Postinfarction Left Ventricular Dysfunction Research Articles

Prognostic value of ventricular arrhythmia in early post-infarction left ventricular dysfunction: the French nationwide WICD-MI study.

Prophylactic implantable cardioverter-defibrillators (ICDs) are not recommended until left ventricular ejection fraction (LVEF) has been reassessed 40 to 90 days after an acute myocardial infarction. In the current therapeutic era, the prognosis of sustained ventricular arrhythmias (VAs) occurring during this early post-infarction phase (i.e. within 3 months of hospital discharge) has not yet been specifically evaluated in post-myocardial infarction patients with impaired LVEF. Such was the aim of this retrospective study. Data analysis was based on a nationwide registry of 1032 consecutive patients with LVEF ≤ 35% after acute myocardial infarction who were implanted with an ICD after being prescribed a wearable cardioverter-defibrillator (WCD) for a period of 3 months upon discharge from hospital after the index infarction. ICDs were implanted either because a sustained VA occurred while on WCD (VA+/WCD, n = 72) or because LVEF remained ≤35% at the end of the early post-infarction phase (VA-/WCD, n = 960). The median follow-up was 30.9 months. Sustained VAs occurred within 1 year after ICD implantation in 22.2% and 3.5% of VA+/WCD and VA-/WCD patients, respectively (P < .0001). The adjusted multivariable analysis showed that sustained VAs while on WCD independently predicted recurrence of sustained VAs at 1 year (adjusted hazard ratio [HR] 6.91; 95% confidence interval [CI] 3.73-12.81; P < .0001) and at the end of follow-up (adjusted HR 3.86; 95% CI 2.37-6.30; P < .0001) as well as 1-year mortality (adjusted HR 2.86; 95% CI 1.28-6.39; P = .012). In patients with LVEF ≤ 35%, sustained VA during the early post-infarction phase is predictive of recurrent sustained VAs and 1-year mortality.

Recombinant human placental growth factor-2 in post-infarction left ventricular dysfunction: a randomized, placebo-controlled, preclinical study.

Placental growth factor (PlGF)-2 induces angio- and arteriogenesis in rodents but its therapeutic potential in a clinically representative post-infarction left ventricular (LV) dysfunction model remains unclear. We, therefore, investigated the safety and efficacy of recombinant human (rh)PlGF-2 in the infarcted porcine heart in a randomized, placebo-controlled blinded study. We induced myocardial infarction (MI) in pigs using 75min mid-LAD balloon occlusion followed by reperfusion. After 4w, we randomized pigs with marked LV dysfunction (LVEF < 40%) to receive continuous intravenous infusion of 5, 15, 45µg/kg/day rhPlGF-2 or PBS (CON) for 2w using osmotic pumps. We evaluated the treatment effect at 8w using comprehensive MRI and immunohistochemistry and measured myocardial PlGF-2 receptor transcript levels. At 4w after MI, infarct size was 16-18 ± 4% of LV mass, resulting in significantly impaired systolic function (LVEF 34 ± 4%). In the pilot study (3 pigs/dose), PIGF administration showed sustained dose-dependent increases in plasma concentrations for 14days without systemic toxicity and was associated with favorable post-infarct remodeling. In the second phase (n = 42), we detected no significant differences at 8 w between CON and PlGF-treated pigs in infarct size, capillary or arteriolar density, global LV function and regional myocardial blood flow at rest or during stress. Molecular analysis showed significant downregulation of the main PlGF-2 receptor, pVEGFR-1, in dysfunctional myocardium. Chronic rhPIGF-2 infusion was safe but failed to induce therapeutic neovascularization and improve global cardiac function after myocardial infarction in pigs. Our data emphasize the critical need for properly designed trials in representative large animal models before translating presumed promising therapies to patients.

Heart Rate Variability and Its Associations with Organ Complications in Adults after Fontan Operation.

Reduction of heart rate variability (HRV) parameters may be a risk factor and precede the occurrence of arrhythmias or the development of heart failure and complications in people with postinfarct left ventricular dysfunction and after coronary artery bypass grafting. Data on this issue in adults after a Fontan operation (FO) are scarce. This study assessed the association between HRV, exercise capacity, and multiorgan complications in adults after FO. Data were obtained from 30 FO patients (mean age 24 ± 5.4 years) and 30 healthy controls matched for age and sex. HRV was investigated in all patients by clinical examination, laboratory tests, echocardiography, a cardiopulmonary exercise test, and 24-h electrocardiogram. The HRV parameters were reduced in the FO group. Reduced HRV parameters were associated with patients’ age at the time of FO, time since surgery, impaired exercise capacity, chronotropic incompetence parameters, and multiorgan complications. Univariate analysis showed that saturated O2 at rest, percentage difference between adjacent NN intervals of >50 ms duration, and peak heart rate were associated with chronotropic index. Multivariable analysis revealed that all three variables were independent predictors of the chronotropic index. The results of this study suggest novel pathophysiological mechanisms that link HRV, physical performance, and organ damage in patients after FO.

Proteomics of Mouse Heart Ventricles Reveals Mitochondria and Metabolism as Major Targets of a Post-Infarction Short-Acting GLP1Ra-Therapy.

Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein–protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.

Regionally Influenced Content of Selenium and Its Capacity under Postoperative Myocardial Remodeling in Cardiac Surgery Patients

Selenium (Se) is an essential micronutrient in living organisms; however, some aspects of its metabolism and function remain unknown. Se deficiency causes significant disturbances in the cardiovascular system along with left ventricular (LV) fibrosis. Simultaneously, an understanding of pathways that influence Se role in heart failure progression is insufficient. Therefore, clinical studies are needed to characterize Se importance in developing post-infarct LV dysfunction and postoperative remodeling. In the Tomsk region, the level of Se in healthy people and the myocardium of patients with ischemic cardiomyopathy was close to normal. Quantitative chemical analysis of Se content in hair samples and LV myocardium was based on stripping voltammetry to determine mass concentrations of the micro-element. Nevertheless, a significant number of cardiac surgery patients showed negative dynamics of postoperative LV myocardium remodeling with the development of heart failure. We obtained preliminary results of a direct correlation between favorable outcomes of postoperative adaptive myocardial remodeling (AR) and maladaptive myocardial remodeling (MALR) with different Se concentrations in the myocardium. Simultaneously, about 84% of patients showed abnormal postoperative LV MALR in high Se in the myocardium. Further in-depth studies are required to translate novel data from the laboratory bench to the clinics.

A REVIEW ON THE EFFECTIVENESS OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN REDUCING CARDIOVASCULAR MORBIDITY AND MORTALITY RISKS

ABSTRACT Angiotensin converting enzyme inhibitors (ACEIs) are long been preferred as a therapeutic choice for cardiovascular disease due to its safe supremacy to overcome the deleterious effects of Angiotensin II, which is a strong vasoconstrictor increases the levels of different growth factors and adhesion molecules. It produces an oxidative stress that accounts for its apoptotic properties. The cardiac myocyte undergoes necrosis induced by angiotensin II and it also activates neurohumoral system in post infarction left ventricular dysfunction patients. ACE inhibitors reduce the production of angiotensin II by endothelial cells. It also simultaneously diminishes the deprivation of bradykinin that results in vasodilation to overcome the effects of angiotensin II by exerting its anti-apoptotic actions. Clinical trials such as SAVE, SOLVD, AIRE and TRACE indicated that the life expectancy can be increase by ACE inhibitors in patients having left ventricular dysfunction. EUROPA study suggested that in all patients of coronary heart diseases, perindopril is a treatment of choice along with other preventive therapies. Evidences of clinical researches supports the usage of ACE inhibitors and showed improve clinical results in patients with primary hypertension, stable coronary artery diseases, stable ischemic diseases with preserved ventricular function or reduced ventricular function, and myocardial infarction.FDA has approved that ACE inhibitors as adjunctive therapy in systolic heart failure, and in patients with a history of myocardial infarction and those having reduced ejection fraction to prevent HF. Perindopril is also approved by FDA for cases of stable coronary artery diseases and it is helpful to reduce the risk of mortality with Myocardial infarction. Key Words: Angiotensin II, Cardiac Dysfunction, Coronary artery disease, Heart Failure, Hypertension

Augmented glycaemic gap is a marker for an increased risk of post-infarct left ventricular systolic dysfunction

BackgroundLeft ventricular systolic dysfunction (LVSD) occurs frequently after acute ST-segment elevation myocardial infarction (STEMI). The predisposing factors and underlying mechanism of post-infarct LVSD are not fully understood. The present study mainly investigated the correlation between glycaemic gap, a novel index of stress-induced hyperglycaemia (SIH), and post-infarct LVSD.MethodsA total of 274 first STEMI patients were enrolled in this cross-sectional study. Transthoracic echocardiography was performed within 48 h after admission and at 6 months after discharge to obtain left ventricular ejection fraction (LVEF). The change in LVEF was calculated as LVEF at 6 months after discharge minus baseline LVEF. Additionally, post-infarct LVSD was defined as LVEF ≤ 50%. Most importantly, glycaemic gap was calculated as admission blood glucose (ABG) minus the estimated average glucose over the previous 3 months.ResultsIn patients without diabetes mellitus (DM), multivariate linear regression analysis revealed that both glycaemic gap (Beta = − 1.214, 95% CI − 1.886 to − 0.541, p < 0.001) and ABG (Beta = − 1.124, 95% CI − 1.795 to − 0.453, p = 0.001) were associated with change in LVEF. In DM patients, only glycaemic gap was still associated with change in LVEF, although this association was not observed in univariate linear regression analysis. Regarding the association between SIH and post-infarct LVSD, multivariate logistic regression analysis revealed that both glycaemic gap (OR = 1.490, 95% CI 1.043 to 2.129, p = 0.028) and ABG (OR = 1.600, 95% CI 1.148 to 2.229, p = 0.005) were associated with an increased risk of having post-infarct LVSD in non-DM patients. However, after multivariate adjustment in DM patients, only glycaemic gap (OR = 1.399, 95% CI 1.021 to 1.919, p = 0.037) remained associated with an increased risk of having post-infarct LVSD. Furthermore, the predictive value of glycaemic gap for post-infarct LVSD was not inferior to ABG in non-DM patients (p = 0.499), and only glycaemic gap, instead of ABG, could significantly predict post-infarct LVSD in DM patients (AUC = 0.688, 95% CI 0.591 to 0.774, p = 0.002).ConclusionsGlycaemic gap was strongly associated with a change in LVEF and an increased risk of having post-infarct LVSD in patients following STEMI. In STEMI patients with DM, glycaemic gap could provide more valuable information than ABG in identifying patients at high risk of developing post-infarct LVSD.

Experts of the Heart Rhythm Section of the Polish Cardiac Society: opinion on the use of wearable cardioverter-defibrillators in Poland.

Sudden cardiac death (SCD) is one of the main causes of mortality in developed countries. Implantable cardioverter-defibrillators (ICDs) have become a widely used and efficient method for SCD prevention in high-risk populations. Nevertheless, there are clinical situations in which the benefit of ICD is uncertain, such as: early postinfarction left ventricular dysfunction, reversible causes of cardiomyopathy, presence of temporary or permanent ICD contraindications in high-risk populations, or when ICD is not accepted by SCD prevention candidates. Wearable cardioverter-defibrillator (WCD) can be an alternative option in these clinical circumstances. However, even though WCDs are available in the United States and many countries of Western Europe, they are still not available in Poland. The authors present clinical and organisational recommendations for WCD use in Poland, with respect to medical evidence.

Association of High Sensitive C - Reactive Protein with Severity of the Left Ventricular Systolic Dysfunction in Acute Anterior ST Elevation Myocardial Infarction

High Sensitive C-reactive protein (hs- CRP) is an established risk marker in coronary artery disease. It is a marker of inflammation activated early after Acute Myocardial Infarction (AMI) and its quantity depends upon extent of myocardial damage. Release of inflammatory marker occur after acute myocardial infarction leading to cardiac remodeling which clinically manifests as Heart failure (HF). Heart failure is a common complication after acute anterior myocardial infarction (AMI). The prevalence of post-infarct Left Ventricular Systolic Dysfunction (LVSD) ranges from 27 to 60 % and half of patients having early post-infarct LVSD subsequently develop chronic heart failure. The purpose of this study is to show association between hs-CRP with LVSD in AMI and early detection of HF. This was a cross-sectional analytical study in which hs-CRP was done among all the study subjects between 24-48 hours after onset of AMI. The study population was categorized into groups I, II, II according to the lowest to highest hs-CRP level. Transthoracic echocardiography was done between 24-48 hours of anterior ST Elevation Myocardial Infarction (STEMI). Then LVSD was assessed between those three groups and searched for association. Severely reduced ejection fraction (EF) was found in patients of group III (highest hs-CRP tertile) only. Severe and moderately reduced EF and FS was found significantly more in group III and II than group I (mid and lowest hs-CRP tertile) (p&lt;0.001). High level of hs-CRP in patient of acute anterior STEMI patients was associated with moderate to severe reduction in EF and Fractional Shortening (FS). So hs- CRP may be a prognostic marker in acute anterior STEMI complicating LVSD and early management would improved the short and long term prognosis.

The usefulness of C-reactive protein for the prediction of post-infarct left ventricular systolic dysfunction and heart failure.

Acute myocardial infarction (MI) provokes a systemic inflammatory response that may contribute to the development of left ventricular systolic dysfunction (LVSD) and heart failure (HF). Patients with post-infarct HF with concomitant LVSD have the most unfavourable long-term prognosis. Measurement of C-reactive protein (CRP) concentration reflecting an involvement of inflammatory pathways in post-infarct myocardial damage offers an attractive strategy to improve risk stratification and clinical decision-making for early management of high-risk patients. Despite growing evidence for the prognostic value of CRP both as a single factor and as a component of multi-marker approach in MI, CRP measurement is not yet incorporated into current guidelines. This may be due to conflicting results reported in existing studies related to various limitations in study designs, such as retrospective case control design, prior myocardial damage, CRP measurement with low-sensitivity assays, non-homogenous populations with acute coronary syndromes, different treatment strategies, small sample sizes, and the lack of left ventricular ejection fraction assessment and long-term clinical and echocardiographic monitoring. As a result, previous studies have not provided conclusive evidence of the prognostic value of CRP for post-infarct LVSD or HF. Future studies with an adequate design including upstream mediators of inflammation as inflammatory markers are needed to identify the best biomarker-based strategies for identifying high-risk patients. Further clinical trials involving anti-inflammatory therapies target-ing different pathways of inflammatory activation in MI should test the inflammatory hypothesis of post-infarct LVSD and HF. Identifying high-risk patients with persistent post-infarct inflammatory response may allow incorporation of pathophysiological guidance for implementation of personalised treatment approaches.

Randomized placebo controlled trial evaluating the safety and efficacy of single low-dose intracoronary insulin-like growth factor following percutaneous coronary intervention in acute myocardial infarction (RESUS-AMI)

BackgroundResidual and significant postinfarction left ventricular (LV) dysfunction, despite technically successful percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), remains an important clinical issue. In preclinical models, low-dose insulin-like growth factor 1 (IGF1) has potent cytoprotective and positive cardiac remodeling effects. We studied the safety and efficacy of immediate post-PCI low-dose intracoronary IGF1 infusion in STEMI patients. MethodsUsing a double-blind, placebo-controlled, multidose study design, we randomized 47 STEMI patients with significantly reduced (≤40%) LV ejection fraction (LVEF) after successful PCI to single intracoronary infusion of placebo (n = 15), 1.5 ng IGF1 (n = 16), or 15 ng IGF1 (n = 16). All received optimal medical therapy. Safety end points were freedom from hypoglycemia, hypotension, or significant arrhythmias within 1 hour of therapy. The primary efficacy end point was LVEF, and secondary end points were LV volumes, mass, stroke volume, and infarct size at 2-month follow-up, all assessed by magnetic resonance imaging. Treatment effects were estimated by analysis of covariance adjusted for baseline (24 hours) outcome. ResultsNo significant differences in safety end points occurred between treatment groups out to 30 days (χ2 test, P value = .77). There were no statistically significant differences in baseline (24 hours post STEMI) clinical characteristics or LVEF among groups. LVEF at 2 months, compared to baseline, increased in all groups, with no statistically significant differences related to treatment assignment. However, compared with placebo or 1.5 ng IGF1, treatment with 15 ng IGF1 was associated with a significant improvement in indexed LV end-diastolic volume (P = .018), LV mass (P = .004), and stroke volume (P = .016). Late gadolinium enhancement (±SD) at 2 months was lower in 15 ng IGF1 (34.5 ± 29.6 g) compared to placebo (49.1 ± 19.3 g) or 1.5 ng IGF1 (47.4 ± 22.4 g) treated patients, although the result was not statistically significant (P = .095). ConclusionsIn this pilot trial, low-dose IGF1, given after optimal mechanical reperfusion in STEMI, is safe but does not improve LVEF. However, there is a signal for a dose-dependent benefit on post-MI remodeling that may warrant further study.

Safety and efficacy of cardiopoietic stem cells in the treatment of post-infarction left-ventricular dysfunction – From cardioprotection to functional repair in a translational pig infarction model

To date, clinical success of cardiac cell-therapies remains limited. To enhance the cardioreparative properties of stem cells, the concept of lineage-specification through cardiopoietic-guidance has been recently suggested. However, so far, only results from murine studies and from a clinical pilot-trial in chronic heart-failure (CHF) are available, while systematic evidence of its therapeutic-efficacy is still lacking. Importantly, also no data from large animals or for other indications are available. Therefore, we here investigate the therapeutic-efficacy of human cardiopoietic stem cells in the treatment of post-infarction LV-dysfunction using a translational pig-model. Using growth-factor priming, lineage-specification of human bone-marrow derived MSCs was achieved to generate cardiopoietic stem cells according to GMP-compliant protocols. Thereafter, pigs with post-infarction LV-dysfunction (sub-acute phase;1-month) were randomized to either receive transcatheter NOGA 3D electromechanical-mapping guided intramyocardial transplantation of cardiopoietic cells or saline (control). After 30days, cardiac MRI (cMRI) was performed for functional evaluation and in-vivo cell-tracking. This approach was coupled with a comprehensive post-mortem cell-fate and mode-of-repair analysis. Cardiopoietic cell therapy was safe and ejection-fraction was significantly higher when compared to controls (p=0.012). It further prevented maladaptive LV-remodeling and revealed a significantly lower relative and total infarct-size (p=0.043 and p=0.012). As in-vivo tracking and post-mortem analysis displayed only limited intramyocardial cardiopoietic cell-integration, the significant induction of neo-angiogenesis (∼40% higher; p=0.003) and recruitment of endogenous progenitors (∼2.5x higher; p=0.008) to the infarct border-zone appeared to be the major modes-of-repair. This is the first report using a pre-clinical large animal-model to demonstrate the safety and efficacy of cardiopoietic stem cells for the treatment of post-infarction LV-dysfunction to prevent negative LV-remodeling and subsequent CHF. It further provides insight into post-delivery cardiopoietic cell-fate and suggests the mechanisms of cardiopoietic cell-induced cardiac-repair. The adoption of GMP-/GLP-compliant methodologies may accelerate the translation into a phase-I clinical-trial in patients with post-ischemic LV-dysfunction broadening the current indication of this interesting cell-type.

Microvascular obstruction by delayed contrast-enhanced MRI remains a strong predictor of left ventricular remodeling even after successful reperfusion in acute myocardial infarction

Background Microvascular obstruction (MVO) after coronary reperfusion for acute myocardial infarction (AMI) implies advanced myocardial damage and is recognized as a negative prognostic value. Delayed contrast-enhanced MRI is the preferred MR imaging technique for evaluation of MVO. In this study, we assessed the influence of MVO on post-infarction left ventricular (LV) remodeling and dysfunction.

Scar characteristics for prediction of ventricular arrhythmia in ischemic cardiomyopathy.

Better risk-stratification tools are needed to identify the best candidates for implantable cardioverter defibrillator implantation. Infarct characterization by cardiac magnetic resonance (CMR) has become an evolving potential tool for risk stratification. We assessed the ability of scar characteristics by CMR in patients with postinfarction left ventricular (LV) dysfunction to predict sustained monomorphic ventricular tachycardia (SMVT). Forty-eight patients with postinfarction LV dysfunction underwent CMR study. Twenty-four patients had history of SMVT and the other 24 were control group and underwent electrophysiological study to assess SMVT inducibilty. Various scar characteristics were assessed in the spontaneous SMVT group and were compared with the inducible and noninducible SMVT groups. Only six patients in the control group had inducible SMVT. In univariable analysis, total scar (absolute and as percent of LV), scar core (absolute and as percent of LV), peri-infarct zone (absolute and as percent of LV), mean infarct transmurality, and number of segments with late gadolinium enhancement (LGE) were statistically significant predictors of spontaneous SMVT experience and SMVT inducibility. In multivariable analysis, total infarct as percent of LV mass was the only significant independent predictor of spontaneous SMVT experience (odds ratio [OR] 1.33 per% change, 95% confidence interval [CI] 1.12-1.6, P = 0.001) and SMVT inducibility (OR 1.3 per% change, 95% CI 1.1-1.6, P = 0.004). Characterization of myocardial infarct by LGE-CMR, specifically total infarct size, is better predictor of spontaneous SMVT experience and SMVT inducibility than LV ejection fraction.

Discrepancy between MRI and echocardiography in assessing functional left ventricular parameters and scar characteristics in patients with chronic ischemic cardiomyopathy

Abstract Background Studies have demonstrated that infarct size estimated by CMR-LGE was an independent determinant of adverse LV remodeling and dysfunction. Objective We sought to assess relationship between different scar characteristics and left ventricular remodeling and dysfunction using late gadolinium enhancement CMR (LGE-CMR) and echocardiography in patients with ischemic cardiomyopathy. Methods Forty-eight patients with post-infarction left ventricular (LV) dysfunction underwent CMR and 2D echocardiographic studies. Various scar characteristics were assessed by a freely available software and were correlated with functional parameters. Results All patients had LGE in CMR indicating prior myocardial infarction (MI). A statistically significant but modest negative association was found between left ventricular ejection fraction (LVEF) and number of segments with LGE (r = −0.4, p = 0.005). Additionally, there was a statistically significant modest to moderate positive relationship between LV end diastolic volume (LV EDV) and absolute total scar mass (r = 0.38, p = 0.007), absolute scar core mass (r = 0.32, p = 0.026), peri-infarct zone as absolute (r = 0.45, p = 0.001) and as percent of LV (r = 0.29, p = 0.045) and number of segments with LGE (r = 0.32, p = 0.029). Similarly, statistically significant modest positive correlations were observed between LV end systolic volume (LV ESV) and absolute total scar mass (r = 0.37, p = 0.009), absolute scar core mass (r = 0.32, p = 0.02), peri-infarct zone as absolute (r = 0.4, p = 0.004) and number of segments with LGE (r = 0.38, p = 0.007). There was a mild to moderate correlation between LVEF as assessed by TTE and LVEF measured by CMR (r = 0.49, p Conclusion Different scar characteristics as assessed by CMR were associated with the extent of LV remodeling and dysfunction. This highlights the potential importance of myocardial scarring assessment in risk stratification of patients with ischemic cardiomyopathy. Wide agreement limits for ejection fraction assessment by TTE and CMR suggest that both methods are not interchangeable. Given its 3D approach and superior image quality, CMR may be the preferred technique for volume and ejection fraction estimation.

Catheter-Based Endomyocardial Delivery of Mesenchymal Precursor Cells Using 3D Echo Guidance Improves Cardiac Function in a Chronic Myocardial Injury Ovine Model

The administration of bone marrow-derived stem cells may provide a new treatment option for patients with heart failure. Transcatheter cell injection may require multi-imaging modalities to optimize delivery. This study sought to evaluate whether endomyocardial injection of mesenchymal precursor cells (MPCs) could be guided by real-time 3D echocardiography (RT3DE) in treating chronic, postinfarction (MI) left ventricular (LV) dysfunction in sheep. Four weeks after induction of an anterior wall myocardial infarction in 39 sheep, allogeneic MPCs in doses of either 25 × 10(6) (n = 10), 75 × 10(6) (n = 9), or 225 × 10(6) (n = 10) cells or nonconditioned control media (n = 10) were administered intramyocardially into infarct and border zone areas using a catheter designed for combined fluoroscopic and RT3DE-guided injections. LV function was assessed before and after injection. Infarct dimension and vascular density were evaluated histologically. RT3DE-guided injection procedures were safe. Compared to controls, the highest dose MPC treatment led to increments in ejection fraction (3 ventricula 3% in 225M MPCs vs. -5 ± 4% in the control group, p < 0.01) and wall thickening in both infarct (4 ± 4% in 225M MPCs vs. -3 ± 6% in the control group, p = 0.02) and border zones (4 ± 6% in 225M MPCs vs. -8 ± 9% in the control group, p = 0.01). Histology analysis demonstrated significantly higher arteriole density in the infarct and border zones in the highest dose MPC-treated animals compared to the lower dose or control groups. Endomyocardial implantation of MPCs under RT3DE guidance was safe and without observed logistical obstacles. Significant increases in LV performance (ejection fraction and wall thickening) and neovascularization resulted from this technique, and so this technique has important implications for treating patients with postischemic LV dysfunction.

In Patients with Post-Infarction Left Ventricular Dysfunction, How Does Impaired Basal Rotation Affect Chronic Ischemic Mitral Regurgitation?

The aim of this study was to explore the contribution of left ventricular (LV) basal rotation to the mechanism of chronic ischemic mitral regurgitation (MR). Fifty-seven patients (52 men; mean age, 68.3 ± 11.8 years) with postinfarction LV dysfunction (defined as an ejection fraction ≤ 45%) were prospectively enrolled. Each invariably had functional MR. To assess MR degree, the effective regurgitant orifice area (EROA) was quantified by echocardiography using the proximal isovelocity surface area method. Furthermore, mitral valve deformation (valve tenting and annular function) and LV global (systolic and diastolic volumes, function, and sphericity) and local remodeling (displacement of papillary muscles, regional strain, and rotation by speckle-tracking) were assessed. The patients were subsequently subdivided into two groups according to the absence (group A) or presence (group B) on transthoracic echocardiography of infarct area in the inferior and/or posterior basal segments. A larger EROA was found in group B than in group A (P = .034) and in subjects with asymmetric rather than symmetric tethering in either group (P = .036 and P = .040 for groups A and B, respectively). Basal radial (P = .009), circumferential (P = .042), and longitudinal (P = .005) strain and rotation (P = .021) were lower in group B than in group A. There was also a significant inverse correlation between EROA and basal rotation in group B (r = -0.75, P < .001). Furthermore, using multivariate linear regression analysis, we found that the independent determinants of EROA were end-diastolic volume (P < .001) and tenting area (P = .004) in group A and asymmetric tethering (P = .029) and basal rotation (P < .001) in group B. Impaired basal rotational mechanics occurring after an inferior-posterior myocardial infarction is associated with increased MR.

Usefulness of C-reactive protein as a marker of early post-infarct left ventricular systolic dysfunction

ObjectiveTo assess the usefulness of in-hospital measurement of C-reactive protein (CRP) concentration in comparison to well-established risk factors as a marker of post-infarct left ventricular systolic dysfunction (LVSD) at discharge.Materials and methodsTwo hundred and four consecutive patients with ST-segment-elevation myocardial infarction (STEMI) were prospectively enrolled into the study. CRP plasma concentrations were measured before reperfusion, 24 h after admission and at discharge with an ultra-sensitive latex immunoassay.ResultsCRP concentration increased significantly during the first 24 h of hospitalization (2.4 ± 1.9 vs. 15.7 ± 17.0 mg/L; p < 0.001) and persisted elevated at discharge (14.7 ± 14.7 mg/L), mainly in 57 patients with LVSD (2.4 ± 1.8 vs. 25.0 ± 23.4 mg/L; p < 0.001; CRP at discharge 21.9 ± 18.6 mg/L). The prevalence of LVSD was significantly increased across increasing tertiles of CRP concentration both at 24 h after admission (13.2 vs. 19.1 vs. 51.5 %; p < 0.0001) and at discharge (14.7 vs. 23.5 vs. 45.6 %; p < 0.0001). Multivariate analysis demonstrated CRP concentration at discharge to be an independent marker of early LVSD (odds ratio of 1.38 for a 10 mg/L increase, 95 % confidence interval 1.01–1.87; p < 0.04).ConclusionMeasurement of CRP plasma concentration at discharge may be useful as a marker of early LVSD in patients after a first STEMI.

Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial

c-kit-positive, lineage-negative cardiac stem cells (CSCs) improve post-infarction left ventricular (LV) dysfunction when administered to animals. We undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiOmyopathy [SCIPIO]) of autologous CSCs for the treatment of heart failure resulting from ischaemic heart disease. In stage A of the SCIPIO trial, patients with post-infarction LV dysfunction (ejection fraction [EF] ≤40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomisation scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. This study is registered with ClinicalTrials.gov, number NCT00474461. This study is still in progress. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30·3% (SE 1·9) before CSC infusion to 38·5% (2·8) at 4 months after infusion (p=0·001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30·1% [2·4] at 4 months after CABG vs 30·2% [2·5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12·3 ejection fraction units [2·1] vs baseline, p=0·0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32·6 g (6·3) by 7·8 g (1·7; 24%) at 4 months (p=0·004) and 9·8 g (3·5; 30%) at 1 year (p=0·04). These initial results in patients are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies. University of Louisville Research Foundation and National Institutes of Health.

Exercise training does not improve cardiac function in compensated or decompensated left ventricular hypertrophy induced by aortic stenosis

There is ample evidence that regular exercise exerts beneficial effects on left ventricular (LV) hypertrophy, remodeling and dysfunction produced by ischemic heart disease or systemic hypertension. In contrast, the effects of exercise on pathological LV hypertrophy and dysfunction produced by LV outflow obstruction have not been studied to date. Consequently, we evaluated the effects of 8weeks of voluntary wheel running in mice (which mitigates post-infarct LV dysfunction) on LV hypertrophy and dysfunction produced by mild (mTAC) and severe (sTAC) transverse aortic constriction. mTAC produced ~40% LV hypertrophy and increased myocardial expression of hypertrophy marker genes but did not affect LV function, SERCA2a protein levels, apoptosis or capillary density. Exercise had no effect on global LV hypertrophy and function in mTAC but increased interstitial collagen, and ANP expression. sTAC produced ~80% LV hypertrophy and further increased ANP expression and interstitial fibrosis and, in contrast with mTAC, also produced LV dilation, systolic as well as diastolic dysfunction, pulmonary congestion, apoptosis and capillary rarefaction and decreased SERCA2a and ryanodine receptor (RyR) protein levels. LV diastolic dysfunction was likely aggravated by elevated passive isometric force and Ca2+-sensitivity of myofilaments. Exercise training failed to mitigate the sTAC-induced LV hypertrophy and capillary rarefaction or the decreases in SERCA2a and RyR. Exercise attenuated the sTAC-induced increase in passive isometric force but did not affect myofilament Ca2+-sensitivity and tended to aggravate interstitial fibrosis. In conclusion, exercise had no effect on LV function in compensated and decompensated cardiac hypertrophy produced by LV outflow obstruction, suggesting that the effect of exercise on pathologic LV hypertrophy and dysfunction depends critically on the underlying cause.