The Postoperative Paradoxical Septum (POPS): A Comprehensive Review on Physio-Pathological Mechanisms.

The interventricular septum (IVS) is a core myocardial structure involved in biventricular coupling and performance. Physiologically, during systole, it moves symmetrically toward the center of the left ventricle (LV) and opposite during diastole. Several pathological conditions produce a reversal or paradoxical septal motion, such as after uncomplicated cardiac surgery (CS). The postoperative paradoxical septum (POPS) was observed in a high rate of cases, representing a unicum in the panorama of paradoxical septa as it does not induce significant ventricular morpho-functional alterations nor negative clinical impact. Although it was previously considered a postoperative event, evidence suggests that it might also appear during surgery and gradually resolve over time. The mechanism behind this phenomenon is still debated. In this article, we will provide a comprehensive review of the various theories generated over the past fifty years to explain its pathological basis. Finally, we will attempt to give a heuristic interpretation of the biventricular postoperative motion pattern based on the switch of the ventricular anchor points.

Improvement of Left Ventricular Global Longitudinal Strain after 6-Month Therapy with GLP-1RAs Semaglutide and Dulaglutide in Type 2 Diabetes Mellitus: A Pilot Study.

(1) Background: Glucagone-Like Peptide-1 Receptor Agonists (GLP-1 RAs) (GLP-1 RAs) are incretine-based medications recommended in the treatment of type 2 Diabetes Mellitus (DM2) with atherosclerotic cardiovascular disease (ASCVD) or high or very high cardiovascular (CV) risk. However, knowledge of the direct mechanism of GLP-1 RAs on cardiac function is modest and not yet fully elucidated. Left ventricular (LV) Global Longitudinal Strain (GLS) with Speckle Tracking Echocardiography (STE) represents an innovative technique for the evaluation of myocardial contractility. (2) Methods: an observational, perspective, monocentric study was conducted in a cohort of 22 consecutive patients with DM2 and ASCVD or high/very high CV risk, enrolled between December 2019 and March 2020 and treated with GLP-1 RAs dulaglutide or semaglutide. The echocardiographic parameters of diastolic and systolic function were recorded at baseline and after six months of treatment. (3) Results: the mean age of the sample was 65 ± 10 years with a prevalence of the male sex (64%). A significant improvement in the LV GLS (mean difference: -1.4 ± 1.1%; p value < 0.001) was observed after six months of treatment with GLP-1 RAs dulaglutide or semaglutide. No relevant changes were seen in the other echocardiographic parameters. (4) Conclusions: six months of treatment with GLP-1 RAs dulaglutide or semaglutide leads to an improvement in the LV GLS in subjects with DM2 with and high/very high risk for ASCVD or with ASCVD. Further studies on larger populations and with a longer follow-up are warranted to confirm these preliminary results.

Advances in Multimodality Cardiovascular Imaging in the Diagnosis of Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a syndrome defined by the presence of heart failure symptoms and increased levels of circulating natriuretic peptide (NP) in patients with preserved left ventricular ejection fraction and various degrees of diastolic dysfunction (DD). HFpEF is a complex condition that encompasses a wide range of different etiologies. Cardiovascular imaging plays a pivotal role in diagnosing HFpEF, in identifying specific underlying etiologies, in prognostic stratification, and in therapeutic individualization. Echocardiography is the first line imaging modality with its wide availability; it has high spatial and temporal resolution and can reliably assess systolic and diastolic function. Cardiovascular magnetic resonance (CMR) is the gold standard for cardiac morphology and function assessment, and has superior contrast resolution to look in depth into tissue changes and help to identify specific HFpEF etiologies. Differently, the most important role of nuclear imaging [i.e., planar scintigraphy and/or single photon emission CT (SPECT)] consists in the screening and diagnosis of cardiac transthyretin amyloidosis (ATTR) in patients with HFpEF. Cardiac CT can accurately evaluate coronary artery disease both from an anatomical and functional point of view, but tissue characterization methods have also been developed. The aim of this review is to critically summarize the current uses and future perspectives of echocardiography, nuclear imaging, CT, and CMR in patients with HFpEF.

Mid-Diastolic Events (L Events): A Critical Review.

Mid-diastolic events (L events) include three phenomena appreciable on echocardiography occurring during diastasis: mid-diastolic transmitral flow velocity (L wave), mid-diastolic mitral valve motion (L motion), and mid-diastolic mitral annular velocity (L' wave). L wave is a known marker of advanced diastolic dysfunction in different pathological clinical settings such as left ventricle and atrial remodeling, overloaded states, and cardiomyopathies. Patients with L events have poor outcomes with a higher risk of developing heart failure symptoms and arrhythmic complications, including sudden cardiac death. The exact mechanism underlying the genesis of mid-diastolic events is not fully understood, just as the significance of these events in healthy young people or their presence at the tricuspid valve level. We also report an explicative case of a patient with L events studied using speckle tracking imaging of the left atrium and ventricle at the same reference heartbeat supporting the hypothesis of a post-early diastolic relaxation or a "two-step" ventricular relaxation for L wave genesis. Our paper seeks to extend knowledge about the pathophysiological mechanisms on mid-diastolic events and summarizes the current knowledge.

Tricuspid Annular Plane Systolic Excursion in Acute Decompensated Heart Failure: Relevance for Risk Stratification.

BACKGROUND: Although the prognostic value of right ventricular dysfunction in chronic heart failure (HF) has been studied extensively, it remains insufficiently characterized in the setting of acute decompensated HF (ADHF). We sought to assess whether measurement of tricuspid annular plane systolic excursion (TAPSE) or TAPSE-to-estimated pulmonary arterial systolic pressure (ePASP) ratio allows improvement of risk prediction in ADHF. METHODS: Four hundred ninety-nine patients with ADHF were studied. Cox regression analyses were used to analyze the association of TAPSE and TAPSE-to-ePASP ratio with 1-year mortality and logistic regression analyses to analyze the association of the 2 variables of interest with adverse in-hospital outcome (AiHO) (in-hospital death plus worsening HF). RESULTS: During the 365-day follow-up, 143 patients (28.7%) died. At univariable analysis, both TAPSE (P = 0.026) and TAPSE-to-ePASP ratio (P < 0.0001) were significantly associated with 1-year mortality. At multivariable Cox analysis, age (P = 0.0270), ischemic heart disease (P = 0.020), systolic blood pressure (P = 0.006), log N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (P < 0.0001), serum sodium levels (P = 0.001), and hemoglobin levels (P = 0.001) at admission were independently associated with 1-year mortality. Adjusting for these covariates, neither TAPSE (P = 0.314) nor TAPSE-to-ePASP ratio (P = 0.237) remained independently associated with 1-year mortality. Eighty-three patients (16.6%) had an AiHO. At multivariable logistic regression analysis, the TAPSE-to-ePASP ratio was independently associated with an AiHO (P = 0.024). The association of TAPSE alone or ePASP alone was not statistically significant. CONCLUSIONS: Our data strongly suggest that early assessment of TAPSE or TAPSE-to-ePASP ratio does not improve prediction of 1-year mortality over other key risk markers in ADHF. Nonetheless, the TAPSE-to-ePASP ratio did appear to be independently associated with AiHO.

The metabolic exercise test data combined with Cardiac And Kidney Indexes (MECKI) score and prognosis in heart failure. A validation study.

BACKGROUND: The Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score is a prognostic model to identify heart failure (HF) patients at risk for cardiovascular mortality (CVM) and urgent heart transplantation (uHT) based on 6 routine clinical parameters: hemoglobin, sodium, kidney function by the Modification of Diet in Renal Disease (MDRD) equation, left ventricle ejection fraction (LVEF), percentage of predicted peak oxygen consumption (VO2) and VE/VCO2 slope. OBJECTIVES: MECKI score must be generalizable to be considered useful: therefore, its performance was validated in a new sequence of HF patients. METHODS: Both the development (MECKI-D) and the validation (MECKI-V) cohorts were composed of consecutive HF patients with LVEF <40% able to perform a symptom-limited cardiopulmonary exercise testing. The CVM or uHT rates were analyzed at one, two and three years in both cohorts: all patients with a censoring time shorter than the scheduled follow-up were excluded, while those with events occurring after 1, 2 and 3 years were considered as censored. RESULTS: MECKI-D and MECKI-V consisted of 2009 and 992 patients, respectively. MECKI-V patients had a higher LVEF, higher peak VO2 and lower VE/VCO2 slope, higher prescription of beta-blockers and device therapy: after the 3-year follow-up, CVM or uHT occurred in 206 (18%) MECKI-D and 44 (13%) MECKI-V patients (p<0.000), respectively. MECKI-V AUC values at one, two and three years were 0.81 ± 0.04, 0.76 ± 0.04, and 0.80 ± 0.03, respectively, not significantly different from MECKI-D. CONCLUSIONS: MECKI score preserves its predictive ability in a HF population at a lower risk.

Predicting short-term mortality in advanced decompensated heart failure - role of the updated acute decompensated heart failure/N-terminal pro-B-type natriuretic Peptide risk score.

BACKGROUND: The first few months after admission are the most vulnerable period in patients with acute decompensated heart failure (ADHF). METHODS AND RESULTS: We assessed the association of the updated ADHF/N-terminal pro-B-type natriuretic peptide (NT-proBNP) risk score with 90-day and in-hospital mortality in 701 patients admitted with advanced ADHF, defined as severe symptoms of worsening HF, severely depressed left ventricular ejection fraction, and the need for i.v. diuretic and/or inotropic drugs. A total of 15.7% of the patients died within 90 days of admission and 5.2% underwent ventricular assist device (VAD) implantation or urgent heart transplantation (UHT). The C-statistic of the ADHF/NT-proBNP risk score for 90-day mortality was 0.810 (95% CI: 0.769-0.852). Predicted and observed mortality rates were in close agreement. When the composite outcome of death/VAD/UHT at 90 days was considered, the C-statistic decreased to 0.741. During hospitalization, 7.6% of the patients died. The C-statistic for in-hospital mortality was 0.815 (95% CI: 0.761-0.868) and Hosmer-Lemeshow χ(2)=3.71 (P=0.716). The updated ADHF/NT-proBNP risk score outperformed the Acute Decompensated Heart Failure National Registry, the Organized Program to Initiate Lifesaving Treatment in Patients Hospitalized for Heart Failure, and the American Heart Association Get with the Guidelines Program predictive models. CONCLUSIONS: Updated ADHF/NT-proBNP risk score is a valuable tool for predicting short-term mortality in severe ADHF, outperforming existing inpatient predictive models.

Combined use of high-sensitivity C-reactive protein and N-terminal pro-B-type natriuretic peptide for risk stratification of vascular surgery patients.

BACKGROUND: We sought to assess whether high-sensitivity C-reactive protein (hs-CRP) and pro-B-type natriuretic peptide (NT-proBNP) improve risk prediction when added to an established predictive tool and develop a point-based risk score. METHODS: Four hundred eleven vascular surgery patients were enrolled. The primary outcome was a composite of death, acute coronary syndromes, pulmonary edema within 30 days of surgery, and postoperative troponin-I elevation. The risk score was developed from a logistic regression model by using an integer-based scoring system. RESULTS: The rate of the primary outcome was 18%. Adding both hs-CRP and NT-proBNP to the Revised Cardiac Risk Index led to an increase in C statistic from 0.670 to 0.774. The net reclassification improvement was 0.210 (P = 0.004) and the integrated discrimination improvement was 0.112 (P = 0.0001). In the multivariable regression analysis used to develop the risk score, insulin therapy for diabetes (odds ratio [OR]: 2.8; P = 0.003), open surgery (OR: 1.95; P = 0.027), fibrinogen >377 mg/dL (OR: 2.83; P = 0.001), hs-CRP >3.2 mg/L (OR: 3.85; P < 0.0001), and NT-proBNP >221 ng/L (OR: 4.05; P < 0.0001) were associated with the primary outcome. There was no statistical evidence of overfit. The C index was 0.82 and the Hosmer-Lemeshow statistic was 1.61 (P = 0.0447). The observed and predicted rates of the primary outcome across quartiles of risk score were highly correlated. CONCLUSIONS: Hs-CRP and NT-proBNP substantially improve risk prediction when added to an established predictive tool. The biochemical marker-based risk score may be useful for accurately risk-stratifying vascular surgery patients; nonetheless, further validation studies on external datasets are needed before it can be used in clinical practice.

Head-to-head comparison of peak upright bicycle and post-treadmill echocardiography in detecting coronary artery disease: a randomized, single-blind crossover study.

BACKGROUND: Post-treadmill digital echocardiography (post-TME) is the most widely used form of exercise echocardiography, but ischemia can rapidly resolve in the postexercise period; peak upright bicycle digital echocardiography (UBE) has the advantage of providing images at peak exercise that reflect normal physiology. However, the comparative accuracy of the two methods in detecting ischemia in the same patients is unknown. To compare the relative diagnostic value of peak UBE and post-TME in detecting coronary artery disease, both tests were performed in 86 consecutive patients undergoing coronary angiography. METHODS: Eighty-six patients referred for evaluation of coronary disease underwent peak UBE (starting at 25 W, with 25-W increments every 3 min) and post-TME (Bruce protocol) in a random sequence. Digitized images of peak UBE and post-TME were interpreted in a random and blinded fashion. RESULTS: More transient wall motion abnormalities were detected with peak UBE than post-TME (55 vs 42, P < .001), and such exercise-induced wall motion abnormalities were more extensive (5.5 ± 3.0 vs 3.4 ± 2.1 dyskinetic segments, P < .001) and more severe (regional wall motion score index, 2.7 ± 0.5 vs 2.5 ± 0.5; P = .003). By angiography, 59 patients had coronary artery disease (a coronary stenosis of ≥50% diameter narrowing); the sensitivity of peak UBE for detecting coronary artery disease was greater than that of post-TME in the population as a whole (88% vs 66%, P < .01) and in the single-vessel subgroup (72% vs 44%, P < .05), with no worsening in specificity (89% vs 89%, P = NS). CONCLUSIONS: Peak UBE is more capable of detecting ischemia than post-TME, and this is achieved with no worsening of specificity. Thus, peak UBE should be preferred in patients able to perform bicycle exercise.

Amino-terminal pro-B-type natriuretic peptide for risk prediction in acute decompensated heart failure.

Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) has been associated with prognosis in heart failure. The aim of this study was to assess whether NT-proBNP enhances risk prediction in acute decompensated heart failure (ADHF). The authors enrolled 453 patients hospitalized for ADHF. The primary outcome was 12-month mortality. Two separate multivariable predictive models were built by using standard variables-only and NT-proBNP concentrations. The models were internally validated using the bootstrapping method. Twelve-month mortality was 28.3%. There was no statistical evidence of overfit. Compared with the standard variables-only model, the NT-proBNP model had a better predictive performance as judged by the Nagelkerke R(2) (0.410 vs 0.374) and the Brier score (0.136 vs 0.141), which are measures of overall performance; the Akaike Information Criterion (399.2 vs 415.0), which is a tool for model selection; and the C index (0.844 vs 0.831), which is a measure of the discriminative ability. Both models were well calibrated, as judged by the Hosmer-Lemeshow chi-square test. Both models predicted 12-month mortality significantly better than the Enhanced Feedback for Effective Cardiology Treatment risk score. In conclusion, the NT-proBNP model improved risk prediction compared with the standard variables-only model.

Inpatient cardiac rehabilitation soon after hospitalization for acute decompensated heart failure: a propensity score study.

PURPOSE: Postdischarge management of acute decompensated heart failure (ADHF) remains an ongoing challenge. We sought to assess whether inpatient cardiac rehabilitation (CR) soon after hospitalization for ADHF improves outcome. METHODS: Patients (N = 275) hospitalized for ADHF were enrolled. The primary outcome was a composite of all-cause mortality and urgent heart transplantation (UHT) at 1 year. The followup started at the time of discharge from the acute care setting. Because of the observational nature of the study, a propensity score analysis was used to predict the likelihood of undergoing CR. A multivariable Cox regression analysis adjusted for propensity score was used to assess the effect of CR on the primary outcome. RESULTS: Of the 275 patients, 130 underwent CR. Among the baseline variables of the index hospitalization for ADHF, propensity score derivation identified male gender, New York Heart Association Class IV, refractory HF, moderate to severe mitral or tricuspid regurgitation, nonuse of renin-angiotensin-aldosterone system inhibitors, and daily dosage of furosemide, as being independently associated with the likelihood of undergoing CR. No patient was lost to followup. During the 12-month followup, 74 patients died and 3 underwent UHT. The overall incidence of the primary outcome was 28%. On propensity score-adjusted Cox multivariable analysis, the relative risk of the primary outcome for participants in CR compared with nonparticipants in CR was 0.58 (confidence interval [CI]: 0.34-0.99; P = .04). CONCLUSIONS: Results suggest that the strategy of inpatient CR soon after discharge from the acute care setting improves 1-year UHT-free survival of patients with ADHF.

Carotid artery intima-media thickness: normal and percentile values in the Italian population (camp study).

AIMS: Carotid intima-media thickness (IMT) is one of the best non-invasive parameters for evaluating previous vascular lesions and could be used to identify a preclinical stage of the atherosclerotic process. The aim of our research was to develop an epidemiological study of the normal mean values of IMT of the common carotid artery, adjusted for age and sex, in the Italian population. METHODS AND RESULTS: In this multicenter study, a total of 1017 patients (596 males, mean age: 58.5 + 13.2 years) were enrolled at four different Italian centers. Inclusion criteria were the absence of cardiovascular risk factors or presence of not more than one. Patients underwent two-dimensional echo-color Doppler scanning of the carotid arteries, adopting a high-definition vascular echographic apparatus and a 11-3 MHz linear electronic probe. The arithmetical mean of the IMT value was calculated. Data obtained from this study show the carotid IMT changes in relation to age and sex. In particular, it grows higher with increasing age, and is always higher in men than in women. CONCLUSION: In relation to the percentile distribution of the values in the population analyzed, the normal range of m-IMT could be established just on the basis of the patient's age and sex. In this way, the ultrasound scan operator can rely on a simple reference scheme. This will help to refine the use of carotid ultrasound as an excellent tool for detecting asymptomatic carotid alterations and patients at high risk for cerebral and cardiovascular disease.

High-sensitivity C-reactive protein predicts cardiovascular events and myocardial damage after vascular surgery.

OBJECTIVE: To assess the association of high-sensitivity C-reactive protein (hsCRP) to adverse cardiovascular events and perioperative myocardial damage in patients after elective vascular surgery. METHODS: This was a prospective observational study in a tertiary-care teaching hospital, with 239 patients undergoing elective vascular surgery. The receiver-operating characteristic (ROC) curve was calculated to assess the optimal cut-off value of hsCRP. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Multiple logistic regression analysis was used to identify the predictors of the primary outcome. The primary outcome was a composite of periprocedural myocardial damage, defined as cardiac troponin I (cTn-I) elevation above the decision limit of 0.15 µg/L, death, acute coronary syndrome, stroke, acute heart failure, or intrastent thrombosis within 30 days of surgery. RESULTS: On ROC analysis, the optimal cut-off value of hsCRP was 3.2 mg/L. The primary outcome occurred in 48 patients (20.1%). On univariate analysis, smoking (P = .009), known hypercholesterolemia (P = .01), previous ischemic heart disease (P = .0003), open surgery (P = .03), and hsCRP levels (P < .0001) were associated with the primary outcome. On multiple logistic regression analysis, only hsCRP was independently associated with the primary outcome. The unadjusted and adjusted ORs for the primary outcome among patients with hsCRP levels >3.2 mg/L were 7.5 (CI, 3.7-15.2; P < .0001) and 4.6 (CI, 2.1-9.9; P = .0001), respectively. CONCLUSION: Our data suggest that higher levels of hsCRP are independently associated with an increased risk of perioperative myocardial damage and early adverse cardiovascular events in patients undergoing elective vascular surgery. This may have implications for risk stratification and therapeutic approach.

Detection and prognostic impact of renal dysfunction in patients with chronic heart failure and normal serum creatinine.

BACKGROUND: Accurate identification of renal dysfunction (RD) is crucial to risk stratification in chronic heart failure (CHF). Patients with CHF are at special risk of having RD despite normal serum creatinine (SCr), owing to a decreased Cr generation. At low levels of SCr, the equations estimating renal function are less accurate. This study was aimed to assess and compare the prognostic value of formulas estimating renal function in CHF patients with normal SCr. METHODS: We studied 462 patients with systolic CHF and normal SCr. Creatinine clearance was estimated by the Cockcroft-Gault (eCrCl) and glomerular filtration rate by the 4-variable MDRD equation (eGFR); eCrCl normalized for body-surface area (eCrCl(BSA)) was calculated. The primary outcome was all-cause mortality at 2 years. RESULTS: Seventy five patients died. At multivariate Cox regression analysis, only eCrCl(BSA) was significantly associated with mortality (p = 0.006); eGFR (p = 0.24), eCrCl (p = 0.09) and BUN (p = 0.14) were not statistically significant predictors. The patients in the lowest eCrCl(BSA) quartile had an adjusted 2.1-fold (CI: 1.06-4.1) increased risk of mortality, compared with those in the referent quartile. Two-year survival was 70.4% in the lowest eCrCl(BSA) quartile and 89.7% in the referent quartile. Other independent predictors of mortality were ischemic etiology (RR: 2.16 [CI: 1.3-3.5], p = 0.0017), NYHA III/IV class (RR: 2.45 [CI: 1.51-3.97], p = 0.0003), LVEF <0.25 (RR: 3.38 [CI: 1.69-6.75], p = 0.014), and anemia (RR: 1.86 [CI: 1.16-2.99], p = 0.009). CONCLUSIONS: A sizeable proportion of CHF patients have prognostically significant RD despite normal SCr. Such patients represent a high-risk subgroup and can more accurately be identified by the CG formula corrected for BSA than the MDRD.

The cardiorenal anaemia syndrome in systolic heart failure: prevalence, clinical correlates, and long-term survival.

AIMS: We sought to assess the prevalence and clinical correlates of cardiorenal anaemia (CRA) syndrome in systolic heart failure and the relationship between renal dysfunction and anaemia on hard clinical outcomes. METHODS AND RESULTS: We studied 951 patients with chronic heart failure (CHF) and systolic dysfunction. The primary outcome was all-cause mortality and urgent heart transplantation (UHT). Cox's regression analyses were used to assess the relation of the variables to the primary outcome. Hazard ratios (HRs) with 95% confidence intervals (CI) were calculated. The prevalence of CRA syndrome was 21.1%. Age (P < 0.001), body mass index (P< 0.001), diabetes (P =< 0.001), ischaemic aetiology (P< 0.006), left ventricular ejection fraction (P= 0.018), and treatment with renin-angiotensin system inhibitors (P< 0.001) were independently related to CRA syndrome. During a median follow-up of 3.7 years, the primary outcome occurred in 404 patients (42.5%). Compared with patients with preserved renal function and normal haemoglobin (Hb) levels, those with CRA syndrome had a significantly increased risk for the primary outcome; the univariate and multivariate-adjusted HRs were 4.04 (CI: 3.11-5.24; P< 0.0001) and 2.22 (CI: 1.64-2.98; P< 0.0001), respectively. Three-year UHT-free survival was 86 and 47%, respectively. Among patients with renal dysfunction, the adjusted HR for the primary outcome increased by 17% (CI: 8-26; P= 0.0001) for each 1g/dL decrease below an Hb value of 13.0 g/dL. CONCLUSION: Heart failure, renal dysfunction, and anaemia are a fatal combination. Despite a relatively low prevalence, the CRA syndrome contributes to considerable mortality due to CHF.

Prognostic value of formulas estimating excretory renal function in the elderly with systolic heart failure.

BACKGROUND: reduced renal excretory function (REF) is increasingly being appreciated as a potent prognostic factor in chronic heart failure (CHF). The Cockroft-Gault (CG) and the simplified Modification of Diet in Renal Disease (MDRD) equations have been recommended to estimate REF. However, limitations for both formulas have been reported in the elderly. Their prognostic performance in older CHF patients has not been investigated. OBJECTIVES: to assess the factors independently associated with all-cause mortality and compare the prognostic value of formulas estimating REF in CHF patients aged > or =70 years. DESIGN: a longitudinal study with a median follow-up of 859 days. The end-point was all-cause mortality. SETTING: Division of Cardiology and Cardiac Rehabilitation. SUBJECTS: two hundred and sixty-six patients aged > or =70 years with systolic CHF. METHODS: REF was estimated using the CG (eCrCl(CG)) and the MDRD (eGFR(MDRD)) formulas. Cox proportional hazards model was used to assess the factors independently associated with mortality and compare the prognostic value of estimating formulas. Receiver-operating characteristic (ROC) curve analysis was also performed. RESULTS: Kaplan-Meier estimates of the rates of death at 1 and 2 years were 85% and 73%, respectively At multivariate analysis, eCrCl(CG) <50 mL/min (P = 0.005), anaemia (P = 0.012), non-prescription of beta-blockers (P = 0.006) and left ventricular ejection fraction (P = 0.03) were the only independent predictors of mortality. On ROC analysis, the eCrCl(CG) was significantly more accurate than the eGFR(MDRD). CONCLUSIONS: among CHF patients aged > or =70 years, reduced REF is the most powerful independent predictor of survival. The excess in risk conferred by reduced REF is better appraised by means of the CG than the MDRD equation.

Induction of functional neovascularization by combined VEGF and angiopoietin-1 gene transfer using AAV vectors.

Vectors based on the adeno-associated virus (AAV) deliver therapeutic genes to muscle and heart at high efficiency and maintain transgene expression for long periods of time. Here we report about the synergistic effect on blood vessel formation of AAV vectors expressing the 165 aa isoform of vascular endothelial growth factor (VEGF165), a powerful activator of endothelial cells, and of angiopoietin-1 (Ang-1), which is required for vessel maturation. High titer AAV-VEGF165 and AAV-Ang-1 vector preparations were injected either alone or in combination in the normoperfused tibialis anterior muscle of rats. Long term expression of VEGF165 determined massive cellular infiltration of the muscle tissues over time, with the formation of a large set of new vessels. Strikingly, some of the cells infiltrating the treated muscles were found positive for markers of activated endothelial precursors (VEGFR-2/KDR and Tie-2) and for c-kit, an antigen expressed by pluripotent bone marrow stem cells. Expression of VEGF165 eventually resulted in the formation of structured vessels surrounded by a layer of smooth muscle cells. Presence of these arteriolae correlated with significantly increased blood perfusion in the injected areas. Co-expression of VEGF165 with angiopoietin-1-which did not display angiogenic effect per se-remarkably reduced leakage of vessels produced by VEGF165 alone.