Stem cell mechanisms during left ventricular remodeling post-myocardial infarction:Repair and regeneration

Post-myocardial infarction(MI),the left ventricle(LV)undergoes a series of events collectively referred to as remodeling.As a result,damaged myocardium is replaced with fibrotic tissue consequently leading to contractile dysfunction and ultimately heart failure.LV remodeling post-MI includes inflammatory,fibrotic,and neovascularization responses that involve regulated cell recruitment and function.Stem cells(SCs)have been transplanted post-MI for treatment of LV remodeling and shown to improve LV function by reduction in scar tissue formation in humans and animal models of MI.The promising results obtained from the application of SCs post-MI have sparked a massive effort to identify the optimal SC for regeneration of cardiomyocytes and the paradigm for clinical applications.Although SC transplantations are generally associated with new tissue formation,SCs also secrete cytokines,chemokines and growth factors that robustly regulate cell behavior in a paracrine fashion during the remodeling process.In this review,the different types of SCs used for cardiomyogenesis,markers of differentiation,paracrine factor secretion,and strategies for cell recruitment and delivery are addressed.     

Functional significance of post-myocardial infarction left ventricular hypertrophy: a beneficial response.

Hypertrophy of noninfarcted myocardium occurs as a chronic response to myocardial infarction, but no previous study has related the changes in wall thickness to serial changes in left ventricular function. Thus the functional significance of postinfarction hypertrophy is unknown. The purpose of this study was to determine the relationship between the development of postinfarction hypertrophy and the resting left ventricular ejection fraction measured by two-dimensional echocardiography. After occlusion of the proximal left anterior descending coronary artery in 11 dogs, the ejection fraction fell acutely (0.63 +/- 0.08 to 0.33 +/- 0.10, p less than 0.001) and rose at 3.5 months to 0.62 +/- 0.12. End-diastolic thickness of the noninfarcted left ventricle increased (11 +/- 1.0 mm to 13 +/- 1.4 mm, p less than 0.01) as did left ventricular mass (101 +/- 18 gm to 134 +/- 21 gm, p less than 0.0001). Restoration of the ejection fraction toward the baseline value correlated with the increases in left ventricular mass (r = 0.79, p = 0.007) and wall thickness (r = 0.71, p = 0.025). Hypertrophy of the noninfarcted myocardium correlated with the magnitude and approximately paralleled the time course of the improvement in the ejection fraction and therefore may have had a beneficial effect on resting left ventricular function as a chronic adaptation to myocardial infarction.     

Chronic high-dose creatine feeding does not attenuate left ventricular remodeling in rat hearts post-myocardial infarction.

OBJECTIVE: In heart failure, cardiac energy metabolism is compromised. The failing myocardium is characterized by reduced contents of both phosphorylated (phosphocreatine) and non-phosphorylated (free) creatine content as well as decreased energy reserve via creatine kinase (creatine kinase reaction velocity). These changes may contribute to cardiac dysfunction. The purpose of the present study was to determine whether chronic feeding with high-dose dietary creatine prevents the derangement of energy metabolism and the development of left ventricular remodeling in a rat model of heart failure, i.e. post-myocardial infarction (MI). METHODS AND RESULTS: Rats were subjected to sham operation or left coronary artery ligation. Surviving rats were fed with 0% (untreated) or 3% creatine (related to weight of diet) for 8 weeks. Creatine feeding increased serum creatine levels significantly approximately 2-fold. Thereafter, hearts were isolated, perfused and left ventricular pressure-volume curves obtained. Steady state and dynamic (CK reaction velocity) high-energy phosphate metabolism was determined with 31P NMR spectroscopy. In both MI groups (treated n = 8, untreated n = 7), pressure-volume curves were shifted right- and downward compared to both sham groups (treated n = 5, untreated n = 7), i.e. creatine had no effect on left ventricular remodeling. Likewise, similar reductions of phosphocreatine, free creatine and creatine kinase reaction velocity (untreated sham 12.0 +/- 0.7 mmol/lxs; untreated MI 7.8 +/- 0.7*; treated sham 13.6 +/- 1.0; treated MI 7.2 +/- 1.1*; *p < 0.025 sham vs. MI) were found in both MI groups. CONCLUSIONS: Chronic creatine feeding of post-MI rats is ineffective in preventing the functional and energetic derangements occurring post-MI. Inspite of increased serum creatine levels, neither the normal nor the failing heart accumulates additional creatine.     

Sutureless patch repair of post-myocardial infarction left ventricular rupture

Ventricular rupture following myocardial infarction is a serious clinical problem with a high mortality. A 60-year-old man with left ventricular rupture and cardiac tamponade following myocardial infarction was managed successfully by emergency surgery. An onlay patch of Teflon held in place by an adhesive without any sutures was used to repair the ruptured myocardium.     

急性心肌梗死与左室重构

急性心肌梗死(AMI)后左室发生细胞学,分子学及细胞间质的变化,进而引起左室在大小、形态、组织结构和功能状态的改变,此即目前许多研究所提及的AMI后的左室重构.AMI后左室的重构贯穿于整个病程的始终,成为影响AMI患者近远期预后的主要原因之一.     

Left ventricular dilatation and failure post-myocardial infarction: Pathophysiology and possible pharmacologic interventions

Summary An important antecedent to the development of late congestive heart failure is left ventricular dilatation and remodeling following myocardial infarction, which occurs in 30–40% of acute anterior transmural infarcts. Dilatation and remodeling commence within the first 24 hours following myocardial infarction and may be steadily progressive over months to years. Both the infarcted and uninfarcted regions of the myocardium are equally involved in the process. The remodeling process comprises left ventricular wall thinning (mainly due to cell slippage), chamber dilatation, and compensatory hypertrophy of the uninfarcted segment of the myocardium. The hypertrophy may initially be physiologic but may ultimately become a pathologic process, and thereby contribute to pump dysfunction. The possible reasons why the ventricualr hypertrophy may ultimately be dysfunctional include alterations in local architecture and their sequelae alone or in concert with local changes in the beta-adrenergic, alpha-adrenergic, or renin angiotensin systems. At the present time, there are encouraging data to suggest that nitroglycerin, or the angiotensin converting enzyme inhibitor captopril, may ameliorate this process.     

Recent insights into cardiac hypertrophy and left ventricular remodeling

Cardiac hypertrophy is a compensatory mechanism of the heart to maintain cardiac output under stresses that compromise cardiac function. Mechanical stretch and neurohumoral factors induce changes in intracellular signaling pathways resulting in increased protein synthesis and activation of specific genes promoting cardiac growth, eventually leading to left ventricular remodeling and cardiac dysfunction. The remodeling process results from alterations in cardiac myocytes as well as the extracellular matrix.     

Biomarkers of left ventricular hypertrophy and remodeling in blacks

Left ventricular (LV) hypertrophy, a marker for adverse cardiovascular events, is more common in blacks than in non-Hispanic whites. Mechanisms leading to LV hypertrophy and mediating its clinical sequelae in blacks are not fully understood. We investigated the associations of 39 candidate biomarkers in distinct biological pathways with LV mass and geometry in blacks. Participants included 1193 blacks (63±9 years of age; 72% women; 78% hypertensive) belonging to hypertensive sibships. LV mass was measured by transthoracic echocardiography and indexed to height.(2.7) LV geometry was categorized as normal, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy. Generalized estimating equations were used to assess associations of the 39 biomarkers with LV mass index after adjustment for age, sex, and conventional risk factors. After adjustment for potential confounders, log-transformed levels of the following biomarkers were independently associated with LV mass index: N-terminal pro-brain natriuretic peptide (β±SE=0.07±0.01 pg/mL; P<0.0001), mid-regional pro-atrial natriuretic peptide (β±SE=0.08±0.02 pmol/L; P<0.0001), mid-regional pro-adrenomedullin (β±SE=0.09±0.03 nmol/L; P=0.0006), C-terminal pro-endothelin (β± SE=0.05±0.02 pmol/L; P=0.0009), and osteoprotegerin (β±SE=0.07±0.02 pg/mL; P=0.0005) (β is for 1 log increase in biomarker level). The associations of these biomarkers with LV mass index were mainly due to their association with eccentric hypertrophy. Higher circulating levels of natriuretic peptides, adrenomedullin, endothelin, and osteoprotegerin were associated with increased LV mass index, providing insights into the pathophysiology of LV hypertrophy in blacks.     

Management of post-myocardial infarction patients with left ventricular systolic dysfunction

After a myocardial infarction (MI), patients are at risk for reinfarction, heart failure (HF), and sudden death. This risk is much higher in patients with left ventricular systolic dysfunction (LVSD). Although post-MI patients with LVSD have an even greater risk of mortality and morbidity, they had been generally excluded from clinical trials. This article reviews recent clinical trials that included post-MI patients with LVSD with or without signs and symptoms of HF. These trials have defined the benefits of pharmacologic management and device therapy in patients who survive an MI in the presence of LVSD.     

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.     

Progressive left ventricular remodeling in patients with hypertrophic cardiomyopathy and severe left ventricular hypertrophy

OBJECTIVES: The aim of this study was to determine the natural history of patients with hypertrophic cardiomyopathy (HCM) and severe left ventricular hypertrophy (LVH) (i.e., maximal left ventricular wall thickness [MLVWT] >/=30 mm) and whether changes in cardiac morphology influence the course of the disease. BACKGROUND: Severe LVH is common in young and rare among elderly patients with HCM. This has been explained by a high incidence of sudden death. We hypothesized that this age-related difference might be explained by left ventricular wall thinning. METHODS: A total of 106 (age 33 +/- 15 years; 71 males) consecutive patients with severe LVH underwent history taking, examination, electrocardiography, echocardiography, cardiopulmonary exercise testing, and Holter analysis. Survival data were collected at subsequent clinic visits or by communication with patients and their general practioners. In order to assess morphologic and functional changes, 71 (67.0%) patients (mean age 31 +/- 15 years; 47 males) followed at our institution underwent serial (>/=1 year) assessment. RESULTS: Of the 106 patients, the majority (78 [71.6%]) were <40 years of age. During follow-up (92 +/- 50 months [range 1 to 169]), 18 (17.0%) patients died or underwent heart transplantation (13 sudden cardiac deaths, 2 heart failure deaths, 1 heart transplantation, 1 stroke, 1 postoperative death). Five-year survival from sudden death was 90.1% (95% confidence interval [CI] 84.0% to 96.3%), and that from heart failure death or transplantation was 97.7% (95% CI 94.5 to 100). In patients serially evaluated over 85 +/- 51 months, there was an overall reduction in MLVWT of 0.6 mm/year (95% CI 0.31 to 0.81, p = 0.00004). Wall thinning >/=5 mm was observed in 41 patients (57.7%; age 35 +/- 13 years; 28 males). On multivariate analysis, the follow-up duration only predicted wall thinning (0.6 mm/year, 95% CI 0.38 to 0.85, p < 0.00001). CONCLUSIONS: Left ventricular remodeling is common in patients with severe LVH and contributes to the low prevalence of severe LVH seen in middle age and beyond.     

CRNK gene transfer improves function and reverses the myosin heavy chain isoenzyme switch during post-myocardial infarction left ventricular remodeling

PYK2 is a Ca²⁺-dependent, nonreceptor protein tyrosine kinase that is involved in the induction of left ventricular hypertrophy (LVH) and its transition to heart failure. We and others have previously investigated PYK2's function in vitro using cultured neonatal and adult rat ventricular myocytes as model systems. However, the function of PYK2 in the in vivo adult heart remains unclear. Here we evaluate the effect of PYK2 inhibition following myocardial infarction (MI) using adenoviral (Adv) overexpression of the C-terminal domain of PYK2, known as CRNK. First we demonstrate that CRNK functions as a dominant-negative inhibitor of PYK2-dependent signaling, presumably by displacing PYK2 from focal adhesions and costameres. Then, male Sprague–Dawley rats (~ 300 g) underwent permanent left anterior descending coronary artery ligation. One wk post-MI, either Adv-GFP (n = 34) or Adv-CRNK (n = 28) was administered (10¹⁰ pfu, 0.1 ml) via catheter-based, Optison^®-mediated gene transfer. LV structure and function were evaluated by echocardiography 1 and 3 wk after gene transfer, and LV tissue was analyzed by real-time RT-PCR and Western blotting. CRNK overexpression was readily detected by Western blotting 1 wk following gene transfer. Adv-CRNK improved overall survival (P = 0.03; Logrank Test) and LV fractional shortening (23 ± 2% vs. 31 ± 2% for Adv-GFP vs. Adv-CRNK infected animals, respectively; P < 0.05). Whereas MI hearts exhibited increased β-, and decreased α-myosin heavy chain (MHC) mRNA expression characteristic of LVH, Adv-CRNK reversed the MHC isoenzyme switch (3.3 ± 1.4 fold increase in αMHC; 0.4 ± 0.1 fold decrease in βMHC; P < 0.05 for both). In summary, CRNK gene transfer improves survival, increases LV function, and alters MHC gene expression suggesting an attenuation of LV remodeling post-MI.     

Concentric left ventricular remodeling in endothelial nitric oxide synthase knockout mice by chronic pressure overload

OBJECTIVE: Heart failure as a consequence of sustained hemodynamic overload is among the most prevalent diseases in developed countries. The aim of the present study was to investigate the specific role of endothelial nitric oxide synthase (eNOS) in pressure overload-induced left ventricular (LV) hypertrophy. METHODS AND RESULTS: Chronic pressure-overload LV hypertrophy was induced by abdominal aortic banding (AC) in wild-type (WT) and eNOS(-/-) mice. Six weeks after abdominal AC, the consequences of the sustained pressure overload on LV morphology and function were noninvasively and invasively assessed using echocardiography and a 1.4 F conductance catheter. Sham-operated eNOS(-/-) mice had significantly increased systolic blood pressure, slightly enhanced systolic function (preload recruitable stroke work) and normal diastolic function but no evidence of left ventricular hypertrophy when compared to sham-operated WT animals. AC resulted in a greater increase in anterior wall thickness in eNOS(-/-) mice (0.8+/-0.03 mm) compared to WT mice (0.7+/-0.03 mm; P<0.05). The LV end-diastolic diameter was unchanged by AC in eNOS(-/-) mice (sham: 3.8+/-0.1 mm, AC: 3.7+/-0.2 mm) but significantly increased in WT mice (sham: 3.9+/-0.1 mm, AC: 4.5+/-0.2 mm; P<0.05). Interstitial fibrosis and myocyte hypertrophy were greater in eNOS(-/-) than in WT mice after AC. AC in eNOS(-/-) mice caused a greater diastolic than systolic dysfunction compared to WT mice. CONCLUSION: Chronic pressure overload in eNOS(-/-) mice results in concentric LV hypertrophy without LV dilation and impaired systolic and diastolic function. These findings suggest that eNOS limits LV remodeling and dysfunction and modulates extracellular matrix proteins under chronic pressure overload.     

Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice

Background- To investigate the role of endothelial nitric oxide synthase (NOS3) in left ventricular (LV) remodeling after myocardial infarction (MI), the impact of left anterior descending coronary artery ligation on LV size and function was compared in 2- to 4-month-old wild-type (WT) and NOS3-deficient mice (NOS3(-/-)). Methods and Results- Two days after MI, both strains of mice had a similar LV size, fractional shortening, and ejection fraction by echocardiography. Twenty-eight days after MI, both strains had dilated LVs with decreased fractional shortening and lower ejection fractions. Although the infarcted fraction of the LV was similar in both strains, LV end-diastolic internal diameter, end-diastolic volume, and mass were greater, but fractional shortening, ejection fraction, and the maximum rate of developed LV pressure (dP/dt(max)) were lower in NOS3(-/-) than in WT mice. Impairment of diastolic function, as measured by the time constant of isovolumic relaxation (tau) and the maximum rate of LV pressure decay (dP/dt(min)), was more marked in NOS3(-/-) than in WT mice. Mortality after MI was greater in NOS3(-/-) than in WT mice. Long-term administration of hydralazine normalized blood pressure in NOS3(-/-) mice, but it did not prevent the LV dilatation, impaired systolic and diastolic function, and increased LV mass that followed MI. In WT mice, capillary density and myocyte width in the nonischemic portion of the LV did not differ before and 28 days after MI, whereas in NOS3(-/-) mice, capillary density decreased and myocyte width increased after MI, whether or not hydralazine was administered. Conclusions- These results suggest that the presence of NOS3 limits LV dysfunction and remodeling in a murine model of MI by an afterload-independent mechanism, in part by decreasing myocyte hypertrophy in the remote myocardium.