Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction

Cellular FLICE-inhibitory protein (cFLIP) is a member of the tumour necrosis factor signalling pathway and a regulator of apoptosis, and it has a role in cardiac remodelling following myocardial infarction (MI) that remains largely uncharacterised. This study aimed to determine the function of cFLIP as a potential mediator of post-infarction cardiac remodelling. Our results show diminished cFLIP expression in failing human and murine post-infarction hearts. Genetically engineered cFLIP heterozygous (cFLIP+/-, HET) mice, cardiac-specific cFLIP-overexpressing transgenic (TG) mice and their respective wild-type (WT) and non-transgenic controls were subjected to MI by permanent ligation of their left anterior descending artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Apoptosis, inflammation, angiogenesis, and fibrosis were evaluated in the myocardium. The HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and remodelling compared with WT mice 28 days after MI. Impaired LV function in the HET mice was associated with increases in infarct size, hypertrophy, apoptosis, inflammation, and interstitial fibrosis, and reduced capillary density. The TG mice displayed the opposite phenotype after MI. Moreover, adenovirus-mediated overexpression of cFLIP decreased LV dilatation and improved LV function and remodelling in both HET and WT mice. Further analysis of signalling events suggests that cFLIP promotes cardioprotection by interrupting JNK1/2 signalling and augmenting Akt signalling. In conclusion, our results indicate that cFLIP protects against the development of post-infarction cardiac remodelling. Thus, cFLIP gene delivery shows promise as a clinically powerful and novel therapeutic strategy for the treatment of heart failure after MI.     

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

Deficiency in cellular thiol tripeptide glutathione (L-gamma glutamyl-cysteinyl-glycine) determines the severity of several chronic and inflammatory human diseases that may be relieved by oral treatment with the glutathione precursor N-acetylcysteine (NAC). Here, we showed that the left ventricle (LV) of human failing heart was depleted in total glutathione by 54%. Similarly, 2-month post-myocardial infarction (MI) rats, with established chronic heart failure (CHF), displayed deficiency in LV glutathione. One-month oral NAC treatment normalized LV glutathione, improved LV contractile function and lessened adverse LV remodelling in 3-month post-MI rats. Biochemical studies at two time-points of NAC treatment, 3 days and 1 month, showed that inhibition of the neutral sphingomyelinase (N-SMase), Bcl-2 depletion and caspase-3 activation, were key, early and lasting events associated with glutathione repletion. Attenuation of oxidative stress, downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and its TNF-R1 receptor were significant after 1-month NAC treatment. These data indicate that, besides glutathione deficiency, N-SMase activation is associated with post-MI CHF progression, and that blockade of N-SMase activation participates to post-infarction failing heart recovery achieved by NAC treatment. NAC treatment in post-MI rats is a way to disrupt the vicious sTNF-alpha/TNF-R1/N-SMase cycle.     

Beneficial effects of ramipril on left ventricular end-diastolic and end-systolic volume indexes after uncomplicated invasive revascularization are associated with a reduction in cardiac events in patients with moderately impaired left ventricular function and no clinical heart failure

OBJECTIVES We sought to assess the effect of ramipril on left ventricular (LV) volumes, and the clinical significance thereof, in patients with moderate LV dysfunction and no clinical heart failure undergoing invasive revascularization for chronic stable angina. BACKGROUND: It is unsettled whether treatment with an angiotensin-converting enzyme inhibitor has an impact on LV volumes in this patient group, and, if so, whether this is associated with the clinical outcome. METHODS: A total of 133 patients with a left ventricular ejection fraction (LVEF) between 0.30 and 0.50 and no clinical heart failure undergoing invasive revascularization for chronic stable angina were randomized to receive ramipril 10 mg once daily or placebo and were followed for a median of 33 months with echocardiography at baseline and 3, 12 and 24 months postoperatively. RESULTS: Repeated measures analysis of all time points showed that ramipril significantly reduced the end-diastolic volume index (EDVI) (p = 0.032) and end-systolic volume index (ESVI) (p = 0.006) as compared with placebo. Ramipril also reduced the incidence of the triple composite end point of cardiac death, acute myocardial infarction or development of heart failure (p = 0.046). Cox regression analysis, controlling for baseline LVEF and assignment to ramipril, revealed: 1) that increases in EDVI and ESVI up to three months predicted an increasing risk of a future adverse clinical outcome; and 2) that the benefit with ramipril on clinical outcome was partly dependent on a reduction in LV volumes. CONCLUSIONS: Even in this patient group, LV dilation may supervene and lead to an adverse clinical outcome. Ramipril reduces the postoperative increase in LV volumes and may thereby improve clinical outcome.     

辛伐他汀对家兔心肌梗死后心室重构及心功能的影响

目的研究辛伐他汀对家兔心肌梗死后(MI)心室重构及心功能的影响。方法家兔20只采用结扎冠状动脉左前降支的方法建立急性心肌梗死模型,随机分MI组(10只)和辛伐他汀组(10只)。MI组术后不给任何处理和干预,辛伐他汀干预组在MI术后3d口服辛伐他汀(10mg.kg-1.d-1)10周。术前和术后10周进行超声心动图检查。术后10周进行有创血液动力学测定,而后摘取心脏称重。取两组家兔左心室进行HE染色,做组织细胞学检查。结果10周后辛伐他汀组家兔左室重量、左室舒张期末径、左室收缩期末径、左房直径及左室舒张期末压显著低于MI组,射血分数、缩短分数明显高于MI组(P<0.05)。HE染色辛伐他汀组与MI组比较,心肌细胞变性坏死明显减轻,炎性细胞浸润减少,间质纤维化减轻,非梗死区心肌细胞的代偿性肥大增生较MI组为低。结论辛伐他汀能够改善心肌梗死后家兔心室重构和心功能。     

Cardiovascular Effects of the Converting Enzyme Inhibitor Ramipril (HOE 498) In Anesthetized Dogs with Acute Ischemic Left Ventricular Failure

The non-sulfhydryl converting enzyme inhibitor Ramipril (HOE 498) is characterized by long lasting antihypertensive activity in man. To examine its cardiovascular potential in heart failure, ramipril was administered during acute ischemic left ventricular failure in pentobarbital anesthetized dogs, induced by repeated injections of plastic microspheres into the left main coronary artery.

Repeated embolizations produced stable left ventricular (LV) pump failure characterized by LV enddiastolic pressure of 22 mmHg, reductions in LV dp/dt max and cardiac output. Blood pressure and heart rate were not changed while total peripheral resistance increased. After a stabilization period ramipril was administered in two doses at 30 or 100 μg/kg as an intravenous bolus followed by continuous infusion of 3 or 10 μg/kg/min for 150 min. Ramipril in the lower dose decreased LV enddiastolic pressure by 8 mmHg, mean pulmonary artery pressure by 4 mmHg, systemic blood pressure by 40 mmHg and total peripheral resistance by 1280 dyn × sec × cm^?5. LV dp/dt max, heart rate and cardiac output remained unchanged during ramipril administration. More pronounced effects were obtained with the higher dose.

In conclusion, the improvements of hemodynamics produced by ramipril during acute ischemic left ventricular failure in anesthetized dogs are best explained by a reduction in both preload and afterload.     

Circulating levels of hepatocyte growth factor and left ventricular remodelling after acute myocardial infarction (from the REVE-2 study)

Aim As experimental studies suggest that hepatocyte growth factor (HGF) is cardioprotective after myocardial infarction (MI), this study sought to investigate relationships between circulating levels of HGF and left ventricular (LV) remodelling in patients after acute MI. METHODS AND RESULTS: This prospective multicentre study included 246 patients with a first anterior Q-wave MI. Serial echocardiographic studies were performed at hospital discharge and 3 and 12 months after MI; quantitative analysis was performed at a core echocardiography laboratory. Blood samples to measure HGF, brain natriuretic peptide (BNP), and C-reactive protein were obtained at discharge and at the 1, 3, and 12 month follow-up visits. Plasma HGF levels were high at baseline, decreased at 1 month, and remained stable thereafter. In the post-MI period (at 3 and 12 months), HGF levels were positively associated with LV volumes, wall motion systolic index, E/Ea, and BNP; and negatively with LV ejection fraction. High HGF levels were associated with higher C-reactive protein levels. Multivariate analysis showed that both BNP (P < 0.0001) and C-reactive protein (P < 0.0001) were independently associated with HGF levels at 3 and 12 months. Patients who died or were rehospitalized for heart failure during follow-up had higher HGF levels at 1 month (P = 0.0006), 3 months (P = 0.018), and 1 year (P = 0.006) after MI. CONCLUSIONS: Circulating HGF levels correlate with all markers of LV remodelling after MI and are associated with rehospitalization for heart failure.     

Regional wall stress predicts ventricular remodeling after anteroseptal myocardial infarction in the Healing and Early Afterload Reducing Trial (HEART): an echocardiography-based structural analysis

BACKGROUND: Increased left ventricular (LV) wall stress after myocardial infarction (MI) has been implicated in LV remodeling. However, the relationship between LV wall stress and LV remodeling is incompletely defined. METHOD: We prospectively studied the relationship between regional wall stress and LV remodeling by application of the finite element method to end-systolic LV models from patients enrolled in the Healing and Early Afterload Reducing Therapy (HEART) Trial. Individual LV models were constructed from orthogonal apical echocardiographic views obtained at day 14 after anteroseptal MI in 64 patients. Of these, 31 patients received low-dose (0.625 mg) ramipril and 33 patients received full-dose (10 mg) ramipril. LV wall stress was calculated by the finite element method and correlated with change in LV volume from day 14 to day 90 after MI. RESULTS: Among all patients, increases in apical regional wall stress were associated with LV volume changes (P -trend =.015). The relationship between apical regional wall stress and change in LV volume was strongest in the low-dose ramipril group (r = 0.53, P =.002) and remained significant after adjustment for end-diastolic volume, infarct size, ejection fraction, and systolic blood pressure yet was attenuated in the full-dose ramipril group. CONCLUSIONS: Apical regional wall stress is an independent predictor of subsequent LV remodeling after MI. The relationship between increased apical wall stress and LV dilatation appears to be attenuated by full-dose angiotensin-converting enzyme inhibition.     

Effect of ramipril and furosemide treatment on interstitial remodeling in post-infarction heart failure rat hearts

Extracellular matrix (ECM) remodeling and increased matrix metalloproteinase (MMP) expression and activity have been observed to be relevant in the development of heart failure (HF). We examined the effects of ramipril alone or with furosemide on ECM in a heart failure model. HF was induced by occlusion of the left coronary artery in spontaneously hypertensive rats (SHR). Rats were assigned to placebo (n=9), ramipril 1 mg/kg/day (n=11), furosemide 2 x 2 mg/kg/day (n=7) or both (1 mg/kg/day + 2 x 2 mg/kg/day n=8). LV-function, collagen content, MMP/TIMP (tissue inhibitor of matrix metalloproteinases) protein- and mRNA-expression were examined in non-infarcted LV tissue. MMP-2/TIMP-4 ratio was increased in HF. Ramipril reduced MMP-2 expression (active form), collagen type I mRNA expression and content and increased TIMP-4 levels associated with decreased left ventricular end diastolic pressure (LVEDP), mortality rate and increased LV pressure (LVP). Combination therapy with furosemide is less efficient with regard to collagen content and MMP-2 (active form) reduction but did not worsen beneficial effects of ramipril on LV function and mortality rate. Furosemide alone had no effect on MMP-2 (active form) expression, collagen content, LV function and mortality rate. Prevention of LV dilatation by ramipril was associated with decreased gelatinolytic activity and increased MMP-inhibition in heart failure SHR. Furthermore, ramipril reduced fibrosis by enhanced interstitial collagenase expression. Furosemide did not show the beneficial effects of ramipril on ECM remodeling but did not worsen LV function. Positive effects of furosemide treatment alone on LV remodeling and function were not observed.     

Prevention of adverse electrical and mechanical remodeling with biventricular pacing in a rabbit model of myocardial infarction.

BACKGROUND: Biventricular (BIV) pacing can improve cardiac function in heart failure (HF). OBJECTIVE: This study sought to investigate the mechanisms of benefit of BIV pacing using a rabbit model of myocardial infarction (MI). METHODS: New Zealand White rabbits were divided into 4 groups (sham-operated [C], MI with no pacing [MI], MI with right ventricular pacing [MI+RV], and MI with BIV pacing [MI+BIV]) and underwent serial electrocardiograms and echocardiograms. At 4 weeks, hearts were excised and tissue was extracted from various areas of the left ventricle (LV). RESULTS: Four weeks after coronary ligation, BIV pacing prevented systolic and diastolic dilation of the LV as well as the reduction in its fractional shortening, restored the QRS width and the rate-dependent QT intervals to their baseline values, and prevented the decline of the ether-a-go-go (Erg) protein levels. This prevention of remodeling was not documented in the MI+RV groups. CONCLUSION: In this rabbit model of BIV pacing and MI, we show prevention of adverse mechanical and electrical remodeling of the heart. These changes may underlie some of the benefits seen with BIV pacing in HF patients with more severe LV dysfunction.     

Decreased level of melatonin in serum predicts left ventricular remodelling after acute myocardial infarction

Abstract: As experimental studies suggest that melatonin is cardioprotective after myocardial infarction (MI), this study sought to investigate the relationships between circulating levels of melatonin and left ventricular (LV) remodelling in patients after acute MI. This prospective study included 161 patients (age 61 ± 3 yr; 78% men) undergoing primary percutaneous coronary intervention who were assessed echocardiographically at hospital discharge (day 3–7) and at 12 months. LV remodelling was defined as >20% increase in LV end‐diastolic volume at 12‐month follow‐up compared with baseline. Serum melatonin concentrations were measured at admission, during the light period. Twenty‐four patients showed LV remodelling, and 137 had no evidence of LV remodelling. Patients with LV remodelling had lower levels of melatonin at study entry [9.96 (8.28–11.03) versus 16.74 (13.77–19.59) pg/mL, respectively; P < 0.0001]. Multivariate analysis showed that melatonin levels (OR = 2.10, CI 95% 1.547–2.870, P < 0.001) were an independent predictor of LV remodelling at 12‐month follow‐up. Receiver operating characteristic (ROC) analysis showed an area under the curve of 0.959 (CI 95% 0.93–0.98; P < 0.0001). To our knowledge, this is the first study to show the relationship between melatonin and LV remodelling during the chronic phase post‐MI.     

Cardiac remodelling in the era of aggressive medical therapy: does it still exist?

AIM: To delineate the natural history of left ventricular remodelling following large anterior myocardial infarction (MI), in the era of aggressive medical therapy. METHODS: Seventeen selected patients underwent cardiovascular magnetic resonance (CMR) at 2 weeks and 1, 3, 6 and 12 months post infarction. RESULTS: There was a significant increase in left ventricular (LV) end-diastolic volume index (EDVI) and LV ESVI from 2 weeks to 1 month (P<0.05) but no significant change thereafter. The LV ejection fraction (EF) decreased from 2 weeks to 1 month (P<0.05) and then increased over the year (P=0.02). Throughout the study period the sphericity index increased. There was a significant and progressive decrease in LV mass index over the year, which was associated with a decrease in wall thickness at both the infarct and non-infarct sites. Independent predictors of an early increase in LVESVI were increasing age, increasing CK-MB and not receiving treatment with a statin. CONCLUSION: This study delineates the natural history of left ventricular remodelling in the modern medical era in those patients who have suffered a large anterior MI. Classical remodelling occurred up to 1 month, but thereafter was attenuated. These findings would suggest that remodelling is not as prevalent in the modern era, and that combined medical management with thrombolysis, ACEi, beta-blockers and statins may strongly influence the development of this remodelling.     

Effects of ramipril on left ventricular mass and function in cardiovascular patients with controlled blood pressure and with preserved left ventricular ejection fraction: a substudy of the Heart Outcomes Prevention Evaluation (HOPE) Trial

OBJECTIVES: The purpose of this study was to assess the effects of ramipril on left ventricular mass (LVM) and function in vascular disease patients with controlled blood pressure (BP) and with preserved left ventricular ejection fraction (LVEF). BACKGROUND: Increased LVM and left ventricular (LV) volume and decreased LVEF predict clinical events. Angiotensin-converting enzyme inhibitors reduce LVM and LV volume and preserve LVEF in patients with hypertension and/or LV dysfunction, but have not been studied in patients with controlled BP and preserved LVEF. METHODS: We compared the effects of two doses of ramipril (10 mg/day and 2.5 mg/day) versus placebo in 506 patients with vascular disease on echocardiographic measures of LVM and LV function. RESULTS: Baseline BP and LVEF were similar, 131/76 mm Hg and 58%, in all treatment groups. After four years, LVM index increased by 3.98 +/- 2.08 g/m2 in the placebo and by 4.16 +/- 1.86 g/m2 in the ramipril 2.5 mg/day groups and decreased by 2.02 +/- 2.25 g/m2 in the ramipril 10 mg/day group (p = 0.02). The changes in LV end-diastolic and end-systolic volumes were 4.16 +/- 2.55 ml and 5.31 +/- 1.67 ml in the placebo, -0.43 +/- 2.75 ml and 2.90 +/- 1.45 ml in the ramipril 2.5 mg/day, and -5.90 +/- 2.93 ml and -1.90 +/- 1.55 ml in the ramipril 10 mg/day groups (p = 0.02 and p = 0.001). The changes in LVEF were -2.02 +/- 0.72%, -1.54 +/- 0.74%, and -0.17 +/- 0.72%, respectively (p = 0.01). CONCLUSIONS: Ramipril has beneficial effects on LV structure and function in vascular patients with controlled BP and with preserved LVEF.     

Late coronary artery recanalization effects on left ventricular remodelling and contractility by magnetic resonance imaging.

AIMS: To assess the recanalization effects of post-myocardial infarction (MI) on left ventricular (LV) remodelling and contractility in relation to conservative therapy. METHODS AND RESULTS: Thirty-six patients with occluded infarct-related artery between 12 h and 14 days post-anterior MI were randomized to percutaneous coronary intervention (PCI group) or conservative therapy (no-PCI group). Magnetic resonance imaging was performed at enrollment and after 6 months. The left ventricle was divided into infarct, adjacent, and remote segments. There was no difference in relation to LV volume between groups at the 6 month follow-up. Change in LV ejection fraction was favourable to the PCI group: 5.00% vs. -0.76%, P=0.012. Change in circumferential shortening (Ecc) of the remote segments in the PCI group was significantly better than in the no-PCI group: -1.67+/-6.30% vs. 0.29+/-6.02%, P<0.001. Infarct size and LV mass were similar between groups. CONCLUSIONS: Late recanalization improved LV ejection fraction and myocardial contractility in late follow-up, but did not change the ventricular volumes. Improvement in the left ventricle global and regional contractility may benefit the long-term outcome in post-MI patients with sustained patency of the infarct-related artery.     

Stress hyperglycaemia is an independent predictor of left ventricular remodelling after first anterior myocardial infarction in non-diabetic patients.

AIMS: Stress hyperglycaemia (SH) is associated with adverse outcome in patients with acute myocardial infarction (MI) but the mechanisms underlying this association are unknown. Our hypothesis was that SH on admission for acute MI may be associated with left ventricular (LV) remodelling. METHODS AND RESULTS: We analysed LV remodelling in 162 non-diabetic patients with anterior MI. SH was defined as a glycaemia on admission >or=7 mmol/L. Systematic echocardiographic follow-up was performed at 3 months and 1 year after MI. The changes in end-diastolic volume (EDV) and end-systolic volume (ESV) from baseline to 1 year were 11.4 +/- 16.5 and 6.4 +/- 12.4 ml/m(2), respectively, in patients with SH vs. 1.9 +/- 11.1 and 0.2 +/- 8.5 ml/m(2), respectively, in patients without SH (both P < 0.0001). When LV remodelling was defined as a >20% increase in EDV, it was observed in 46% patients in the SH group vs. 19% patients in the no SH group (P = 0.0008). By multivariable analysis, baseline wall motion score index (P = 0.001) and SH (P = 0.009) were independently associated with changes in EDV. SH was an independent predictor of LV remodelling [adjusted OR: 3.22 (1.31-7.94)]. CONCLUSION: SH is a major and independent predictor of LV remodelling after anterior MI in non-diabetic patients.     

Serial echocardiographic assessment of the left ventricular function after direct PCI

BACKGROUND: Acute myocardial infarction (AMI) causes remodelling of the left ventricle (LV). Restoration of patency of an infarct-related artery by percutaneous coronary interventions (PCI) may prevent or inhibit cardiac remodelling. AIM: To assess LV contractility and function by serial echocardiographic examinations. METHODS: The study group consisted of 61 patients (47 males, mean age 60+/-10 years) with acute MI treated with direct PCI. Echocardiography was performed 6-8 days after PCI, and 1, 6 and 12 months thereafter. RESULTS: LV ejection fraction increased significantly at the end of the first month in comparison with the baseline examination whereas EF values obtained after 6 months and after 1 year were not significantly different. Wall motion score index showed a significant improvement after one month, whereas it did not show any further improvement when measured after 6 or 12 months after AMI. The baseline LV end-diastolic diameter was 49+/-6 mm and did not change after one or 6 months, whereas it increased significantly 12 months after AMI. The baseline LV end-systolic diameter was 37+/-5 mm. At the one-month and six-month examinations it was similar to the baseline values but increased significantly to 38+/-6 mm after one year. CONCLUSIONS: These results confirm the beneficial effects of PCI-induced infarct-related artery patency on LV remodelling after AMI.     

Left atrial remodelling in patients with myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: the VALIANT Echo Study

Aims: To assess the relationship between left atrial (LA) size andoutcome after high-risk myocardial infarction (MI) and to studydynamic changes in LA size during long-term follow-up. Methods and results: The VALIANT Echocardiography study prospectively enrolled 610patients with left ventricular (LV) dysfunction, heart failure(HF), or both following MI. We assessed LA volume indexed tobody surface area (LAVi) at baseline, 1 month, and 20 monthsafter MI. Baseline LAVi was an independent predictor of all-causedeath or HF hospitalization (P = 0.004). In patients who survivedto 20 months, LAVi increased a mean of 3.00 ± 7.08 mL/m²from baseline. Hypertension, lower estimated glomerular filtrationrate, and LV mass were the only baseline independent predictorsof LA remodelling. Changes in LA size were related to worseningin MR and increasing in LV volumes. LA enlargement during thefirst month was significantly greater in patients who subsequentlydied or were hospitalized for HF than in patients without events. Conclusion: Baseline LA size is an independent predictor of death or HFhospitalization following high-risk MI. Moreover, LA remodellingduring the first month after infarction is associated with adverseoutcome.