Postinfarction Congestive Heart Failure Research Articles

Implantation of atriobiventricular pacemaker during cabg procedure ¿ description of 3 cases

We report on three cases of cardiac resynchronization therapy (CRT) system implantation during coronary artery bypass grafting (CABG) procedure. All 3 patients were men with coronary artery disease and postinfarction congestive heart failure in NYHA class III despite optimal medical treatment and without classical indications for permanent pacing. In echocardiography, intraventricular dyssynchrony was present in all patients. Methods During on-pump CABG epicardial bipolar leads (Medtronic CapSure Epi) were fixed on the right atrium, the right and left ventricle and connected to the CRT pacemaker (Medtronic InSync III) located in the left subclavicular portion. Postoperative period was uncomplicated. After 2 months pacing and sensing parameters remained excellent and significant clinical improvement was observed in all patients. Patients' characteristics and results (b=before, a=2 months after CABG + CRT) View this table: View this table: Conclusion CRT can be regarded as important supplement to surgical revascularization in still growing population of patients with severe heart failure and systolic dyssynchrony, for optimization of treatment results.

Appearance of a ventricular 5-HT receptor-mediated inotropic response to serotonin in heart failure

Current pharmacological treatment of congestive heart failure (CHF) addresses changes in neurohumoral stimulation or cardiac responsiveness to such stimulation. Yet, undiscovered neurohumoral changes, adaptive or maladaptive, may occur in CHF and suggest novel pharmacological treatment. Serotonin [5-hydroxytryptamine (5-HT)] enhances contractility and causes arrhythmias through 5-HT(4) receptors in human atrium and ventricle but not through rat ventricular 5-HT(4) receptors. We investigated whether CHF could induce ventricular responsiveness to serotonin. Postinfarction CHF was induced in male Wistar rats by coronary artery ligation. Contractility was measured in left ventricular papillary muscles 6 weeks after infarction. Messenger RNA was quantified by RT-PCR and cAMP by RIA. Serotonin caused positive inotropic (-logEC(50)=7.5) and lusitropic effects in CHF but not Sham papillary muscles. The inotropic effect of 10 muM serotonin in CHF (31.3+/-2.2%) was of similar size as the effect of 10 muM isoproterenol (34.0+/-1.7%). The effects of serotonin were antagonised by GR113808 (0.5-5 nM), consistent with mediation through 5-HT(4) receptors. This was further supported by positive inotropic effects of the 5-HT(4)-selective partial agonist RS67506. Carbachol blunted the serotonin responses and serotonin increased ventricular and cardiomyocyte cAMP, consistent with coupling to G(s) and adenylyl cyclase. Quantitative RT-PCR revealed fourfold increased 5-HT(4(b)) mRNA expression in CHF vs. Sham ventricles. Functional ventricular 5-HT(4) receptors are induced by myocardial infarction and CHF of the rat heart. We propose that they are a model for ventricular 5-HT(4) receptors of human failing heart and may play a pathophysiological role in heart failure.

Muscle dysfunction during exercise of a single skeletal muscle in rats with congestive heart failure is not associated with reduced muscle blood supply.

Inadequate muscle blood flow is a possible explanation for reduced fatigue resistance in patients with congestive heart failure (CHF). In rats with post-infarction CHF we electrically stimulated the soleus muscle (SOL) in situ with intact blood supply. Contractile properties, blood flow, high-energy phosphates and metabolites were measured during 30 min of intermittent stimulation, and in addition capillarization of SOL was recorded. During stimulation, SOL contracted more slowly in rats with CHF compared with sham-operated rats. However, the blood flow in SOL was unaltered and capillary density was maintained in CHF rats. Further, the content of ATP, ADP, AMP, NAD, CrP, P(i) and lactate in SOL was not different between the groups. The cause of contractile dysfunction in a single exercising skeletal muscle in rats with CHF cannot be explained simply by reduced blood supply. In addition, absence of changes in high-energy phosphates and metabolites indicate that the oxidative metabolism of SOL is intact in rats with CHF.

Bone marrow stromal cells improve cardiac performance in healed infarcted rat hearts.

Postinfarct congestive heart failure is one of the leading causes of morbidity and mortality in developed and developing countries. The main purpose of this study was to investigate whether transplantation of bone marrow stromal cells (BMSC) directly into the myocardium could improve the performance of healed infarcted rat hearts. Cell culture medium with or without BMSC was injected into borders of cardiac scar tissue 4 wk after experimental infarction. Cardiac performance was evaluated 2 wk after cellular (n = 10) or medium (n = 10) injection by electro- and echocardiography. Histological study was performed 3 wk after treatment. Electrocardiography of BMSC-treated infarcted rats showed electrical and mechanical parameters more similar to those in control than in medium-treated animals: a normal frontal QRS axis in 6 of 10 BMSC-treated and all control rats and a rightward deviation of the QRS axis in all 10 medium-treated animals. BMSC treatment, assessed by echocardiography, improved fractional shortening (39.00 +/- 4.03%) compared with medium-treated hearts (18.20 +/- 0.74%) and prevented additional changes in cardiac geometry. Immunofluorescence microscopy revealed colocalization of 4',6-diamidino-2-phenylindole-labeled nuclei of transplanted cells with cytoskeletal markers for cardiomyocytes and smooth muscle cells, indicating regeneration of damaged myocardium and angiogenesis. These data provide strong evidence that BMSC implantation can improve cardiac performance in healed infarctions and open new promising therapeutic opportunities for patients with postinfarction heart failure.

Stem Cells for Cardiovascular Disease

Adult stem cells, when exposed to new environments, are remarkably plastic in their developmental potential. Bone marrow stem cells provide a promising therapy in the restoration of myocardial infarction and prevent post infarct congestive heart failure, as there is evidence that cells, such as mesenchymal stem, hematopoietic stem and multipotent adult progenitor, can generate new cardiomyocytes in animals and humans. This review summarizes stem cell therapy for cardiac regeneration after myocardial infarction, including a brief overview of ongoing clinical trials, and outlines the scientific and clinical hurdles that need to be overcome before this therapy can be fully used clinically. (Korean Circulation J 2004;34(5):435-440)

Selective beta1-blockade attenuates post-infarct remodelling without improvement in myocardial energy metabolism and function in rats with heart failure.

To investigate in vivo effects of long-term selective beta1-blockade on cardiac energy metabolism, remodelling, function and plasma cytokines in a rat model of post-infarct congestive heart failure (CHF). Myocardial infarction (MI) was induced in male rats by ligation of the left coronary artery. Three different groups of rats were studied, MI rats treated with metoprolol (n=17), MI rats treated with saline (n=14) and sham-operated rats (n=12). The treatment with metoprolol 1 mg/kg/h was initiated in the third week post-infarct for a period of 6 weeks. All rats were investigated non-invasively with volume-selective 31P magnetic resonance spectroscopy and echocardiography for evaluation of left ventricular (LV) energy metabolism, morphology and function. Plasma concentration of IL-1beta and IL-6 and density of beta-adrenergic receptors were analyzed. Metoprolol attenuated the increase in LV dimensions and volumes. Treatment with metoprolol had no effect on PCr/ATP and LV function. Plasma level of IL-1beta was higher and IL-6 was lower in the metoprolol group. Density of beta-adrenergic receptors was similar in all three groups. Selective beta1-blockade in rats with chronic CHF attenuates post-infarct structural remodelling, without concomitant improvement in myocardial energy metabolism and function. Improvements in myocardial energy metabolism and function do not precede and are not a prerequisite for an anti-remodelling effect of beta1-blockade in the setting of chronic CHF.

Myocardial Replacement Therapy

Case Presentation: A 56-year-old farmer who experienced a transmural anterior myocardial infarction (MI) 3 years ago was referred for evaluation of progressive dyspnea and fatigue. During the acute phase of MI, he was treated with fibrinolysis, as primary angioplasty was not available at his local hospital. Angiography performed 3 months after MI revealed occlusion of the left anterior descending artery with diffuse changes distal to the occluded segment. An attempt at percutaneous recanalization had failed. Despite treatment with β-blockers and angiotensin-converting enzyme inhibitors, serial echocardiograms performed by his local cardiologist had shown a large dyskinetic area and subsequently progressive dilatation and remodeling of the left ventricle. The patient is currently presenting with New York Heart Association class III symptoms and a history of several recent episodes of pulmonary edema. The development of postinfarction congestive heart failure in survivors of the acute phase of MI is related to myocardial cell loss in the area supplied by the infarct-related artery and the subsequent formation of a scar. As the most important strategies during the acute phase of MI, primary angioplasty and fibrinolysis are aimed at the restoration of blood flow to minimize necrosis. In addition, late revascularization procedures may enable recovery of contractility, but only in areas of the hibernating myocardium that contain a minimal number of viable, reversibly injured myocytes. In patients with a large myocardial necrotic area resulting from acute MI, and especially when the necrotic zone is weakly supplied by collaterals, the loss of cardiomyocytes results in the formation of fibrous tissue and, subsequently, in left ventricular remodeling, aneurysm formation, and progression of congestive heart failure. In some patients, cardiac transplantation may be an option, but because of the shortage of organs, its practical use is limited to end-stage heart failure cases. Stem cell implants have been discovered to …

Normal contractions triggered by I(Ca,L) in ventricular myocytes from rats with postinfarction CHF.

Attenuated L-type Ca(2+) current (I(Ca,L)), or current-contraction gain have been proposed to explain impaired cardiac contractility in congestive heart failure (CHF). Six weeks after coronary artery ligation, which induced CHF, left ventricular myocytes from isoflurane-anesthetized rats were current or voltage clamped from -70 mV. In both cases, contraction and contractility were attenuated in CHF cells compared with cells from sham-operated rats when cells were only minimally dialyzed using high-resistance microelectrodes. With patch pipettes, cell dialysis caused attenuation of contractions in sham cells, but not CHF cells. Stepping from -50 mV, the following variables were not different between sham and CHF, respectively: peak I(Ca,L) (4.5 +/- 0.3 vs. 3.8 +/- 0.3 pApF(-1) at 23 degrees C and 9.4 +/- 0.5 vs. 8.4 +/- 0.5 pApF(-1) at 37 degrees C), the bell-shaped voltage-contraction relationship in Cs(+) solutions (fractional shortening, 15.2 +/- 1.0% vs. 14.3 +/- 0.7%, respectively, at 23 degrees C and 7.5 +/- 0.4% vs. 6.7 +/- 0.5% at 37 degrees C) and the sigmoidal voltage-contraction relationship in K(+) solutions. Caffeine-induced Ca(2+) release and sarcoplasmic reticulum Ca(2+)-ATPase-to-phospholamban ratio were not different. Thus CHF contractions triggered by I(Ca,L) were normal, and the contractile deficit was only seen in undialyzed cardiomyocytes stimulated from -70 mV.

Surgical Anterior Ventricular Restoration for Ischemic Cardiomyopathy

Emergency angioplasty or thrombolytic therapy for acute anterior wall infin'ction revascularizes the infarct-related artery. The damaged region includes the anterolateral left ventricle and septum. Revascularization avoids transmural scarring and suhsequent aneurysm because it spares the elficardial muscle. Regional akinesia develops due to damage to the inner two-thirds of the left ventricular and/or apical and anteroseptal wall. The epicardium, spared of transmural necrosis, may remain pink. The underlying midventricular and endoventricular muscles contain seglnental nonfllctional muscle with trabecular scarring. This region cannot thicken during systole to contribute to cardiac OUtlmt. Tile elulocardiuln often remains completely trabecuiated, so that the transmural thinning characteristic of aneuryslns is allsent. Akinesia of a large segment of ventricle resuhs in rclnodeling of the remaining ventricle, with increased sphericity and loss of elliptical apical contour. Occurring within hours of infarction, this may result in depressed ventricular flmetion that worsens over time as the remote, normally perfllsed nmscle dilates. The administration of lleta-blockers and ACE inhibitors early postinfarction has a salutary effect on tile remodeling process, but nevertheless about one-half of patients receiving aggressive treatment still display signs and SynllltOlnS of congestive heart failure due to progressive dihltion and sphericity of the noninfarcted muscle. For many )'ears, endoventricular circular patchplasty has been applied to the thinned dyskinetic ventricular aneurysm, llecause transmural necrosis avoids the thickened appearance that characterizes reperfused muscle. The anatomic changes lwo,luced l,y this rebuihling technique improve ventricular fimction as COnllmred to excision and linear closure. 1 Aneurysm is now uncolnmOl~ due to acute revascularization of the infarct-related artery. A similar ol,erative technique using an endoventricular l,atch has been al,l,lic,l to postinfarction akinesia, l This surgical al,l,roach is not commonly used because of surgical rehlctance to incise tile normal-appearing anterior wall due to epicardial muscle salvage. Tile ventricle surface may appear pink and rotate during systole. Ilowever, the underlying myocardium does,not thicken before bypass or collapse by venting during extracorporeal circulation. The recently organized RESTORE group includes an intermttional group of cardiac surgeons and cardiologists from four continents. One of its lnwposes has been to confirm the efficacy of surgical anterior ventrieular restoration (SAVI{) of postinfarction akinesia. This procedure was initially aplllied to akinetic muscle that does not collapse by venting due to epicardial sah'age by rewlscularization. Inferences allout intraoperative protection to preserve postcardiotomy ventricular function were drawn fi'om Batista's Ollerative techni(lue for llartial ventriculotomy using tile l,eating ol,en (as ol)posed to the cardiol)legically arrested) heart. This report describes the operative technique used in our 52-patient subsegment of RESTORE centers with the lleating open heart technique of protection. It outlines the SAVR technique applied to anterior akinetic postinfarction ventricle eardiomyolmthy and congestive heart failure (ejection fraction 28%, left ventriculogram systolic vohnne index [LVESVI] 132 mL/m2).

DNA enzyme targeting TNF-alpha mRNA improves hemodynamic performance in rats with postinfarction heart failure.

Tumor necrosis factor-alpha (TNF-alpha) probably affects the pathogenesis of heart failure. Here we have investigated the therapeutic potential of a nuclease-resistant DNA enzyme that specifically cleaves TNF-alpha mRNA. A phosphorothioate-modified DNA enzyme was designed to retain similar cleavage activity as its unmodified version, and that inhibited the expression of TNF-alpha in vitro. To test its efficacy in vivo, postinfarction congestive heart failure was induced in anesthetized rats by ligation of the left coronary artery. A 4-wk treatment with the DNA enzyme induced a substantial reduction in left ventricular end-diastolic pressure and lung weight concomitant with an increase in arterial blood pressure and myocardial blood flow compared with controls. The concentration of TNF-alpha in coronary sinus blood was markedly lowered on treatment, and myocardial TNF-alpha mRNA was substantially reduced. Recovery studies showed that the DNA enzyme cleavage activity was present within the myocardium throughout the observation period and had no apparent toxic effects. Our findings indicate that DNA enzyme-based therapy may hold promise in the treatment of this debilitating disease.

Redistribution and abnormal activity of phospholipase A(2) isoenzymes in postinfarct congestive heart failure.

Cardiac sarcolemmal (SL) cis-unsaturated fatty acid sensitive phospholipase D (cis-UFA PLD) is modulated by SL Ca(2+)-independent phospholipase A(2) (iPLA(2)) activity via intramembrane release of cis-UFA. As PLD-derived phosphatidic acid influences intracellular Ca(2+) concentration and contractile performance of the cardiomyocyte, changes in iPLA(2) activity may contribute to abnormal function of the failing heart. We examined PLA(2) immunoprotein expression and activity in the SL and cytosol from noninfarcted left ventricular (LV) tissue of rats in an overt stage of congestive heart failure (CHF). Hemodynamic assessment of CHF animals showed an increase of the LV end-diastolic pressure with loss of contractile function. In normal hearts, immunoblot analysis revealed the presence of cytosolic PLA(2) (cPLA(2)) and secretory PLA(2) (sPLA(2)) in the cytosol, with cPLA(2) and iPLA(2) in the SL. Intracellular PLA(2) activity was predominantly Ca(2+) independent, with minimal sPLA(2) activity. CHF increased cPLA(2) immunoprotein and PLA(2) activity in the cytosol and decreased SL iPLA(2) and cPLA(2) immunoprotein and SL PLA(2) activity. sPLA(2) activity and abundance decreased in the cytosol and increased in SL in CHF. The results show that intrinsic to the pathophysiology of post-myocardial infarction CHF are abnormalities of SL PLA(2) isoenzymes, suggesting that PLA(2)-mediated bioprocesses are altered in CHF.

Echocardiographic criteria for detection of postinfarction congestive heart failure in rats.

We evaluated postinfarction myocardial function in rats and determined echocardiographic criteria for congestive heart failure (CHF) using high performance echocardiography. Extensive myocardial infarction (MI) was induced in rats by left coronary occlusion. Sham-operated animals served as controls. Five weeks later, high-frame rate ( approximately 200 Hz), fully digitized, shallow-focus (10-25 mm), two-dimensional, M-mode and Doppler echocardiography was performed. A J-tree cluster analysis was performed using parameters indicative of CHF. Reproducibility was examined. The cluster analysis joined the animals into one Sham and two MI clusters. One of the MI clusters had clinical characteristics of CHF and elevated left ventricular end diastolic pressure. Among the echocardiographic variables, only posterior wall shortening velocity separated the failing and nonfailing MI clusters. We conclude that, by high frame rate echocardiography, it is possible to obtain high- quality recordings in rats. It is feasible to distinguish MI rats with CHF due to myocardial dysfunction from those without failure and to perform longitudinal studies on myocardial function.

Neutrophilia and congestive heart failure after acute myocardial infarction

Background Inflammation associated with acute myocardial infarction (AMI) is frequently marked by a peripheral leukocytosis and relative neutrophilia. Whether this process may contribute to the development of postinfarction congestive heart failure (CHF) is not established. The objective of this study was to examine the association between hospital admission peripheral total leukocyte count and the neutrophil percentage and the subsequent development of CHF in patients with AMI. The study was designed as a retrospective cohort study in the setting of a tertiary referral hospital. Participants included 185 patients discharged with a diagnosis of AMI between May 1 and Sept 30, 1996. Methods and Results Outcome measures included clinical episodes of CHF with confirmatory chest roentgenogram findings and/or echocardiographic evidence of contractile dysfunction. Multivariable logistic regression analyses were performed to examine the relation between the total leukocyte count, neutrophil percentage, and the development of CHF in the first 4 days after AMI while controlling for baseline characteristics and early therapeutic interventions. Thirty-one percent of the cohort had a leukocyte count >11.0 ×10 9/L on admission to the hospital; 65% had a neutrophil percentage >65%, and 61% had a lymphocyte percentage ≤25%. CHF developed in 43% of the cohort. Of these, 92.5% had relative neutrophilia (neutrophil percentage >65%) compared with 45% of those in whom CHF did not develop. Multivariable analysis revealed a highly significant association between relative neutrophilia and the subsequent development of CHF (odds ratio 14.3; 95% confidence interval 5.2 to 39.3). Conclusions Relative neutrophilia on admission to the hospital in patients with AMI is significantly associated with the early development of CHF. This association may help in the identification of individuals at high risk who might benefit from more aggressive interventions to prevent or reduce the risk of CHF. (Am Heart J 2000;139:94-100.)

Changes in sarcolemmal PLC isoenzymes in postinfarct congestive heart failure: partial correction by imidapril.

We have examined the changes in quantity and activity of cardiac sarcolemmal (SL) phosphoinositide-phospholipase C (PLC)-beta(1), -gamma(1), and -delta(1) in a model of congestive heart failure (CHF) secondary to large transmural myocardial infarction (MI). We also instituted a late in vivo monotherapy with imidapril, an ANG-converting enzyme (ACE) inhibitor, to test the hypothesis that its therapeutic action is associated with the functional correction of PLC isoenzymes. SL membranes were purified from the surviving left ventricle of rats in a moderate stage of CHF at 8 wk after occlusion of the left anterior descending coronary artery. SL PLC isoenzymes were examined in terms of protein mass and hydrolytic activity. CHF resulted in a striking reduction (to 6-17% of controls) of the mass and activity of gamma(1)- and delta(1)-isoforms in combination with a significant increase of both PLC beta(1) parameters. In vivo treatment with imidapril (1 mg/kg body wt, daily, initiated 4 wk after coronary occlusion) improved the contractile function and induced a partial correction of PLCs. The mass of SL phosphatidylinositol 4,5-bisphosphate and the activities of the enzymes responsible for its synthesis were significantly reduced in post-MI CHF and partially corrected by imidapril. The results indicate that profound changes in the profile of heart SL PLC-beta(1), -gamma(1), and -delta(1) occur in CHF, which could alter the complex second messenger responses of these isoforms, whereas their partial correction by imidapril may be related to the mechanism of action of this ACE inhibitor.

Calcitonin gene-related peptide is not elevated in rat plasma by heart failure or by neutral endopeptidase inhibition

Some studies have indicated that plasma calcitonin gene-related peptide (CGRP) increases in congestive heart failure (CHF). In vitro, neutral endopeptidase (NEP) cleaves CGRP. We studied CGRP-like immunoreactivity (CGRP-ir) in rat plasma in a coronary artery-ligation model of CHF with and without NEP inhibition. Rats with CHF (n=6) and shamoperated controls (n=6) were administered vehicle and, separately, SCH 34826, a NEP inhibitor, subcutaneously 90 mg/kg. Plasma sample was taken 60 minutes later. Seventeen untreated coronary-ligated rats with various degrees of CHF were studied separately. Systolic arterial pressure (SAP) was measured while conscious. All rats were killed by exsanguination, and heart and lungs were removed and weighed. In CHF rats, plasma atrial natriuretic peptide after vehicle (basal ANP) was 7.6- fold, but basal CGRP-ir was similar compared to controls. After SCH 34826, plasma CGRP-ir decreased marginally in CHF rats (57->51 ng/l, p=0.011), and ANP increased 1.8-fold (418->730 ng/l, p=0.001). In controls, these changes by SCH 34826 were small. Basal ANP correlated strongly with relative weight of heart (HE; R=0.93, p<0.001) and lungs (LU; R=0.96, p<0.001). There was no correlation between basal CGRP-ir, basal plasma renin activity (PRA), HE and LU. In the untreated coronary- ligated rats, plasma CGRP-ir did not correlate with HE, LU, SAP, plasma ANP or PRA, but plasma ANP correlated with HE (R=0.62, p=0.011) and LU (R=0.70, p=0.002). We conclude that, in rat plasma, CGRP-ir is not elevated either by NEP inhibition, or in post-infarction CHF.

Postmyocardial Infarction Complications Requiring Surgery

Papillary muscle rupture, ventricular septal defect, and ventricular aneurysm represent complications of myocardial infarction that require surgical intervention. Since operative mortality and morbidity are increased in proportion to the degree of myocardial and pulmonary disease, early diagnosis and surgical intervention is mandatory. Diagnostic procedures of choice include careful and serial ECG analysis and cardiac auscultation, especially in patients with postinfarction refractory angina or congestive heart failure; Swan-Ganz catheterization, echocardiography; and, in appropriate instances, ventricular and coronary angiography should also be performed preoperatively. With early identification of patients at risk of developing these complications, and careful preoperative hemodynamic studies, surgical repair should lead to improvement in myocardial function and more effective response to post-operative medications in patients previously resistant to such therapy.