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Background: The causes of heart failure (HF) during high-grade atrioventricular block (AVB) are poorly understood. This study assessed the mechanisms of HF in patients with AVB., Methods: We studied patients presenting (between 2012 and 2016) with high-grade AVB not related to acute myocardial infarction. Patients with preexisting significant valvular heart disease were excluded. All patients underwent comprehensive echocardiographic evaluation during AVB, before pacemaker implantation. The diagnosis of HF was based on the Framingham criteria., Results: A total of 122 patients were included in the study, 50% male, average age 76 ± 13 years. Twenty-eight patients (23%) with AVB presented with HF. Univariate correlates associated with HF were decrease in cardiac output (CO) (odds ratio [OR] 0.68 [95% confidence interval 0.49-0.9] per L/min; P = 0.007), measures of impaired left ventricular (LV) compliance, and increase in diastolic mitral regurgitation (MR) volume (OR 1.04 [1.01-1.07] per cc; P = 0.0016). Ventricular rate during AVB and LV ejection fraction were not significantly associated with the presence of HF. By multivariate nominal logistic analysis, the best model associated with HF included diastolic MR volume (OR 1.04 [1.001-1.09]; P = 0.02), A-wave deceleration time (OR 0.96 [0.94-0.9]; P = 0.001), and CO (OR 0.92 [0.4-1.00]; P = 0.005) (χ 2  = 30.6; area under the receiver operating characteristic curve = 0.84; P < 0.0001 for the entire model)., Conclusions: In the setting of high-degree AVB, clinical HF occurrence correlates with impaired LV compliance and diastolic MR volume, but not with heart rate or LV ejection fraction. The cardiac performance of patients with poor LV compliance and high-volume diastolic MR may show maladjustment to slow heart rates, manifesting as low CO and HF., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Current methods do not allow a thorough assessment of causes associated with limited exercise capacity in patients with chronic obstructive pulmonary disease (COPD)., Methods: Twenty patients with COPD and 20 matched control subjects were assessed using combined cardiopulmonary and stress echocardiographic testing. Various echocardiographic parameters (left ventricular [LV] volumes, right ventricular [RV] area, ejection fraction, stroke volume, S', and E/e' ratio) and ventilatory parameters (peak oxygen consumption [Vo 2 ] and A-Vo 2 difference) were measured to evaluate LV and RV function, hemodynamics, and peripheral oxygen extraction (A-VO 2 difference)., Results: Significant differences (both between groups and for group-by-time interaction) were seen in exercise responses (LV volume, RV area, LV volume/RV area ratio, S', E/e' ratio, tricuspid regurgitation grade, heart rate, stroke volume, and Vo 2 ). The major mechanisms of reduced exercise tolerance in patients with COPD were bowing of the septum to the left in 12 (60%), abnormal increases in E/e' ratio in 12 (60%), abnormal stroke volume reserve in 16 (80%), low peak A-Vo 2 difference in 10 (50%), chronotropic incompetence in 13 (65%), or a combination of several mechanisms. Patients with COPD and poor exercise tolerance showed attenuated increases in stroke volume, heart rate, and A-Vo 2 difference and exaggerated changes in LV/RV ratio and LV compliance (ratio of LV volume to E/e' ratio) compared with patients with COPD with good exercise tolerance., Conclusions: Combined cardiopulmonary and stress echocardiographic testing can be helpful in determining individual mechanisms of exercise intolerance in patients with COPD. In patients with COPD, exercise intolerance is predominantly the result of chronotropic incompetence, limited stroke volume reserve, exercise-induced elevation in left filling pressure, and peripheral factors and not simply obstructive lung function. Limited stroke volume is related to abnormal RV contractile reserve and reduced LV compliance introduced through septal flattening and direct ventricular interaction., (Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: Discriminating circulatory problems with reduced stroke volume (SV) from deconditioning, in which the muscles cannot consume oxygen normally, by gas exchange parameters is difficult., Methods: We performed combined stress echocardiography (SE) and cardiopulmonary exercise tests (CPET) in 110 patients (20 with normal effort capacity, 54 with attenuated SV response, and 36 with deconditioning) to evaluate multiple hemodynamic parameters and oxygen content difference (A-V.o 2 Diff) in four predefined activity levels to assess which of the gas measures may help in the discrimination., Results: Reduced anaerobic threshold (AT), low unchanging peak oxygen pulse, periodic breathing, shallow Δ peak oxygen consumption (V.o 2 )/Δwork rate (WR) ratio, and high expired volume per unit time/carbon dioxide production (V. e /V.co 2 ) slope were all associated with abnormal SV response (P < .05 for all). The best discriminator was V. e /V.co 2 slope to V.o 2 ratio (≥ 2.7; area under the curve [AUC], 0.79; P < .0001). The optimal gas exchange model included ΔV.o 2 /ΔWR < 8.6; V. e /V.co 2 slope to peak V.o 2 ratio ≥ 2.7, and periodic breathing (AUC of 0.84; P < .0001)., Conclusions: The best single gas exchange parameter to discriminate between circulatory problems and deconditioning is V. e /V.co 2 slope to peak V.O 2 ratio. Combining it with ΔV.o 2 /ΔWR and periodic breathing improves the discriminative ability., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Combining echocardiography and cardiopulmonary stress testing allows noninvasive assessment of hemodynamics, and oxygen extraction (A-VO 2 difference). We evaluated mechanisms of effort intolerance in patients with heart failure with borderline (40% to 49%) left ventricular ejection fraction (EF) (HF and Borderline Ejection fraction). We included 89 consecutive patients with HF and Borderline Ejection fraction (n = 25; 63.6 ± 14 years, 64% men), control subjects (n = 22), patients with HF with preserved EF (n = 26; EF ≥50%), and patients with HF with reduced EF (n = 16; <40%). Various echo parameters (left ventricular volumes, EF, stroke volume, mitral regurgitation [MR] volume, e', right ventricle end-diastolic area, and right ventricle end-systolic area), and ventilatory or combined parameters (peak oxygen consumption [VO 2 ] and A-VO 2 difference) were measured at 4 predefined activity stages. Effort-induced functional MR was frequent and more prevalent in HF and Borderline Ejection fraction than in all the other types of HF. In multivariable analysis heart rate response (p <0.0001), A-VO 2 difference (p = 0.02), stroke volume (p = 0.002), and right ventricle end-systolic area were the only independent predictors of exercise capacity in HF and Borderline Ejection fraction but peak EF was not. In HF and Borderline Ejection fraction exercise intolerance is predominantly due to chronotropic incompetence, peripheral factors, and limited stroke volume reserve, which are related to right ventricle dysfunction and functional MR but not to left ventricular ejection fraction. Combined testing can be helpful in determining mechanisms of exercise intolerance in HF and Borderline Ejection fraction., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to assess individual mechanisms of effort intolerance in patients with heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), or normal cardiac function using combined echocardiography and cardiopulmonary stress testing., Background: Combined stress echocardiography and cardiopulmonary tests visualize cardiac chambers in 4 well-defined activity levels (rest, unloaded, anaerobic threshold, and peak), allowing noninvasive assessment of cardiac function, hemodynamics, and arterial venous oxygen content difference (AVo(2)Diff) during all stages., Methods: Left ventricular volumes, stroke volume (SV), S', E/e', oxygen consumption (Vo(2)), and AVo(2)Diff were measured in all effort stages using ramp semirecumbent cycle prolonged (≥8 min) exercise in 45 consecutive subjects evaluated for effort intolerance (14 normal cardiac function, 16 HFpEF, and 15 HFrEF patients; age 56.5 ± 16 years; 73% male)., Results: In HFpEF and HFrEF, the changes in Vo2 were attenuated (between group p = 0.003; group by time interaction p < 0.0001), as well as peak heart rate (p = 0.0001; p = 0.0001) and SV (p = 0.006; p = 0.0001). End-diastolic volume to E/e' ratio (measure of compliance) was superior in HFrEF and normal patients at baseline but worsened in HFpEF and HFrEF at peak exercise (8.3 ± 4 vs. 11.6 ± 5 vs. 19.1 ± 8; p = 0.004; p = 0.01). Functional mitral regurgitation worsened even during the unloaded stage, mostly in patients with HFrEF, but also in several patients with HFpEF. In multivariable analysis, heart rate response (p = 0.007), and AVo(2)Diff (p < 0.0001) were the most significant independent predictors of effort capacity; SV was not., Conclusions: Combined tests are feasible and allow noninvasive evaluation of effort intolerance. In HFpEF and HFrEF patients, exercise intolerance is predominantly due to chronotropic incompetence and peripheral factors. Combined stress echocardiography and cardiopulmonary tests may have potential for clinical management and selection of patients for trials., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Elevated filling pressures of the left atrium (LA) are associated with poorer outcomes in patients with chronic heart failure. The V-Wave is a new percutaneously implanted device intended to decrease the LA pressure by the shunting of blood from the LA to the right atrium. This report describes the first-in-man experience with the V-Wave device., Methods and Results: A 70-year-old man with a history of heart failure of ischaemic origin, left ventricular dysfunction (LVEF: 35%, pulmonary wedge: 19 mmHg), no right heart dysfunction, NYHA Class III and orthopnoea despite optimal treatment, was accepted for V-Wave device implantation. The device consists of an ePTFE encapsulated nitinol frame that is implanted at the level of the interatrial septum and contains a trileaflet pericardium tissue valve sutured inside which allows a unidirectional LA to right atrium shunt. The procedure was performed through a transfemoral venous approach under fluoroscopic and TEE guidance. The device was successfully implanted and the patient was discharged 24 hours after the procedure with no complications. At three-month follow-up a left-to-right shunt through the device was confirmed by TEE. The patient was in NYHA Class II, without orthopnoea, the Kansas City Cardiomyopathy index was 77.6 (from 39.1 at baseline) and NT-proBNP was 322 ng/mL (from 502 ng/mL at baseline). The QP/QS was 1.17 and the pulmonary wedge was 8 mmHg, with no changes in pulmonary pressure or right ventricular function., Conclusions: Left atrial decompression through a unidirectional left-to-right interatrial shunt represents a new concept for the treatment of patients with left ventricular failure. The present report shows the feasibility of applying this new therapy with the successful and uneventful implantation of the V-Wave device, which was associated with significant improvement in functional, quality of life and haemodynamic parameters at 90 days.

Red blood cell distribution width (RDW), which is routinely reported in complete blood counts, is a measure of the variability in size of circulating erythrocytes. RDW is a novel, independent predictor of prognosis in patients with cardiovascular diseases. The aim of the present study was to evaluate the significance of this biomarker in a relatively large cohort of patients, and to assess its association with a more severe underlying cardiovascular disease. A cohort of 3,222 consecutive patients undergoing coronary angiography was divided according RDW median. The association between RDW and 3-year outcome in the context of other predictors was assessed using Cox's proportional hazards analysis. Patients with elevated RDWs were older, had higher body mass indices, and had more cardiovascular risk factors and more cardiovascular diseases. The total rate of mortality, MI and stroke (MACE) was 7.7% (120 events) in the lower RDW group, and 18.2% (303 events) in the higher RDW group, p < 0.001. Following adjustment for multiple background risk factors, medications, and laboratory results, the RDW value was independently associated with worse outcome (HR = 1.12, 95% CI 1.07-1.18, p < 0.001, for each 1% increase in RDW). Elevated RDW values are independently associated with adverse 3-year outcome in patients undergoing coronary angiography.

Low lymphocyte count has been considered a predictive marker of unfavorable outcomes for patients with heart failure (HF). Baseline blood samples for complete blood counts, differential counts, renal function tests. and lipid profile were prospectively obtained to assess the association between lymphocyte count and clinical outcomes in 305 patients with HF (average New York Heart Association [NYHA] class 2.8). The mean follow-up duration was 4.7 years (range 8 months to 8.4 years), and 111 patients (36%) died during the follow-up period. The mean lymphocyte count for the group was 1,803.64 ± 740.3, and the mean left ventricular ejection fraction (LVEF) was 37%. Patients with low lymphocyte counts (<1,600 median count) after 8 years had significantly lower survival rates than those with lymphocyte counts ≥1,600 (58% vs 72%, p=0.012). The prediction of poorest survival was for patients in NYHA class III or IV and with lymphocyte counts <1,600. Regression analysis showed that lymphocyte level, the LVEF, and NYHA class were predictors of mortality. Of these, NYHA class was the most prominent predictor, followed by lymphocyte count, which was even more significant than the LVEF (hazard ratio 0.76, p=0.037). In conclusion, the findings of this study demonstrate that total lymphocyte count is an important prognostic factor, inversely associated with predicted mortality. Although the total low lymphocyte count was correlated with a lower NYHA class and a lower LVEF, it emerged as an independent death risk factor in patients with chronic HF., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The incidence of heart failure (HF) is constantly increasing in the Western world. Treatment with statins is well established for the primary and secondary prevention of cardiac events by lowering low-density lipoprotein (LDL) cholesterol levels. There are conflicting reports on the role of LDL cholesterol as an adverse prognostic predictor in patients with advanced HF. The aim of this study was to investigate the association between LDL cholesterol levels and clinical outcomes in 297 patients with severe HF (average New York Heart Association class 2.8). The mean follow-up period was 3.7 years (range 8 months to 11.5 years), and 37% of the patients died during follow-up. The mean time to first hospital admission for HF was 25 +/- 17 months. The study group was divided according to plasma LDL level < or =89, >89 to < or =115, >115 mg/dl. Patients with the highest baseline LDL cholesterol levels had significantly improved outcomes, whereas those with the lowest LDL cholesterol levels had the highest mortality. When analyzed with respect to statin use, it emerged that the negative association between LDL cholesterol level and mortality was present only in the patients with HF who were treated with statins. In conclusion, lower LDL cholesterol levels appear to predict less favorable outcomes in patients with HF, particularly those taking statins, raising questions about the need for aggressive LDL cholesterol-lowering strategy in patients with HF, regardless of its cause.

Background: Oxidative stress appears to play a significant role in the pathogenesis of heart failure (HF). Antibodies to oxidized low-density lipoprotein (Ox LDL Abs) reflect an immune response to LDL over a prolonged period and may thus represent oxidative stress over an extended time. Ox LDL Abs have been shown to correlate with clinical control in HF patients. We evaluated the predictive power of Ox LDL Abs on the outcome in patients with HF., Methods and Results: Baseline levels of Ox LDL Abs were determined by enzyme-linked immunosorbent assay in 284 consecutive outpatients with severe chronic HF who were being treated in the cardiology services of our medical center. Their mean New York Heart Association (NYHA) Class was 2.8. The mean follow-up for the group was 3.7 years, during which 107 (37%) died. The mean time from symptom onset to first hospital admission from HF was 25.8 months. Ox LDL Abs were found to predict morbidity and mortality as evaluated by a Cox multivariate regression analysis with a hazard ration of 1.013 (P < .013), whereas N-terminal pro-B-type natriuretic peptide (NT pro-BNP) levels achieved a HR of 1.028 (P < .099)., Conclusions: Ox LDL Abs level maybe a useful parameter for monitoring and planning better management of patients with HF. It was superior to pro-BNP as a predictor of clinical course as expressed by time to hospitalization.

Isolated ventricular non-compaction is a frequently underdiagnosed rare congenital cardiomyopathy. The importance of diagnosing this cardiomyopathy lies especially in asymptomatic patients, screening relatives of index cases in order to focus on their follow-up, and searching for criteria warranting prophylactic anticoagulation, implantable cardioverter defibrillator and anti-remodeling drugs such as angiotensin-converting inhibitors. We present the clinical and imaging characteristics of this entity and discuss some of the therapeutic dilemmas involving these patients.

Background: Myeloperoxidase levels were shown to reflect endothelial dysfunction, inflammation, atherosclerosis and oxidative stress., Objectives: To examine the role of circulating myeloperoxidase, a leukocyte-derived enzyme, as a predictor of mortality in patients with congestive heart failure., Methods: Baseline serum MPO levels were measured in 285 consecutive CHF patients and 35 healthy volunteers. N-terminal pro-brain natriuretic peptide and high sensitivity C-reactive protein concentrations were also measured. The primary outcome endpoint was overall mortality., Results: MPO levels were significantly elevated in patients with CHF compared to healthy volunteers (P = 0.01). During a mean follow-up of 40.9 +/- 11.3 months there were 106 deaths. On a univariate Cox regression analysis MPO levels were of marginal value (P = 0.07) whereas NT-proBNP was of considerable value (P < 0.0001) in predicting all-cause mortality. By dividing our cohort according to NT-proBNP levels into high, intermediate and low risk groups a clear difference in mortality was shown. By further dividing the patient cohort according to MPO levels above or below the median (122.5 ng/ml), mortality prediction improved in the patients with intermediate NT-proBNP values., Conclusions: MPO levels are elevated in CHF and correlate with disease severity. MPO has an additive predictive value on mortality in patients with intermediate NT-proBNP levels.

Background: Circulating CD34+ endothelial progenitor cells (EPCs) are capable of differentiating into mature endothelial cells to assist in angiogenesis and vasculogenesis. We sought to quantify the numbers of apoptotic progenitors in patients with congestive heart failure., Methods and Results: Peripheral blood mononuclear cells were isolated by Ficoll density-gradient from 58 patients with various degrees of heart failure and 23 matched controls. Apoptosis in progenitor CD34+ cells was assessed using the Annexin V-PE/PI detection kit, and FACS analysis was performed with triple staining for CD34, annexin-V and propidium iodide. The percentage of early and late apoptotic progenitor cells was determined in the subject groups and was correlated with clinical characteristics. While there was no significant difference in total CD34 positive cells or early apoptotic progenitors between control subjects and CHF patients (p = 0.42) or between severe and mild/moderate CHF groups (p = 0.544), there was an elevated number of late apoptotic progenitors in the severe CHF group compared with the mild/moderate CHF group (p = 0.03). Late apoptotic progenitors were significantly increased in CHF patients as compared to matched controls. There was also an inverse correlation between late apoptotic progenitors and ejection fraction (r = -0.252, p = 0.028) as well as a positive association with NYHA class (r = 0.223, p = 0.046)., Conclusion: Severe heart failure patients exhibited higher numbers of late apoptotic progenitors, and this was positively associated with NYHA class and negatively correlated with ejection fraction. This finding may shed light on the numerous factors governing the pathophysiology of CHF.

Background: Circulating endothelial progenitor cells (EPCs) are increased in conditions associated with ischaemia and can potentially support angiogenesis and vasculogenesis. EPC levels were also shown to predict outcome in patients with atherosclerotic vascular disease. We tested the hypothesis that circulating EPC can predict outcome in patients with congestive heart failure (CHF)., Methods: EPC-colony-forming units were measured in the peripheral blood of 107 consecutive patients with CHF with New York Heart Association (NYHA) functional class II-IV. Serum levels of vascular endothelial growth factor (VEGF), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and high-sensitivity C-reactive protein (hsCRP) were also measured. End points were defined as CHF-related hospital admissions and all-cause mortality., Results: Age (p = 0.01), diabetes mellitus (p = 0.002) and EPC levels (p = 0.02) were found to be independent predictors of all-cause mortality. EPC levels did not predict CHF-related hospitalisations. EPC levels correlated positively with NYHA (p = 0.05, r = 0.19), but did not correlate with VEGF, NT-pro-BNP or hsCRP. EPC levels did not differ by the aetiology of CHF., Conclusions: EPC levels are independent predictors of all-cause mortality among patients with CHF.

The purpose of the present study was to evaluate the effects of losartan and the combination of losartan and L-arginine on endothelial function and hemodynamic variables in patients with heart failure (HF). Endothelium-dependent vasodilation is impaired in patients with HF. It was hypothesized that the administration of losartan and the combination of losartan and L-arginine might increase nitric oxide production and have a beneficial additive effect on endothelial function and hemodynamic variables in patients with HF. Nine patients with HF (ejection fraction<35%) were given losartan 50 mg orally on 2 consecutive days. On the second day, 1 hour after losartan 50 mg administration, L-arginine 20 g was given by intravenous infusion. Endothelial function in the form of endothelium-dependent brachial artery flow-mediated vasodilation (FMV) was measured by ultrasound. Hemodynamic variables were estimated using Doppler echocardiography at baseline and at 2 and 4 hours after losartan alone and after combination therapy. Urinary levels of nitrite (NO2) or nitrate (NO3) were measured. Four hours after losartan administration, significant reductions in systemic vascular resistance and estimated end-systolic elastase were observed. On the second day, 1 hour after L-arginine infusion, an additive hemodynamic effect was observed, with significant increases in the cardiac index and stroke volume and significant reductions in systemic vascular resistance and calculated left ventricular end-diastolic pressure. A trend toward improved FMV was observed with losartan alone, but without statistical significance. Combination therapy significantly improved postintervention FMV compared with baseline. The increase in urinary nitric oxide excretion after losartan treatment and combination therapy was significantly correlated with improved hemodynamic variables and improved FMV. In conclusion, losartan induces significant afterload reduction, reduced contractility, and increased nitric oxide urinary excretion. The combination of L-arginine and losartan seems to have superior effects on hemodynamic variables and endothelium-dependent vasodilation compared with losartan alone.

Background: Cardiac resynchronization therapy is a modality with proven morbidity and mortality benefit in advanced systolic heart failure. Nevertheless, not all patients respond favorably to CRT. Natriuretic peptides and inflammatory markers are elevated in congestive heart failure and reflect disease severity., Objectives: To test whether an early change in neurohormonal and inflammatory markers after implantation can predict the clinical response to CRT., Methods: The study group included 32 patients with advanced symptomatic systolic heart failure and a prolonged QRS complex who were assigned to undergo CRT. Baseline plasma levels of B-type natriuretic peptide and high sensitivity C-reactive protein were determined in the peripheral venous blood and coronary sinus, Post-implantation levels were determined 2 weeks post-procedure in the PVB. Baseline levels and their change in 2 weeks were correlated with all-cause mortality and hospitalization for congestive heart failure., Results: At baseline, coronary sinus levels of BNP but not hsCRP were significantly elevated compared to the PVB. Compared to baseline levels, BNP and hsCRP decreased significantly within 2 weeks after the implantation (BNP mean difference 229.1 +/- 102.5 pg/ml, 95% confidence interval 24.2-434, P< 0.0001; hsCRP mean difference 5.2 +/- 2.4 mg/dl, 95% CI 0.3-10.1, P= 0.001). During a mean follow-up of 17.7 +/- 8.2 months 6 patients died (18.7%) and 12 (37.5%) were hospitalized due to exacerbation of CHF. Baseline New York Heart Association and CSBNP levels predicted CHF-related hospitalizations. HsCRP levels or their change over 2 weeks did not predict all-cause mortality or hospitalizations., Conclusions: BNP levels in the CS and peripheral venous blood during biventricular implantation and 2 weeks afterwards predict clinical response and may guide patient management.

Background: It has been suggested that oxidative stress may play a role in the pathogenesis of heart failure, this may have potential implications for therapeutic strategies. However, measures of oxidative stress are subject to confounding inaccuracies. IgG antibodies to oxidized LDL reflect exposure to the lipoprotein over an extended period and may thus mirror oxidative stress over a prolonged time frame. Therefore, we tested the hypothesis that anti-oxLDL antibodies correlate with the control of heart failure (HF), as manifested by hospital admissions for cardiac dysfunction., Methods: One hundred and two consecutive patients attending the HF clinic with either systolic or diastolic HF were enrolled and the quality of clinical control was evaluated by assessing hospital admissions over the year prior to index determination of the oxidative stress marker. Antibodies to oxLDL were determined by ELISA and pro-BNP levels were also measured., Results: Most patients (mean age 71.5 years) had systolic HF; mean NYHA functional class was 2.7 and mean left ventricular ejection fraction was 39.7%. Anti-oxLDL antibodies, but not pro-BNP, correlated significantly with mean NYHA score (averaged from all clinic visits in the year prior to blood testing), and with hospital admissions over the year prior to blood testing. Mean IgG anti-oxLDL antibody levels in patients with hospital admissions were 3.4 times higher than those in subjects not hospitalized over the previous year., Conclusion: IgG anti-oxLDL antibody levels correlate with the severity of HF.

Objectives: Patients with congestive heart failure (CHF) suffer considerable morbidity and mortality despite advances in therapy. Treatment with erythropoietin (Epo) has shown promise in CHF patients, yet its mechanisms of action remain elusive. Endothelial progenitor cells (EPC) contribute to postnatal angiogenesis and vasculogenesis, and Epo was shown to promote EPC mobilization. We explored the effect of chronic treatment with Epo on the numbers and functional properties of EPC in CHF patients., Methods and Results: Twenty-eight patients with CHF treated with Epo for a mean period of 28 months were compared to a matched group (n = 28) with regard to the number of circulating hematopoietic and endothelial stem cells (either CD34+, CD34+/CD45+, CD34+/CD133+, CD34+/VEGF-R2+ or CD34+/CD133+/VEGF-R2+) as well as their proliferative and adhesive capacity. In vitro, Epo was added to cultured EPC from healthy subjects to test proliferation and adhesion. No differences were observed in circulating numbers of hematopoietic and endothelial stem cells between CHF patients chronically treated with Epo or untreated. EPC from Epo-treated patients exhibited enhanced proliferation as well as a trend towards adhesion to cultured endothelial cells prior to and following stimulation with TNF-alpha. Addition of Epo to EPC from healthy subjects dose-dependently increased their proliferation and adhesion to fibronectin, cultured endothelial cells, and cardiomyocytes. These effects were significantly reduced in the presence of phosphatidylinositol (PI) 3-kinase inhibitors., Conclusions: Chronic Epo treatment is associated with an increase in the adhesive and proliferative properties of circulating EPC in patients with CHF.

The incidence of both congestive heart failure (CHF) and end-stage renal disease both are increasing. Anemia is common in both conditions and is associated with a marked increase in mortality and morbidity in both CHF and chronic kidney insufficiency (CKI). Each of these 3 conditions can cause or worsen the other 2. In other words, a vicious circle frequently is present in which CHF can cause or worsen both anemia and CKI, in which CKI can cause or worsen both anemia and CHF, and in which anemia can cause or worsen both CHF and CKI. We have called this vicious circle the cardio renal anemia syndrome. Optimal treatment of CHF with all the recommended CHF medications at their recommended doses will, in our experience, frequently fail to improve the CHF and CKI if anemia is present and is not corrected. On the other hand, correction of the anemia with subcutaneous erythropoietin and intravenous iron has caused a great improvement in the CHF including a marked improvement in patient and cardiac function and a marked reduction in the need for hospitalization and for high-dose diuretics. It also frequently has caused renal function to improve or at least stabilize. In addition, patients' quality of life and exercise capacity also have improved with the correction of the anemia. In CKI patients, anemia also may play an important role in increasing the risk for death, coronary heart disease, stroke, and progression to end-stage renal disease. Erythropoietin may have a direct positive effect on the heart and brain unrelated to correction of the anemia by reducing cell apoptosis and by increasing neovascularization, both of which could prevent tissue damage. This could have profound therapeutic implications not only in CHF but in the future treatment of myocardial infarction, coronary heart disease, strokes, and renal failure.

Background: Extracellular matrix remodeling is thought to play an important role in the progression of heart failure (HF). Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are matrix-degrading enzymes that have been demonstrated to influence left ventricular properties and serve as targets of potential anti-remodeling agents. Herein we evaluated the potential significance of circulating MMP and TIMP levels in patients with congestive HF (CHF) speculating it may assume prognostic value., Methods: Serum samples were obtained from 88 consecutive patients attending the outpatient HF clinic and analyzed for MMP-2, -3, -9, and TIMP-1 as well as N-terminal probrain natriuretic peptide (NT-ProBNP). Patients were followed up for the occurrence of either mortality or hospitalizations due to CHF or either of each., Results: Circulating levels of MMP-2, -9, and TIMP-1 but not of MMP-3 were increased in patients with CHF as compared with age-matched controls. Only MMP-2 and NT-ProBNP levels correlated significantly with New York Heart Association class. Matrix metalloproteinase-2 and NT-ProBNP levels did not correlate. Patients with circulating MMP-2 above 352 ng/mL were 4.2 times more likely to die, 2.2 times more likely to be hospitalized because of CHF, and 2.3 times more likely to experience either of the 2 end points as compared with patients with MMP-2 concentrations below this threshold. Both MMP-2 and NT-ProBNP were found to be independent predictors of mortality over a 24-month follow-up period., Conclusions: Matrix metalloproteinase-2 but not MMP-3, -9, or TIMP-1 serum levels is an independent predictor of mortality in patients with CHF.

Anaemia is present in approximately 40% of cases of congestive heart failure (CHF) and is associated with a higher mortality, a lower left ventricular ejection fraction, a lower cardiac functional status, a higher rate of hospitalization, signs of malnutrition, a lower exercise capacity, a progressive fall in renal function, an increased need for high dose diuretics, hyponatraemia, an increased plasma volume, a reduced red cell volume and a lower quality of life. In both uncontrolled and controlled studies, correction of the anaemia with subcutaneous erythropoietin and, in some cases, with the addition of intravenous iron, has been shown to improve these parameters. A vicious circle is present between CHF, chronic kidney insufficiency (CKI) and anaemia, each capable of causing or being caused by the other, the so-called cardio renal syndrome. If larger randomized, controlled, double-blind studies confirm these observations, correction of the anaemia may prove to be a useful addition to the prevention and progression of both CHF and CKI. Cooperation between nephrologists, cardiologists and other internists to identify and treat these anaemic CHF patients early will help prevent progression of both the cardiac and renal disease.

Background: Considerable morbidity and mortality are still associated with congestive heart failure (CHF) syndromes, despite improvement in therapy. Activation of neurohormonal, inflammatory, and oxidative mechanisms has been shown to contribute to the significant morbidity and mortality. Erythropoietin (EPO) is a cytokine known to regulate erythroid proliferation, attenuate apoptosis and oxidative stress, and promote angiogenesis. We prospectively evaluated the predictive value of baseline EPO, N-terminal pro-B-type natriuretic peptide, and C-reactive protein levels in patients with clinically controlled chronic CHF., Methods: One hundred eighty-eight outpatients from a CHF clinic had baseline assessment of EPO, N-terminal pro-B-type natriuretic peptide, and C-reactive protein levels and a complete clinical data profile. These patients were followed up for 24 months for any hospitalization due to CHF or mortality., Results: Circulating EPO levels were higher in CHF patients and increased in subjects with higher New York Heart Association scores. Levels of EPO (at a cutoff of 23 mU/mL) and N-terminal pro-B-type natriuretic peptide (cutoff at the median of 1556 pg/mL) were found to be strong predictors of mortality and CHF hospitalization, whereas C-reactive protein levels (cutoff of 10 mg/L) predicted CHF hospitalizations but not mortality. Left ventricular ejection fraction was found to be a predictor of mortality but not of CHF hospitalizations. Serum levels of EPO were significantly correlated with N-terminal pro-B-type natriuretic peptide and C-reactive protein levels but not with left ventricular ejection fraction., Conclusion: If confirmed in large-scale clinical studies, determination of circulating EPO levels may aid in predicting morbidity and mortality in patients with clinically controlled congestive CHF.

Unlabelled: Anaemia is frequently found in patients with chronic heart failure (CHF) and has been associated with an increase in mortality and morbidity, impaired cardiac and renal function and a reduced quality of life (QoL) compared with non-anaemic CHF patients. Correction of anaemia with recombinant human erythropoietin (epoetin) has been associated with an improvement in CHF in both controlled and uncontrolled studies. The present study describes our findings in a series of 78 consecutive patients with symptomatic CHF and anaemia (haemoglobin (Hb) level <12.0 g/dl) treated with epoetin beta and, if necessary, intravenous iron sucrose. Over a mean observation period of 20.7 +/- 12.1 months, mean Hb levels increased from 10.2 +/- 1.1 to 13.5 +/- 1.2 g/dl, p < 0.01. New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF) were significantly improved and the number of hospitalizations was significantly reduced with the period before treatment (all p < 0.01). Serum creatinine and creatinine clearance (CCr) were 2.2 +/- 0.9 mg/dl and 32.5 +/- 26.5 ml/min, respectively, at baseline, and remained stable over the observation period. Interestingly, >90% of the patients had concomitant mild-to-moderate chronic kidney disease at baseline and study end (CKD), as defined by the accepted diagnostic criterion of a CCr <60 ml/min., Conclusions: The correction of the anaemia with epoetin beta together with initial intravenous iron supplementation, resulted in significant improvements in NYHA class and cardiac function, and a reduction in hospitalization rate. Moreover, renal function was maintained stable in most patients.

Objectives: To find the prevalence of anemia in patients hospitalized with the primary diagnosis of congestive heart failure (CHF)., Background: There is growing evidence that anemia is common in CHF and may contribute to the high morbidity and mortality associated with this condition. However, there is considerable disagreement about the prevalence of anemia in this condition., Methods: In 338 consecutive patients who were admitted to the medical wards with a primary diagnosis of CHF we extracted from the charts the hemoglobin (Hb), serum creatinine, age, sex, New York Heart Association (NYHA) functional class, presence of smoking, diabetes, hypertension, hyperlipidemia and the primary cardiac etiology of the CHF. Anemia was considered to be present when the Hb on admission was <12 g/dl., Results: All the patients were NYHA functional class III-IV. One hundred seventy seven (52.4%) of the 338 patients had a Hb on admission that was <12 g/dl. The mean Hb for the entire group was 12.0+/-1.8 g/dl. One hundred three (51.0%) of the 202 males were anemic compared to 74 (54.4%) of the 136 women. The mean serum creatinine was 1.7+/-1.1 mg/dl. The prevalence of renal insufficiency (serum creatinine >1.5 mg%) was 47.6%. There was a negative correlation between the level of serum creatinine and Hb (r=-0.294) P<0.00001. Of the 177 patients who were anemic, most of 114 (64.4%) had a serum creatinine >1.5 mg/dl., Conclusions: Anemia is a common finding in patients hospitalized with CHF and most anemic CHF patients have some degree of renal insufficiency. In view of the negative effect of anemia on cardiac function, it may be a common and important contributor to the mortality and morbidity of CHF in these patients.

Background: Many patients with congestive heart failure (CHF) have chronic kidney insufficiency (CKI) and anemia., Aims: The purpose of this review is to clarify the relationship between these three factors and to study the effect of correction of anemia in CHF and CKI., Findings: Anemia, CHF and CKI are each capable of causing or worsening each other. Thus they form a vicious circle which can result in progressive CHF, CKI and anemia. Aggressive therapy of CHF, CKI and control of the associated anemia with erythropoietin and i.v. iron can prevent the progression of CHF and CKI, reduce hospitalization, and improve quality of life., Conclusion: CHF patients are a major source of end-stage renal failure patients and deserve special attention. If treated well and early, progressive heart failure and renal failure can be prevented. Cooperation between nephrologists, cardiologists, and other internists will improve the care of all three conditions and prevent their progression., (Copyright 2004 S. Karger AG, Basel)

Background: Congestive heart failure is extremely common in octogenarians and is associated with severe fatigue, shortness of breath, recurrent hospitalizations, and death. These patients, many of whom are anemic, are often resistant to standard CHF therapy including angiotensin-converting enzyme inhibitors, beta-blockers and diuretics., Objectives: To examine whether correction of the anemia (hemoglobin < 12 g/dl) in CHF patients can improve their clinical condition., Methods: Forty octogenarians with anemia and severe resistant CHF were administered a combination of subcutaneous erythropoietin and intravenous iron sucrose., Results: This combination therapy led to a marked improvement in cardiac function, shortness of breath and fatigue, a marked reduction in the rate of hospitalization and a stabilizing of renal function., Conclusion: Anemia appears to be an important but ignored contributor to the progression of CHF, and its correction may improve cardiac and renal status as well as the quality of life in elderly patients.

Objectives: We aimed to examine the effects of colchicine, currently in clinical trials for acute myocardial infarction (AMI), on the viability of cardiac cells using a cell line model of AMI. Methods: HL-1, a murine cardiomyocyte cell line, and H9C2, a rat cardiomyoblast cell line, were incubated with TNFa or sera derived from rats that underwent AMI or sham operation followed by addition of colchicine. In another experiment, HL-1/H9C2 cells were exposed to anoxia with or without subsequent addition of colchicine. Cell morphology and viability were assessed by light microscopy, flow cytometry and Western blot analyses for apoptotic markers. Results: Cellular viability was similar in both sera; however, exposing both cell lines to anoxia reduced their viability. Adding colchicine to anoxic H9C2, but not to anoxic HL-1, further increased their mortality, at least in part via enhanced apoptosis. Under any condition, colchicine induced detachment of H9C2 cells from their culture plates. This phenomenon did not apply to HL-1 cells. Conclusions: Colchicine enhanced cardiomyoblast mortality under in vitro conditions mimicking AMI and reduced their adherence capability. HL-1 was not affected by colchicine; nevertheless, no salvage effect was observed. We thus conclude that colchicine may not inhibit myocardial apoptosis following AMI. [ABSTRACT FROM AUTHOR]

Aims To evaluate the prognostic role of pulmonary venous flow parameters and their role in patients with preserved ejection fraction (EF). Methods and results Pulmonary venous flowparameterswere measured in 365 patients in sinus rhythm, without significant mitral disease, and EF > 50% (age 64.9 ± 19; 52% female) by a single sonographer. Survival, time to re-admission for heart failure, and to a combined cardiac end point (cardiac death, heart failure, and atrial fibrillation) were retrospectively analysed and correlated to echo parameters. Systolic (S) and diastolic (D) pulmonary vein flow were obtainable in 73% of patients and Ar in 65%. The lower peak S/D ratio and higher ΔAr-A time were associated with higher rate of heart failure readmission (P = 0.03 for both). The S/D integral ratio was the best pulmonary vein flow predictor of heart failure readmissions (P = 0.0009), better than the peak S/D ratio, or ΔA-Ar time (P < 0.01 for both), and independently predicted worse outcome even when adjusted for diastolic grading (using recent guidelines), left ventricle mass index, E/e', and left atrial volume index (P < 0.05 for all). The addition S/D ratio to diastolic grading recognized patients with pseudonormal filling pattern and S/D ratio >1 with similar clinical outcomes to grade I (P > 0.5), but worse clinical outcomes than in the pseudo-normal patients with lower S/D ratio (P < 0.01). Conclusions PVFP are obtainable in most patients, add prognostic information on top of routine diastolic parameters, and define an early stage of diastolic dysfunction resembling the pseudo-normal pattern in which S/D ratio is >1, and outcome is excellent. [ABSTRACT FROM AUTHOR]

Background Transcatheter aortic valve replacement ( TAVR) has become a treatment option for patients with severe aortic stenosis ( AS) and high surgical risk. Assessment of symptoms in these patients is challenging because of advanced age, comorbidities, and limited physical activity. Noninvasive quantification of pulmonary capillary wedge pressure ( PCWP) in candidates for TAVR may be helpful for risk stratification. The objective of the study was to create a model for estimation of PCWP by echo Doppler in patients with severe AS. Methods and Results Data from 80 patients with severe AS referred for TAVR were used to develop an echo Doppler model for predicting PCWP. Its performance was evaluated in the test cohort of 33 patients who had invasive and noninvasive evaluation. No single echo Doppler parameter estimated PCWP accurately. In the retrospective analysis, the multilinear regression provided an accurate estimate of PCWP (r2 = 0.74). The model included, in order of importance (all P < 0.05), the ratio of early transmitral velocity (E) to annular velocity (E'), the left ventricular ejection fraction, and the velocity time integral of tricuspid regurgitation signal. In the prospective cohort of patients with severe AS, the model demonstrated good predictive ability of PCWP (r = 0.77, P < 0.01). Conclusion In patients with severe AS, noninvasive estimation of PCWP is possible by integration of two-dimensional, spectral, and tissue Doppler variables. [ABSTRACT FROM AUTHOR]

Background: Ischemic cardiac damage is associated with upregulation of cardiac pro-inflammatory cytokines, as well as invasion of lymphocytes into the heart. Regulatory T cells (Tregs) are known to exert a suppressive effect on several immune cell types. We sought to determine whether the Treg pool is influenced by myocardial damage and whether Tregs transfer and deletion affect cardiac remodeling. Methods and Results: The number and functional suppressive activity of Tregs were assayed in mice subjected to experimental myocardial infarction. The numbers of splenocyte-derived Tregs in the ischemic mice were significantly higher after the injury than in the controls, and their suppressive properties were significantly compromised. Compared with PBS, adoptive Treg transfer to mice with experimental infarction reduced infarct size and improved LV remodeling and functional performance by echocardiography. Treg deletion with blocking anti-CD25 antibodies did not influence infarct size or echocardiographic features of cardiac remodeling. Conclusion: Treg numbers are increased whereas their function is compromised in mice with that underwent experimental infarction. Transfer of exogeneous Tregs results in attenuation of myocardial remodeling whereas their ablation has no effect. Thus, Tregs may serve as interesting potential interventional targets for attenuating left ventricular remodeling. [ABSTRACT FROM AUTHOR]

Background. A mild anaemia is often found in patients with congestive heart failure (CHF), but its significance is uncertain. In an open uncontrolled study we investigated the effect of correcting this anaemia [haemoglobin (Hb) 9.5–11.5 g%] with subcutaneous (s.c.) erythropoietin (Epo) and intravenous (i.v.) iron (Fe) in 179 patients, 84 type II diabetics and 95 non‐diabetics, with moderate to severe CHF which was resistant to maximally tolerated doses of standard CHF medications. [ABSTRACT FROM PUBLISHER]

Abstract: Background: C-reactive protein (CRP) has been tested in patients with systolic heart failure (HF) and mixed results have been obtained with regards to its potential predictive value. However, the role of C-reactive protein (CRP) in patients with diastolic HF is not established. We studied the predictive role of high sensitivity CRP (hsCRP) in patients with diastolic HF. Methods: HsCRP levels were measured in a cohort of CHF outpatients, 77 patients with diastolic HF and 217 patients with systolic HF. Concentrations were compared to a large cohort of healthy population (n =7701) and associated with the HF admissions and mortality of the patients. Results: Levels of hsCRP did not differ between patients with systolic and diastolic HF and were significantly elevated compared to the cohort of healthy subjects even after adjustment to various clinical parameters (p <0.0001). In patients with diastolic HF, hsCRP levels associated with New York Heart Association functional class (NYHA-FC) (r =0.31 p =0.01). On univariate Cox regression model hsCRP levels independently predicted hospitalizations in patients with systolic but not diastolic HF (p =0.047). Conclusion: HsCRP concentrations are elevated in patients with diastolic HF and correlate with disease severity; their prognostic value in this patient population should be further investigated. [Copyright &y& Elsevier]