual complication of AML involving a major vessel. This is the first documented case of leukostasis causing coronary artery occlusion as well as the first report of successful induction chemotherapy for AML during a myocardial infarction.     

Prognostic significance of fragmented QRS complex for predicting the risk of recurrent cardiac events in patients with Q-wave myocardial infarction

There are limited data regarding the prognostic value of QRS complex fragmentation, defined as changes in QRS morphology (<120 ms) with different RSR' patterns: additional R waves, notched S wave, or >1 R' wave. The purpose of our analysis was to assess the prognostic value of presence of Q waves and QRS fragmentation for predicting recurrent cardiac events, defined as cardiac death, nonfatal myocardial infarction (MI), or unstable angina, whichever occurs first, in 350 patients with first Q-wave MI. In follow-up (2 months on average) electrocardiograms (ECGs), 277 patients (79%) had persistent Q waves and 73 (21%) had resolution of Q waves. Independently of Q waves, presence of QRS complex fragmentation was found in 187 patients (53%). Resolved Q waves on 2-month ECGs was associated with worsened prognosis (adjusted hazard ratio [HR] 2.33, p = 0.007), whereas presence of any fragmented QRS did not increase risk of recurrent cardiac events (adjusted HR 0.93, p = 0.79). Among patients for whom Q waves disappeared on 2-month ECGs, patients with QRS fragmentation (n = 37) had over twofold higher risk of recurrent events (adjusted HR 2.68, p = 0.004) compared with those without fragmented QRS and persistent Q waves. In conclusion, presence of fragmented QRS independently of Q waves was not associated with increased risk of recurrent events in the general population of patients after MI. However, among patients with resolved Q waves, fragmented QRS was associated with increased risk of cardiac events. Fragmented QRS complex should not be neglected in patients with transient Q waves after myocardial infarction.     

Differences in inflammation, MMP activation and collagen damage account for gender difference in murine cardiac rupture following myocardial infarction

Cardiac rupture remains a fatal complication of acute myocardial infarction (MI) with its mechanism partially understood. We hypothesized that damage to the collagen matrix of infarcted myocardium is the central mechanism of rupture and therefore responsible for the difference in the incidence of rupture between genders. We examined left ventricular (LV) remodeling during the acute phase post-MI in 129sv mice. Following induction of MI, we monitored rupture events and assessed the extent of LV remodeling by echocardiography. Muscle tensile strength, content of insoluble and soluble collagen, expression and activity of matrix metalloproteinases (MMPs) and density of inflammatory cells were determined in the infarcted and non-infarcted myocardium. We then tested the effects of MMP inhibition on rupture. Compared to female mice, males with MI displayed greater extent of LV remodeling, reduced muscle tensile strength, loss of insoluble collagen, local inflammatory response and MMP-9 activation, changes associated with a 3 times higher incidence of rupture than in females. MMP-9 expression by circulating blood mononuclear cells was also increased in male mice with acute MI. Treatment of male mice with an MMP inhibitor reduced MMP activity and halved rupture incidence. Our findings demonstrate that the differences in the severity of inflammation, MMP activation and damage to collagen matrix account for gender difference in cardiac rupture. Our study illustrates the breakdown of fibril collagen as a central mechanism of cardiac rupture.     

Cardiac rupture in patients with acute myocardial infarction

The occurrence of myocardial rupture was evaluated in an unselected population of 1,737 patients with acute myocardial infarction (AMI). Patients with cardiac rupture after AMI were compared with age- and sex-matched control patients with fatal AMI not related to rupture and with AMI survivors discharged home. Rupture was found in 40 patients (15.7 percent of hospital deaths), or 2.3 percent of all cases of AMI. At the highest risk for rupture were women aged 60 to 69, although the age distribution did not differ significantly from that of patients dying of other causes. More patients with myocardial rupture had hypertension during hospitalization, persistent pain, and inferior wall myocardial infarction when compared with controls. The majority (95 percent) of cardiac ruptures occurred within the first six days, 40 percent within the first 24 hours after the onset of symptoms. Approximately 20 percent of ruptures were diagnosed as subacute; in only two was surgical intervention attempted unsuccessfully. The high-risk group of patients should be carefully monitored within the first six days after the onset of symptoms of AMI in an effort to prevent myocardial rupture.     

不同月龄鼠急性心肌梗死后心室重构和心脏破裂的观察

目的 探讨老龄对小鼠急性心肌梗死(AMI)后心室重构心脏破裂的影响. 方法 老龄和低龄C57BL/6小鼠,随机分为假手术组、心肌梗死组.建立AMI模型后,观察心脏破裂发生率,并于AMI后第7天行超声和血流动力学检查;应用酶谱法、病理染色及免疫组化方法 ,分别于AMI后第3、7天检测基质金属蛋白酶-2、-9(MMP-2、MMP-9)活性表达,炎性细胞浸润程度,心肌间质胶原含量(CVF)和类型的变化. 结果 AMI后老龄组心脏破裂率高于低龄组(38.0%与16.0%,X2=6.139,P＜0.05);第7天时,较低龄组出现明显的梗死区扩张、左心室重构、心功能障碍及血流动力学变化(t=5.754,P＜0.05).与低龄组比较,老龄AMI组AMI后第3天炎性细胞浸润程度、MMP-9表达明显增加(P＜0.05).与低龄组比较,老龄组心肌间质胶原含量、Ⅲ型胶原表达增加(P＜0.05). 结论 老龄是小鼠AMI后心脏破裂的高危因素,其原因可能与AMI早期炎性细胞浸润程度增加、MMP-9、Ⅲ型胶原过度表达和早期左心室重构恶化有关.     

Angiotensin-converting enzyme inhibitors in patients with coronary atherosclerosis

Activation of the renin-angiotensin-aldosterone system has been shown to be an independent risk factor for myocardial infarction (MI). The importance of this risk factor has been confirmed by the finding that patients with a DD genotype for the angiotensin-converting enzyme (ACE) gene, which is associated with increased serum ACE levels, have a higher incidence of MI than do patients without this genotype. ACE inhibitors have been shown to significantly reduce the incidence of recurrent MI in patients with left ventricular dysfunction. The mechanism by which activation of the renin-angiotensin-aldosterone system leads to MI has not been ascertained, but it may be related to the effect of angiotensin II or aldosterone on the development of atherosclerosis, endothelial dysfunction, plaque rupture, or thrombosis after plaque rupture. Experimental data suggest that each of these mechanisms may be of importance. Several prospective randomized studies are under way to determine the effect of ACE inhibitors on recurrent ischemic events and the progression of atherosclerosis in patients without left ventricular dysfunction. If these studies yield positive results, ACE inhibitors might assume an important role in the secondary and possibly primary prevention of ischemic heart disease.     

Managing the post-myocardial infarction patient with asymptomatic left ventricular dysfunction

The percentage of post-myocardial infarction (MI) patients with asymptomatic left ventricular dysfunction (ALVD) is now estimated at 10%, and that number is expected to grow as reperfusion procedures increasingly become routine. Since average all-cause mortality risk in these patients is high (up to 27%), definitive diagnostics are recommended to screen all post-MI patients for ALVD, defined as left ventricular systolic dysfunction in the absence of heart failure symptoms. Post-MI management strategies for patients with ALVD target the two routes of progression to heart failure: (1) cardiac remodeling mediated by neurohormonal activation, and (2) continued and recurrent myocardial ischemic events. Clinical trials of neurohormonal antagonists in post-MI ALVD patients have shown that angiotensin-converting enzyme inhibitors attenuate left ventircular remodeling and that beta-blocker therapy reverses remodeling for patients already on angiotensin-converting enzyme inhibitor therapy. Neurohormonal antagonist therapy is also associated with significant reductions in sudden death in post-MI ALVD patients.     

Effects of the calcineurin dependent signaling pathway inhibition by cyclosporin A on early and late cardiac remodeling following myocardial infarction

BACKGROUND: The calcineurin-mediated signaling pathway has been implicated as one of the crucial pathways in cardiac hypertrophy. However, the role of calcineurin pathway on cardiac remodeling after myocardial infarction (MI) has not been well defined. METHODS: Infarcted rats (n = 45) were randomized into calcineurin inhibitor, cyclosporin A (CsA) or vehicle groups, 3 days after MI and treated for 2 weeks (early post-MI cardiac remodeling stage), or randomized 17 days after MI and treated for 2 weeks (late remodeling stage). RESULTS: Calcineurin pathway inhibition during the early cardiac remodeling stage attenuated the myocardial hypertrophy after MI (P < 0.05). However, left ventricular dimensions were further increased and fractional shortening deteriorated with calcineurin inhibition during this stage (P < 0.05, each). During late remodeling stage, CsA treatment did not affect myocardial hypertrophy and cardiac dilation following MI. CONCLUSION: Our results strongly support the hypothesis that calcineurin pathway mediates compensatory myocardial hypertrophy during the early remodeling stage after MI. However, the calcineurin pathway does not seem to affect the late remodeling after MI.     

Postinfarction cardiac rupture despite immediate reperfusion therapy in a patient with severe aortic valve stenosis

A 74-year-old woman with severe aortic valve stenosis (AS) was admitted to our hospital because of dyspnea on exertion. On day 2, she developed acute anterior wall myocardial infarction (MI) with ST elevation. Tissue plasminogen activator (tPA) was administered 10 min after the onset of chest pain, and emergency percutaneous coronary intervention was performed to induce coronary reperfusion after another 50 min. Five hours after MI onset, however, she suddenly went into electromechanical dissociation and died from cardiac rupture. This is the first case report of postinfarct cardiac rupture with severe AS occurring in spite of instituting immediate reperfusion therapy. High intraventricular pressure may be a critical risk factor for cardiac rupture in patients with AS complicated with acute MI. Further studies are required to clarify the risk and benefit of tPA administration before percutaneous coronary intervention and the necessity of the emergency correction of AS to prevent cardiac rupture.     

Extracellular matrix turnover and signaling during cardiac remodeling following MI: Causes and consequences

The concept that extracellular matrix (ECM) turnover occurs during cardiac remodeling is a well-accepted paradigm. To date, a multitude of studies document that remodeling is accompanied by increases in the synthesis and deposition of ECM components as well as increases in extracellular proteases, especially matrix metalloproteinases (MMPs), which break down ECM components. Further, soluble ECM fragments generated from enzymatic action serve to stimulate cell behavior and have been proposed as candidate plasma biomarkers of cardiac remodeling. This review briefly summarizes our current knowledge base on cardiac ECM turnover following myocardial infarction (MI), but more importantly extends discussion by defining avenues that remain to be explored to drive the ECM remodeling field forward. Specifically, this review will discuss cause and effect roles for the ECM changes observed following MI and the potential role of the ECM changes that may serve as trigger points to regulate remodeling. While the pattern of remodeling following MI is qualititatively similar but quantitively different from various types of injury, the basic theme in remodeling is repeated. Therefore, while we use the MI model as the prototype injury model, the themes discussed here are also relevant to cardiac remodeling due to other types of injury.     

Time course of cardiac structural, functional and electrical changes in asymptomatic patients after myocardial infarction: their inter-relation and prognostic impact.

OBJECTIVES: We prospectively studied the relationship between left ventricular (LV) dilation, dysfunction, electrical instability and death in patients after a first myocardial infarction (MI) without symptoms of heart failure and ischemia. BACKGROUND: Mechanisms linking LV dysfunction and sudden death in patients after MI remained controversial. METHODS: Left ventricular volumes, hemodynamics, electrocardiogram and 24-h Holter recordings were sequentially obtained between two days and seven years after MI. Left ventricular catheterization and coronary angiography were performed, and revascularization was performed if appropriate. RESULTS: Death occurred in 16 (12%) of the 134 patients included; it was of cardiac origin in 14 (88%) and sudden in origin in 12 (75%) patients. Of 37 (28%) patients with LV dilation, 12 died (32%); four patients (5.8%) died in the group without dilation. Left ventricular dilation was closely related to signs of electrical instability, as indicated by a significant correlation between end-diastolic LV volume index, Lown score (r = 0.98, p < 0.0001) and QTc prolongation (r = 0.998, p < 0.01), respectively. CONCLUSIONS: Patients with progressive remodeling are at increased risk of sudden death in chronic MI. Cardiac electrical instability is closely related to progressive LV dilation. Parameters of electrical instability and remodeling are predictors of sudden death. The findings suggest that remodeling might serve as a link between dysfunction, electrical instability of the heart and sudden death after MI.     

Effect of Microvascular Obstruction and Intramyocardial Hemorrhage by CMR on LV Remodeling and Outcomes After Myocardial Infarction: A Systematic Review and Meta-Analysis

The goal of this systematic analysis is to provide a comprehensive review of the current cardiac magnetic resonance data on microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH). Data related to the association of MVO and IMH in patients with acute myocardial infarction (MI) with left ventricular (LV) function, volumes, adverse LV remodeling, and major adverse cardiac events (MACE) were critically analyzed. MVO is associated with a lower ejection fraction, increased ventricular volumes and infarct size, and a greater risk of MACE. Late MVO is shown to be a stronger prognostic marker for MACE and cardiac death, recurrent MI, congestive heart failure/heart failure hospitalization, and follow-up LV end-systolic volumes than early MVO. IMH is associated with LV remodeling and MACE on pooled analysis, but because of limited data and heterogeneity in study methodology, the effects of IMH on remodeling require further investigation.     

Unusual Cause of Heart Failure in a 65‐Year‐Old Woman

Left ventricular (LV) free wall rupture is a potentially lethal mechanical complication after myocardial infarction (MI). Pericardial adhesions or slow extracardiac leak and pericardial inflammation may result in a contained cardiac rupture. LV pseudoaneurysm is a relatively uncommon clinical entity. It may occur after MI, but also as a complication of infective endocarditis, cardiac surgery, or trauma. Patients developing LV pseudoaneurysm after MI may present angina pectoris or signs of congestive heart failure (HF) but often are asymptomatic. Surgery is the treatment of choice for LV pseudoaneurysms diagnosed in the first months after MI. The management of chronic LV pseudoaneurysms is still subject of debate. This report highlights a 65‐year‐old patient newly hospitalized for acute decompensated HF who was diagnosed with a large chronic LV pseudoaneurysm and severe mitral regurgitation. The patient underwent successful resection of the pseudoaneurysm and patch repair of the ruptured ventricular wall.     

急性心肌梗塞并发心脏破裂11例临床和病理分析

对１１例经尸检证实的急性心肌梗塞并发心脏破裂（其中４例为心室游离窒不完全破裂）进行临床和病理分析，强调对心脏破裂，尤其是心室游离壁不完全破裂，应早期诊断。心室游离壁不完全破裂的临床表现，类似急性心包填塞和心源性休克，患者存活时间可达数小时，如能及时用超声心动图等检查方法尽早明确诊断，部分患者可望获救。文中就静脉溶栓治疗对心脏破裂的可能影响也进行了探讨。     

Symptoms and signs of heart failure in patients with myocardial infarction: reproducibility and relationship to chest X-ray, radionuclide ventriculography and right heart catheterization

102 patients with myocardial infarction (MI) were examined by three clinicians, who independently recorded the following symptoms and signs: dyspnoea, a displaced apex beat, S3-gallop, rales, neck vein distension, hepatomegaly, and dependent oedema. Chest X-ray, radionuclide ventriculography, and (in 40 patients) right heart catheterization were carried out immediately after the physical examination. The clinicians frequently disagreed as to the presence of physical signs of heart failure in individuals. Moreover, these signs were of limited value in identifying patients with pulmonary vascular congestion on chest X-ray, reduced left or right radionuclide ventricular ejection fractions, enlarged ventricular volumes or haemodynamic evidence of ventricular dysfunction. We conclude that clinicians frequently disagree in the recognition of physical signs of heart failure, and that these signs have an unpredictable relationship to radiographic, radionuclide and haemodynamic measures of ventricular performance in patients with MI. Nevertheless, physical signs are useful in identifying patients with high risk of cardiac death.     

Myocardial infarction and other arterial occlusions in hemophilia a patients. A cardiological evaluation of all 42 cases reported in the literature

Myocardial infarction and other arterial occlusions are considered to be rare in hemophilia A. However, a systematic study of the subject has never been attempted. All case reports of myocardial infarction or other arterial occlusions have been now gathered and properly evaluated from a cardiological point of view. Thirty-six patients with myocardial infarction and 6 patients with documented cerebrovascular event were retrieved from the literature. The age of the patients varied between 7 and 79 years, with a mean of 44 years. In 16 cases, the arterial occlusion occurred in men <40 years of age. The majority of myocardial infarctions (MIs) were anterolateral (12 cases). Posterior-inferior MI was present in 6 cases whereas it was of the non-Q type in 4 patients. It was multiple in 6 cases, and in the remaining patients the type of infarction could not be determined. In 26 cases, the thrombotic event (22 myocardial infarctions and 4 ischemic cerebrovascular accidents) occurred during or after the infusion of factor VIII concentrates and, more frequently, after prothrombin complex concentrates (activated or non-activated ones) or recombinant factor VIIa preparations. In 3 cases, the vascular complication occurred after intravenous desmopressin administration. MI was fatal in 7 instances. After the event, signs and symptoms of heart failure were seen as sequels in 7 patients. One patient had to undergo cardiac transplant 5 months after the MI. No death occurred after ischemic cerebrovascular accidents. Since not all hemophilia patients develop inhibitors and therefore are not usually treated with activated concentrates, this series of patients is somewhat biased and does not allow general conclusions. The high prevalence of MI and other arterial complications which occurred after transfusion therapy, usually in patients with inhibitors, clearly indicates the need for a careful evaluation of the appropriate therapeutic approach in each single patient.     

Intravascular ultrasound assessment of the association between spatial orientation of ruptured coronary plaques and remodeling morphology of culprit plaques in ST-elevation acute myocardial infarction

The aim of this study was to assess the association between the spatial location of plaque rupture and remodeling pattern of culprit lesions in acute anterior myocardial infarction (MI). Positive remodeling suggests a potential surrogate marker of plaque vulnerability, whereas plaque rupture causes thrombus formation followed by coronary occlusion and MI. Intravascular ultrasound (IVUS) can determine the precise spatial orientation of coronary plaque formation. We studied 52 consecutive patients with acute anterior MI caused by plaque rupture of the culprit lesion as assessed by preintervention IVUS. The plaques were divided into those with and without positive remodeling. We divided the plaques into three categories according to the spatial orientation of plaque rupture site: myocardial (inner curve), epicardial (outer curve), and lateral quadrants (2 intermediate quadrants). Among 52 plaque ruptures in 52 lesions, 27 ruptures were oriented toward the epicardial side (52%), 18 toward the myocardial side (35%), and 7 in the 2 lateral quadrants (13%). Among 35 plaques with positive remodeling, plaque rupture was observed in 21 (52%) on the epicardial side, 12 (34%) on the myocardial side, and 2 (6%) on the lateral side. However, among 17 plaques without positive remodeling, plaque rupture was observed in 6 (35%), 6 (35%), and 5 (30%), respectively (p?=?0.047). Atherosclerotic plaques with positive remodeling showed more frequent plaque rupture on the epicardial side of the coronary vessel wall in anterior MI than those without positive remodeling.