Development Of Left Ventricular Failure Research Articles

Behavior of Hypertrophied Right Ventricle during the Development of Left Ventricular Failure Due to Myocardial Infarction.

In order to determine the behavior of the right ventricle, we have reviewed the existing literature in the area of cardiac remodeling, signal transduction pathways, subcellular mechanisms, β-adrenoreceptor-adenylyl cyclase system and myocardial catecholamine content during the development of left ventricular failure due to myocardial infarction. The right ventricle exhibited adaptive cardiac hypertrophy due to increases in different signal transduction pathways involving the activation of protein kinase C, phospholipase C and protein kinase A systems by elevated levels of vasoactive hormones such as catecholamines and angiotensin II in the circulation at early and moderate stages of heart failure. An increase in the sarcoplasmic reticulum Ca2+ transport without any changes in myofibrillar Ca2+-stimulated ATPase was observed in the right ventricle at early and moderate stages of heart failure. On the other hand, the right ventricle showed maladaptive cardiac hypertrophy at the severe stages of heart failure due to myocardial infarction. The upregulation and downregulation of β-adrenoreceptor-mediated signal transduction pathways were observed in the right ventricle at moderate and late stages of heart failure, respectively. The catalytic activity of adenylate cyclase, as well as the regulation of this enzyme by Gs proteins, were seen to be augmented in the hypertrophied right ventricle at early, moderate and severe stages of heart failure. Furthermore, catecholamine stores and catecholamine uptake in the right ventricle were also affected as a consequence of changes in the sympathetic nervous system at different stages of heart failure. It is suggested that the hypertrophied right ventricle may serve as a compensatory mechanism to the left ventricle during the development of early and moderate stages of heart failure.

Control of Cardiac Biomarkers Concentrations, Central Hemodynamics and Their Correlation During Gastrointestinal Bleeding

We did not observe high values of cardiac markers and changes in central hemodynamic parameters in patients with acute gastrointestinal bleeding (AGIB) and a correlation between them, this led to the decision to conduct a study. Clinical materials of 457 patients diagnosed with GIB were analyzed. Cardiac pathology was detected in 150 patients. Dynamic changes in cardiac biomarkers and central hemodynamic indicators in patients were studied in 3 stages. Phase I, period included in ICU; Stage II - 24 hours after admission to the ICU; the third stage covers the next 48 hours. The concentration troponin, BNP, myoglobin and CK-Mb was studied in the patients and it was found that although the concentration of these biomarkers was high in the first stage, these concentrations decreased and reached normal levels in the later stages of the dynamics against the background of the treatment. Dynamic changes of central hemodynamic indicators (CHI): stroke volume, cardiac minute volume, peripheral vascular resistance and myocardial oxygen demand were studied in 3 stages. It was found that although SV was low, it dynamically increased in the later stages and did not reach the normal level. This is a clear example of continued hypovolemia. Peripheral vascular resistance (PVR) from blood loss from the gastrointestinal tract was greater than normal in all three phases. PVR remained high and was statistically honest because the volume of circulating blood was not fully corrected despite the treatments. Also, the correlation between central hemodynamic indicators and cardiac markers was studied, showing that in stage I, there is a strong contrast between CMV and CK-MB; Strong straight between PVR and BNP; In stage II, strong contrast between CMV and BNP; Strongly flat between PVR and CK-MB; In stage III, the average level is between CMV and myoglobin; We proved that there is a moderate inverse correlation between PVR and cTn and it is statistically honest. Thus, although CHI was slightly less than the norm in the initial period, it normalized in the later stages, but PVR remained high in all stages. This caused a sharp increase in PVR as a compensatory response to the decrease in circulating blood volume during acute GIB. Among the cardiac markers, we associate the rise of troponin during the bleeding period with damage to postanemic, hypoxic myocardial muscles. Among the cardiac markers, a sharp increase in BNP is an indicator of the development of left ventricular failure and is associated with a sharp increase in PVR, and we also proved that there is a strong direct relationship between them.

Identification of a novel microRNA profile in pediatric patients with cancer treated with anthracycline chemotherapy.

Anthracycline chemotherapy (AC) is associated with decline in left ventricular ejection fraction (LVEF), yet the mechanisms remain unclear. Although changes in microRNAs (miRs) have been identified in adult cardiovascular disease, miR profiles in pediatric patients with AC have not been well studied. The goal of this study was to examine miR profiles (unbiased array) in pediatric patients with AC compared with age-matched referent normal patients. We hypothesize that pediatric patients with AC will express a unique miR profile at the initiation and completion of therapy and will be related to LVEF. Serum was collected in pediatric patients (10-22 yr, n = 12) with newly diagnosed malignancy requiring AC within 24-48 h after the initiation of therapy (30-60 mg/m2) and ~1 yr after completing therapy. A custom microarray of 84 miRs associated with cardiovascular disease was used (quantitative RT-PCR) and indexed to referent normal profiles (13-17 yr, n = 17). LVEF was computed by cardiac MRI. LVEF fell from AC initiation at ~1 yr after AC completion (64.28 ± 1.78% vs. 57.53 ± 0.95%, respectively, P = 0.004). Of the 84 miRs profiled, significant shifts in 17 miRs occurred relative to referent normal ( P ≤ 0.05). Moreover, the functional domain of miRs associated with myocardial differentiation and development fell over threefold at the completion of AC ( P ≤ 0.05). Moreover, eight miRs were significantly downregulated after AC completion in those patients with the greatest decline in LVEF (≥10%, P < 0.05). This study demonstrates, for the first time, that changes in miR expression occur in pediatric patients with AC. These findings suggest that miRs are a potential strategy for the early identification of patients with AC susceptible to left ventricular dysfunction. NEW & NOTEWORTHY Although anthracycline chemotherapy (AC) is effective for a number of pediatric cancers, an all too often consequence of AC is the development of left ventricular failure. The present study identified that specific shifts in the pattern of microRNAs, which regulate myocardial growth, function, and viability, occurred during and after AC in pediatric patients, whereby the magnitude of this shift was associated with the degree of left ventricular failure.

Apolipoprotein E Polymorphism and Left Ventricular Failure in Beta-Thalassemia: A Multivariate Meta-Analysis.

Apolipoprotein E (ApoE) is potentially a genetic risk factor for the development of left ventricular failure (LVF), the main cause of death in beta-thalassemia homozygotes. In the present study, we synthesize the results of independent studies examining the effect of ApoE on LVF development in thalassemic patients through a meta-analytic approach. However, all studies report more than one outcome, as patients are classified into three groups according to the severity of the symptoms and the genetic polymorphism. Thus, a multivariate meta-analytic method that addresses simultaneously multiple exposures and multiple comparison groups was developed. Four individual studies were included in the meta-analysis involving 613 beta-thalassemic patients and 664 controls. The proposed method that takes into account the correlation of log odds ratios (log(ORs)), revealed a statistically significant overall association (P-value = 0.009), mainly attributed to the contrast of E4 versus E3 allele for patients with evidence (OR: 2.32, 95% CI: 1.19, 4.53) or patients with clinical and echocardiographic findings (OR: 3.34, 95% CI: 1.78, 6.26) of LVF. This study suggests that E4 is a genetic risk factor for LVF in beta-thalassemia major. The presented multivariate approach can be applied in several fields of research.

Abstract 399: End-stage Heart Failure Causes Severe Lung Fibrosis and Dysfunction

Chronic heart failure (CHF) causes trouble breathing in patients. We recently demonstrated that systolic pressure overload by transverse aortic constriction (TAC) causes severe left ventricular (LV) failure that is associated with massive lung fibrosis and lung vascular remodeling, and right ventricular (RV) dysfunction in mice. Here, we further studied the effect of CHF on lung structure and function in mice, and the effect of CHF on lung fibrosis in patients. We demonstrated that chronic TAC resulted in decrease of LV ejection fraction, and increases LV weight, lung weight, and RV weight, as well as their ratios to bodyweight. Interestingly, the development of LV failure is associated with a significant lung dysfunction as evidenced by a ~2-fold increase of lung resistance and a ~50% dramatic decrease of lung compliance in vivo . Lung compliance was also significantly reduced ~50% in lung isolated from CHF mice, indicating the decrease of lung compliance is due to the structure change of lung. The reduced lung compliance in CHF mice is significantly correlated with the decrease of LV ejection fraction, the increase of lung weight, and RV hypertrophy, suggesting the reduced lung compliance might contribute to the development of RV hypertrophy and failure. Histochemical analyses further demonstrated that CHF causes massive lung vascular, perivascular and interstitial fibrosis, as well as increase of lung myofibroblast proliferation. By using the chimeric mice created by transplantation of Bone Marrow Derived Cells (BMDCs) from GFP mice into wild type mice, we demonstrated that BMDCs contribute to the increased lung myofibroblasts and lung fibrosis. However, BMDCs don’t differentiate into lung smooth muscles cells in CHF mice. Moreover, we demonstrated that inhibition of lung inflammation by a cytokine therapy protocol is effective in attenuating TAC-induced lung fibrosis. Finally, we demonstrated that end-stage CHF causes increase of lung fibrosis in patients, and the increased lung fibrosis is associated with RV hypertrophy and dysfunction in patients. Together, our study demonstrated that end-stage CHF causes lung fibrosis and lung dysfunction, and inhibition of inflammation is effective in attenuating heart failure induced lung fibrosis.

GW26-e4818 The L-carnitine Ameliorates Pulmonary Arterial Hypertension by Improving Energy Metabolism Dysfunction of Right Ventricular Failure

L-carnitine is indispensable for energy metabolism and mitochondrial function in the myocardium. Although carnitine deficiency have been implicated in development of left ventricular failure, little is known about the role of L-carnitine in the right ventricular failure in pulmonary arterial

Progression of matrixin and cardiokine expression patterns in an ovine model of heart failure and recovery

BackgroundThe molecular mechanisms underlying the geometrical changes of the left ventricle during the progression to heart failure and recovery are not well defined. ObjectiveHere we investigate the involvement of matrixins and cardiokines in an ovine model of pressure-induced left ventricular failure (LVF). MethodsFifteen sheep underwent supracoronary aortic banding with an inflatable cuff. A controlled and progressive increase of LV pressure was monitored echocardiographically. Endomyocardial biopsies were collected throughout the development of LVF and subsequent recovery after pressure unloading. ResultsThirteen sheep developed LVF with a subsequent recovery. Peak left ventricular hypertrophy (LVH) and dilatation (LVD) occurred at 31.5±1.6weeks and 102.7±2.2weeks post-banding respectively, with an increase in LV internal diameter in diastole (LVIDd 5.11±0.12 compared to the control 3.37±0.07cm, p<0.001), with preserved LV ejection fraction (LVEF). Reduced LVEF became evident 116.5±2.7weeks post-banding. Clinical and echocardiographic improvements were observed following deflation of the aortic banding cuff. By 138.1±3.1weeks cardiac performance recovered with restoration of LVEF. Significant changes in the expression of matrix metalloproteinases (MMP)-1, -2, -3, vascular endothelial cell growth factor (VEGF), fibroblast growth factor (FGF)-2, interferon (INF)-α-2 and soluble CD40 ligand (sCD40L) were observed throughout the progression to failure and recovery. ConclusionsWe used an ovine model to study reversible LV remodelling without interruption and found significant changes in matrixin and cardiokine expression during LV progression to failure and recovery.

The role of systemic inflammation and endothelial dysfunction in the development of left ventricular dysfunction in patients with chronic obstructive pulmonary disease

Summary. The aim of the study – to identify the role of systemic inflammation and endothelial dysfunction in the development of left ventricular dysfunction in patients with chronic obstructive pulmonary disease (COPD). Endothelium-dependent vasodilatation of brachial artery (EDVD), echocardiography parameters of left and right heart chambers, the concentration of pro-inflammatory and anti-inflammatory cytokines and circulating immune complexes (CIC) in plasma were studied in patients with moderate COPD. COPD patients showed a reduction of left ventricular contractile activity compared to the control group. Reducing EDVD was found in 72 % of patients with COPD. In the development of left ventricular failure involved a violation of interventricular interaction. Correlation analysis of the relationship of molecular indicators of inflammatory activity and echocardiography parameters were identified: correlation between the concentration of the CIC and the pulmonary artery systolic pressure (PASP), between the level of IL-1β and PASP, between the concentration of IL-8 and the PASP. COPD patients at an early stage of the disease to detect violations of vasoactive endothelial function, an imbalance of pro-and anti-inflammatory cytokines, increasing the concentration of CIC. Developing systemic inflammation and endothelial dysfunction contribute not only to the formation of pulmonary hypertension and chronic cor pulmonale, but also the development of left ventricular failure.

Chemokines regulate small leucine-rich proteoglycans in the extracellular matrix of the pressure-overloaded right ventricle

Chemokines have been suggested to play a role during development of left ventricular failure, but little is known about their role during right ventricular (RV) remodeling and dysfunction. We have previously shown that the chemokine (C-X-C motif) ligand 13 (CXCL13) regulates small leucine-rich proteoglycans (SLRPs). We hypothesized that chemokines are upregulated in the pressure-overloaded RV, and that they regulate SLRPs. Mice with RV pressure overload following pulmonary banding (PB) had a significant increase in RV weight and an increase in liver weight after 1 wk. Microarray analysis (Affymetrix) of RV tissue from mice with PB revealed that CXCL10, CXCL6, chemokine (C-X3-C motif) ligand 1 (CX3CL1), chemokine (C-C motif) ligand 5 (CCL5), CXCL16, and CCL2 were the most upregulated chemokines. Stimulation of cardiac fibroblasts with these same chemokines showed that CXCL16 increased the expression of the four SLRPs: decorin, lumican, biglycan, and fibromodulin. CCL5 increased the same SLRPs, except decorin, whereas CX3CL1 increased the expression of decorin and lumican. CXCL16, CX3CL1, and CCL5 were also shown to increase the levels of glycosylated decorin and lumican in the medium after stimulation of fibroblasts. In the pressure-overloaded RV tissue, Western blotting revealed an increase in the total protein level of lumican and a glycosylated form of decorin with a higher molecular weight compared with control mice. Both mice with PB and patients with pulmonary stenosis had significantly increased circulating levels of CXCL16 compared with healthy controls measured by enzyme immunoassay. In conclusion, we have found that chemokines are upregulated in the pressure-overloaded RV and that CXCL16, CX3CL1, and CCL5 regulate expression and posttranslational modifications of SLRPs in cardiac fibroblasts. In the pressure-overloaded RV, protein levels of lumican were increased, and a glycosylated form of decorin with a high molecular weight appeared.

Triangulating the Peaks of Arterial Pressure

Increased arterial stiffness and excessive pressure pulsatility have emerged as important risk factors for a number of common disorders of aging, including cardiovascular disease, stroke, cognitive impairment, and renal disease. The triple-threat combination of robust associations between arterial stiffness and the foregoing disorders, a marked increase in arterial stiffness with advancing age and the graying of our society, has led to intensive efforts to identify mechanisms that contribute to arterial stiffening and widening pulse pressure to define interventions to prevent or reverse stiffness and potentially reduce the substantial burden of related disease. Wave reflections complicate the task of evaluating arterial hemodynamics and play an unclear role in the foregoing diseases. When the heart ejects, ventricular outflow interacts with characteristic impedance of the proximal aorta to produce the forward pressure wave, which travels down the normally compliant aorta at a finite pulse wave velocity (PWV). When the forward wave encounters impedance mismatch, such as a branch point or a change in diameter or wall properties, a partial reflection occurs. Innumerable reflections arising from locations distributed throughout the arterial tree summate into a remarkably discrete reflected pressure wave with amplitude ≈40% of the incident wave. The summated reflected wave returns to the central aorta in midsystole, creating an inflection point and secondary late systolic pressure rise that often augments central aortic systolic and pulse pressure.1 Variable timing of this retrograde-traveling reflected wave creates regional inequalities in systolic and pulse pressure and, therefore, complicates interpretation of single point pressure measurements, such as standard brachial blood pressure, which may differ from central aortic pressure. Augmentation index (AI), which expresses late systolic pressure augmentation as a percentage of pulse pressure, is frequently used to assess wave reflection (Figure). AI, which depends on both timing and amplitude of the reflected wave, has also been widely …

Alterations in cultured myocardial fibroblast function following the development of left ventricular failure

A structural event in the progression of left ventricular (LV) failure is myocardial extracellular matrix (ECM) remodeling. The myocardial fibroblast is a major cell type influencing the ECM, but whether and to what degree specific phenotypic differences in myocardial fibroblasts can be demonstrated to occur in culture with the development of LV failure remains unclear. Adult pigs (25 kg) were used for control myocardial fibroblast preparations (N=5) or following pacing-induced LV failure (N=5; 240 bpm, 3 weeks). LV remodeling occurred with pacing as evidenced by increased LV end diastolic volume (132+/-11 vs. 60+/-4 mL for control; P<0.05). Functional parameters including migration, adhesion, collagen and matrix metalloproteinase release were assessed in fibroblast cultures from passages 1-4. The following findings were consistent with each passage and the results were analyzed with control values set to 100%. Migration of LV failure fibroblasts increased by over 170% (P<0.05). Adhesion to collagen I, laminin and fibronectin was increased by over 160% in LV failure fibroblasts (P<0.05). beta(1) integrin density decreased by 50% in LV failure fibroblasts (P<0.05). Fibrillar collagen release increased by over 130% and matrix metalloproteinase-2 increased by 140% in LV failure fibroblasts (P<0.05). The unique findings of this study are two-fold. First, after a pathological stimulus in-vivo, adult myocardial fibroblasts maintain a consistent phenotype through early passages in-vivo. Second, a differential release of, and response to ECM components occurred in LV failure fibroblasts. Thus, a phenotypic transformation of the myocardial fibroblast occurs with the development of LV failure, which in turn may contribute to matrix remodeling and presents as a potential cellular therapeutic target.

Exercise urotensin II dynamics in myocardial infarction survivors with and without hypertension

Background Hypertension is diagnosed in approximately 50% of patients with acute myocardial infarction. Urotensin II (U-II) — a potent vasoactive peptide shown to be elevated in hypertensive subjects, can contribute to negative myocardial remodelling and development of left ventricular failure. Data concerning U-II activity under exercise conditions and its influence on blood pressure in patients after myocardial infarction is scant. Therefore we sought to determine U-II dynamics during exercise in myocardial infarction survivors with and without hypertension. Methods Forty patients with acute myocardial infarction treated with successful primary coronary angioplasty, after four weeks of uneventful and symptom-free period following initial hospitalization underwent treadmill exercise test. U-II plasma concentration was measured before and shortly after the exercise. Results Hypertension was diagnosed in 17 (42.5%) patients. We found no significant differences between normotensive and hypertensive subjects except higher smoking rate and lower calcium channel blockers prescription in normotensive patients. Both systolic and diastolic blood pressure were comparable between study groups before exercise. After exercise we observed higher systolic blood pressure in hypertensive subjects (169.06 ± 30.23 vs. 150.0 ± 18.97 mm Hg; p < 0.05). U-II concentration showed no significant difference in pretest sampling (54.93 ± 38.11 vs. 73.97 ± 48.52 ng/ml; p = NS). After exercise we noted significantly higher peptide level in hypertensive patients (63.32 ± 36.11 vs. 98.03 ± 40.47 ng/ml; p = 0.01). Conclusions The present study is the first one to show differences in U-II concentration exercise dynamics in hypertensive and normotensive myocardial infarction survivors. It sheds additional light on hypertension pathophysiology in myocardial infarction patients, and thus identifies a novel, potentially relevant, target for future therapeutic interventions.

Predictive Factors for Heart Failure in Patients with Unstable Angina and Acute Non-ST Elevation Myocardial Infarction

Background and Objectives:Besides the acute coronary syndrome (ACS), the left ventricular failure (LVF) is the next important determinant of morbidity and mortality after acute coronary syndrome (ACS). The prediction of high risk groups for LVF may be in the initial management of patients with unstable angina (UA) or acute non-ST elevation myocardial infarction (NSTEMI). Subjects and Methods:179 patients (60.4± 11.6 years, 121 male) who underwent diagnostic coronary angiography under the diagnosis of UA/NSTEMI between January and December, 2000, in the Chonnam National University Hospital Heart Center were enrolled for evaluation of relationship between the development LVF and various parameters, including clinical features, initial electrocardiogram, laboratory findings and coronary angiographic findings. Results:Unstable angina was clinically diagnosed in 124 patients, and NSTEMI in 55 patients. During a 12-month follow-up period, less than 40% of the left ventricular ejection fraction (EF), a low amount, was observed in 28 patients (15.7%). In diabetic patients, the incidence of LVF was significantly higher than in non-diabetics (p<0.05). Patients with elevated C-reactive protein (CRP) or positive troponin I had LVF more frequently (p<0.05). On the initial electrocardiogram, the total summation of ST segment change inversely correlated with EF (p<0.05). Patients whose QT dispersion was longer than 80 ms had a higher incidence of LVF (p<0.05). Coronary angiographic findings of total occlusion correlated with the development of LVF (p<0.05), but not with other characteristics. On multiple logistic regression analysis, high CRP level (p=0.024), summation of ST change (p=0.021), total occlusion of the coronary artery (p=0.008) were independent prognostic factors of LVF. Conclusion: Elevated CRP, summation of ST change and total coronary artery occlusion are important predictive factors for LVF in UA/NSTEMI. (Korean Circulation J 2004;34(5):459-467)

How should age affect management of acute myocardial infarction? A prospective cohort study

About 75% of patients with acute myocardial infarction are older than 70 years, but patients in this age group are commonly treated less vigorously than younger patients. This differential treatment may partly reflect clinicians' misconceptions about the outlook of such patients, and the importance of age in clinical decisions. We examined how age does and should affect the management of patients and risk stratification in acute myocardial infarction. In this prospective cohort study, we recruited 1225 consecutive patients admitted with acute myocardial infarction to a district general hospital in east London. The primary endpoint was death. We used tabulation and regression methods to analyse the association between age group and clinical variables. Patients aged 70 years or older took a longer time to arrive in hospital and were less likely to receive thrombolysis or discharge beta-blockers than patients younger than 60 years: odds ratio 0.63 (95% CI 9.45-0.88) for thrombolysis and 0.25 (0.16-0.37) for beta-blockade, adjusted for sex, diabetes, previous acute myocardial infarction, Q wave infarction, and left-ventricular failure. Left-ventricular failure was the strongest independent predictor of death within 1 year of infarction with a hazard ratio of 4.76 (3.53-6.43), adjusted for age, sex, diabetes, and Q wave infarction. Patients aged 70 years or older without left-ventricular failure had significantly better survival at 1 year after acute myocardial infarction than patients under 60 years with left-ventricular failure. 70.8% (62.2-78.2) of the older patients who survived to hospital discharge were still alive 3 years later. Elderly patients with acute myocardial infarction were treated less vigorously than younger patients. The prognosis of acute myocardial infarction, however, was substantially affected by the development of left-ventricular failure and other clinical indices, such that many older patients had a better outlook than younger patients with adverse clinical factors. In planning risk-based management, consideration of age independently of clinical status is inappropriate.

Apolipoprotein E ε4 Allele as a Genetic Risk Factor for Left Ventricular Failure in Homozygous β-Thalassemia

AbstractIn homozygous β-thalassemia, the organ damage is mainly attributed to excessive iron deposition through the formation of oxygen free radicals. Despite appropriate transfusion and chelation therapy and low ferritin levels, patients still develop organ failure, heart failure being the main cause of death. This study was designed to determine whether the decreased antioxidant activity of the apolipoprotein E (APOE) ε4 allele could represent a genetic risk factor for the development of left ventricular failure (LVF) in β-thalassemia homozygotes. A total of 251 Greek β-thalassemia homozygotes were studied. Patients were divided in three groups: group A (n = 151) with no cardiac impairment, group C (n = 47) with LVF, and 53 patients with LV dilatation and normal LV systolic function constituted the group B. DNA was obtained from all patients, and the polymerase chain reaction was used to analyze the polymorphism at the APOE locus. The APOE allele frequencies were compared with those of a Greek control sample of 216 healthy blood donors. Patients with no cardiac impairment had an APOE ε4 allele frequency (7.9%) not different from population controls (6.5%, P > .05), while patients with LVF had a significantly higher frequency of APOE ε4 (12.8%) than the controls (P < .05, odds ratio = 2.11, 95% confidence interval 1.03 to 4.32). The APOE ε4 allele may represent an important genetic risk factor for the development of organ damage in homozygous β-thalassemia.© 1998 by The American Society of Hematology.

Apolipoprotein E 4 Allele as a Genetic Risk Factor for Left Ventricular Failure in Homozygous β-Thalassemia

In homozygous β-thalassemia, the organ damage is mainly attributed to excessive iron deposition through the formation of oxygen free radicals. Despite appropriate transfusion and chelation therapy and low ferritin levels, patients still develop organ failure, heart failure being the main cause of death. This study was designed to determine whether the decreased antioxidant activity of the apolipoprotein E (APOE) 4 allele could represent a genetic risk factor for the development of left ventricular failure (LVF) in β-thalassemia homozygotes. A total of 251 Greek β-thalassemia homozygotes were studied. Patients were divided in three groups: group A (n = 151) with no cardiac impairment, group C (n = 47) with LVF, and 53 patients with LV dilatation and normal LV systolic function constituted the group B. DNA was obtained from all patients, and the polymerase chain reaction was used to analyze the polymorphism at the APOE locus. The APOE allele frequencies were compared with those of a Greek control sample of 216 healthy blood donors. Patients with no cardiac impairment had an APOE 4 allele frequency (7.9%) not different from population controls (6.5%, P &gt; .05), while patients with LVF had a significantly higher frequency of APOE 4 (12.8%) than the controls (P &lt; .05, odds ratio = 2.11, 95% confidence interval 1.03 to 4.32). The APOE 4 allele may represent an important genetic risk factor for the development of organ damage in homozygous β-thalassemia.© 1998 by The American Society of Hematology.

APOLIPOPROTEIN E ε4 ALLELE AS A RISK FACTOR FOR LEFT VENTRICULAR FAILURE IN β-THALASSAEMIA HOMOZYGOTES. 97

The apolipoprotein E (APOE) gene is located on chromosome 19, and the three most common alleles are designated e2, e3, and e4. The e4 allele is associated with atherosclerosis, cardiovascular disease, Alzheimer disease, and decreased longevity. Recently a decreased antioxidant activity of the e4 allele was demonstrated. In our aim to identify genetic risk factors for the development of left ventricular failure (LVF) inβ-thalassaemia homozygotes, which is not explained by the secondary haemosiderosis only, we studied the APOE allele distribution in such patients compared with controls. The material consisted of 42 patients with homozygousβ-thalassaemia and LVF, 67 patients with homozygous β-thalassaemia without heart failure, as compared to a control sample of 216 healthy blood donors. The frequency of allele e4 in patients with LVF (14.3%) was significantly higher than in controls (6.5%, χ2=5.99, p<0.05). In patients without heart failure there was no significant difference in APOE allele distribution compared with controls. We suggest that APOE allelee4 is a risk factor for development of LVF in β-thalassaemia homozygotes. If these preliminary findings are confirmed in bigger materials, it will be of big importance for early intervention in patients with predisposition to LVF.

Early discharge after acute myocardial infarction: risks and benefits.

Thrombolytic treatment reduces mortality in patients with acute myocardial infarction but is associated with recurrent thrombotic events after admission, and it is unclear whether current practices of early hospital discharge are safe. Timing of first major adverse events (death, reinfarction, unstable angina, secondary ventricular fibrillation) in the early post-infarction period was studied to determine the risks. Follow up study. 608 consecutive patients (447 men and 161 women) with confirmed myocardial infarction who were admitted to the coronary care unit of a district general hospital between January 1989 and December 1991. Clinical details, including the development of left ventricular failure and in hospital adverse events, were recorded prospectively. Follow up for out of hospital adverse events was carried out by review of the case notes, postal questionnaire, and where necessary, by telephone contact with the patient and his general practitioner. The risk (95% confidence interval) of major adverse events in the first 10 days was 32.3% (26.3 to 39.4%) in patients with heart failure and 7.3% (5.1 to 9.2%) in those without. Smoothed estimates of the event rate in patients without heart failure decreased from 5.9 events/1000 persons/day on day 6 to 3.4 events/1000 persons/day on day 10 and 0.9 events/1000 persons/day on day 21. The corresponding cumulative risk estimates suggest that about 11 in every 1000 patients suffer a major, but often unpreventable, adverse event on day 6 or 7 after admission, and 23 in every 1000 do so between days 6 and 10. The point at which the risk to the individual becomes acceptably low is a matter of judgement, but the risk of a major adverse event declines rapidly after a heart attack, and particularly for patients without heart failure discharge within a few days may be appropriate. Prolonging stay unnecessarily may use resources which could be more effectively used to treat cardiac disease in other ways.

Role of Intra-Aortic Counterpulsation in Cardiogenic Shock and Acute Myocardial Infarction

IACP has played an important role in the evolution of the therapy of cardiogenic shock. Although IACP has not developed to an independent treatment modality, it is an essential adjunct to facilitate early catheterization and reperfusion strategies. With this combined approach, hospital and long-term survival rates have reached encouraging results. In acute myocardial infarction, IACP may evolve into an intriguing adjunct to thrombolysis and/or PTCA. Preliminary data suggest that IACP might decrease the rate of reocclusion and reinfarction after thrombolysis and/or PTCA and, thus, interrupt the vicious cycle of infarct extension, development of left-ventricular failure and cardiogenic shock. Further research is in progress.

Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding.

Left ventricular hypertrophy (LVH) is associated with reinduction of the fetal program of gene expression. It is unclear whether this pattern of cardiac gene expression changes with the development of left ventricular decompensation and failure. To answer these questions, we quantified steady-state levels of mRNA by the polymerase chain reaction in the left ventricular myocardium of rats 8 and 20 weeks after ascending aortic banding. Clinical and hemodynamic assessment identified two distinct groups of animals 20 weeks after aortic banding. The first group (20-week nonfailed LVH) demonstrated substantial LVH but no depression in systolic developed pressure per gram left ventricular weight compared with the age-matched control group. In contrast, a second group of rats exhibited clinical signs of congestive failure as well as a marked diminution in left ventricular developed pressure per gram. Assessment of the levels of mRNA encoding a panel of cardiac proteins demonstrated a greater than twofold increase in beta-myosin heavy chain mRNA and an approximately sixfold increase in atrial natriuretic factor mRNA in left ventricular myocardium of all three groups (8-week LVH, 20-week nonfailed LVH, 20-week failed LVH) when compared with appropriate age-matched control groups. In contrast, Ca(2+)-ATPase mRNA levels were decreased by 50% only in the left ventricular myocardium of animals with both clinical signs and hemodynamic indexes consistent with cardiac decompensation (20-week failed LVH). These results suggest that in rats with ascending aortic banding the hypertrophic phenotype is associated with a selective reinduction of the fetal gene program, which persists even after the development of left ventricular failure.(ABSTRACT TRUNCATED AT 250 WORDS)