Multiparametric approach to congestion for predicting long-term survival in heart failure.

BACKGROUND: Congestion is a marker of adverse prognosis in patients with heart failure (HF). In addition to brain natriuretic peptide (BNP), estimated plasma volume status (ePVS), bioimpedance vector analysis (BIVA), and blood urea nitrogen/creatinine ratio (BUN/Cr) are emerging as new markers for congestion. The aim of this study was to evaluate the prognostic value of BNP, ePVS, BIVA, and BUN/Cr in HF. METHODS: We analyzed the data from 436 patients with acute or chronic heart failure (AHF, n=184, and CHF, n=252, respectively). BNP, ePVS, hydration index (HI%), and BUN/Cr were collected from all patients at admission. The endpoint was all-cause mortality. RESULTS: Ninety-two patients died after a median follow-up of 463 days (IQR: 287-669). The cumulative mortality of all of the patients was 21% (31% and 13% in AHF and CHF, respectively, p<0.0001). The optimal cut-offs for death occurrence were BNP: >441pg/mL, ePVS: >5.3dL/gr, HI: >73.8%, BUN/Cr: >25. Multivariate Cox regression analysis maintained an independent predictive value for mortality (HR 2. 1, HR 2.2, HR 2.1, and HR 1.7; C-index 0.756). AHF status was no longer associated with death. Together, these variables explained 40% of the risk of death (R2 adjusted=0.40). Patients with all four parameters below or above their optimal cut-off had mortality rates of 4% and 59%, respectively. CONCLUSIONS: BNP, ePVS, BIVA, and BUN/Cr at admission provide independent and complementary prognostic information in patients with HF and, when combined, explain the 40% risk of death in these patients independent from the acute or chronic HF condition.

Right ventriculo-arterial coupling assessed by two-dimensional strain: A new parameter of right ventricular function independently associated with prognosis in chronic heart failure patients.

AIM OF THE STUDY: To evaluate whether right ventriculo-arterial coupling obtained by the estimation of the two-dimensional right ventricular (RV) longitudinal strain and of the pulmonary arterial systolic pressure (PASP) could improve prognostic stratification of chronic heart failure (CHF) outpatients. METHODS: CHF outpatients in a stable clinical condition and in conventional therapy were enrolled. The global RV longitudinal strain (RV-GLS) and the strain of the RV free wall (RV-fwLS) were evaluated. PASP was estimated on the basis of tricuspid regurgitation velocity and the estimated central venous pressure. Both RV-GLS and RV-fwLS were then indexed for PASP. RESULTS: Of the 315 patients evaluated, 69 died during follow-up. Both RV-GLS/PASP and RV-fwLS/PASP were significantly associated with an increased risk of death at univariate (HR: 0.43; 95%CI: 0.34-0.56; p<0.001 and HR: 0.44; 95% CI: 0.34-0.57; p<0.001, respectively) and multivariate analysis (HR: 0.66; 95% CI: 0.49-0.89; p: 0.008 and HR: 0.65; 95% CI: 0.49-0.85; p: 0.002, respectively) after correction for age, NYHA class, mean arterial pressure, left ventricular ejection fraction, natremia, glomerular filtration rate and NT-proBNP. CONCLUSIONS: Indexing RV function, assessed by speckle-tracking analysis, with an estimation of pulmonary systolic arterial pressure provides a parameter of ventricular arterial coupling that is independently associated with an increased risk of mortality.

A Multiparametric Approach Based on NT-proBNP, ST2, and Galectin3 for Stratifying One Year Prognosis of Chronic Heart Failure Outpatients.

Galectin-3 and ST2 are emerging biomarkers involved in myocardial fibrosis. We evaluate the relevance of a multiparametric biomarker approach based on increased serum levels of NT-proBNP, galectin-3, and ST2 in stratifying the prognosis of chronic heart failure (CHF) outpatients. In 315 CHF outpatients in stable clinical condition clinical and echocardiographic evaluations were performed. Routine chemistry and serum levels of NT-proBNP, galectin-3, and ST2 were also assessed. During a 12 month follow-up, cardiovascular death, and/or heart failure (HF) occurred in 64 patients. The presence of NT-proBNP, galectin-3, and ST2 were higher than the recommended cutoffs and were all associated with events at univariate Cox regression analysis, as well as in a multivariate analysis including the three biomarkers. When a score based on the number of biomarkers above the recommended cut-offs was used (in a range of 0-3), it was associated with events both with respect to the univariate (HR 2.96, 95% CI 2.21-3.95, p < 0.001, C-index 0.78) and the multivariate (HR 1.52, 95% CI 1.06-2.17, p: 0.023, C-index 0.87) analyses, after correction for the variables of a reference model. Our results suggest that an easy prognostic approach based on the combination of three biomarkers, although with partially-overlapping pathophysiological mechanisms, is able to identify patients with the highest risk of heart failure progression.

Right Ventricular Longitudinal Strain Measures Independently Predict Chronic Heart Failure Mortality.

The assessment of right ventricular (RV) function still remains a challenge. Two-dimensional (2D) speckle tracking has recently been proposed to evaluate right ventricular function by analyzing myocardial deformation. The aim of this study was to evaluate the role of 2D systolic strain measures of RV in predicting mortality in patients with chronic heart failure (HF). We enrolled 332 outpatients in a stable clinical condition and in conventional therapy. A right ventricular-focused four-chamber view was analyzed by 2D speckle tracking to evaluate the global longitudinal strain of RV (RV-GLS) and the strain of RV free wall (RV-fwLS). During a mean follow-up of 36 ± 26 months, 64 patients died. Both RV-GLS and RV-fwLS were associated with all-cause mortality in univariate (HR: 1.16; 95% CI: 1.10-1.23; P < 0.001; C-index: 0.72; and HR: 1.10; 95% CI: 1.06-1.15; P < 0.001; C-index: 0.68, respectively) as well as multivariate analysis (HR: 1.13; 95% CI: 1.05-1.21; P:0.001; C-index: 0.85; and HR: 1.07; 95% CI: 1.02-1.12; P:0.004; C-index: 0.84, respectively). In conclusion, our findings demonstrate the role of RV 2D strain measures to independently predict mortality. These data highlight the clinical usefulness of this echocardiographic approach in the daily management of HF outpatients.

Effects of a timely therapy with doxycycline on the left ventricular remodeling according to the pre-procedural TIMI flow grade in patients with ST-elevation acute myocardial infarction.

Doxycycline has been demonstrated to reduced left ventricular (LV) remodeling, but its effect in patients with ST-elevation myocardial infarction (STEMI) and a baseline occluded [thrombolysis in myocardial infarction (TIMI) flow grade ≤1] infarct-related artery (IRA) is unknown. According to the baseline TIMI flow grade, 110 patients with a first STEMI were divided into 2 groups. Group 1: 77 patients with TIMI flow ≤1 (40 patients treated with doxycycline and 37 with standard therapy, respectively), and a Group 2: 33 patients with TIMI flow 2-3 (15 patients treated with doxycycline and 18 with standard therapy, respectively). The two randomized groups were well matched in baseline characteristics. A 2D-Echo was performed at baseline and at 6 months, together with a coronary angiography, for the remodeling and IRA patency assessment, respectively. The LV end-diastolic volume index (LVEDVi) decreased in Group 2 [-3 mL/m(2) (IQR: -12 to 4 mL/m(2))], and increased in Group 1 [6 mL/m(2) (IQR: -2 to 14 mL/m(2))], (p = 0.001). In Group 2, LVEDVi reduction was similar regardless of drug therapy, while in Group 1 the LVEDVi was smaller in patients treated with doxycycline as compared to control [3 mL/m(2) (IQR: -3 to 8 mL/m(2)) vs. 10 mL/m(2) (IQR: 1-27 mL/m(2)), p = 0.006]. A similar pattern was observed also for LV end-systolic volume and ejection fraction. In STEMI patients at higher risk, as those with a baseline TIMI flow grade ≤1, doxycycline reduces LV remodeling.

Early short-term doxycycline therapy in patients with acute myocardial infarction and left ventricular dysfunction to prevent the ominous progression to adverse remodelling: the TIPTOP trial.

AIMS: Experimental studies suggest that doxycycline attenuates post-infarction remodelling and exerts protective effects on myocardial ischaemia/reperfusion injury. However, the effects of the drug in the clinical setting are unknown. The aim of this study was to examine the effect of doxycycline on left ventricular (LV) remodelling in patients with acute ST-segment elevation myocardial infarction (STEMI) and LV dysfunction. METHODS AND RESULTS: Open-label, randomized, phase II trial. Immediately after primary percutaneous coronary intervention, patients with STEMI and LV ejection fraction < 40% were randomly assigned to doxycycline (100 mg b.i.d. for 7 days) in addition to standard therapy, or to standard care. The echo LV end-diastolic volumes index (LVEDVi) was determined at baseline and 6 months. (99m)Tc-Sestamibi-single-photon emission computed tomography infarct size and severity were assessed at 6 months. We calculated a sample size of 110 patients, assuming that doxycycline may reduce the increase in the LVEDVi from baseline to 6 months > 50% compared with the standard therapy (statistical power > 80% with a type I error = 0.05). The 6-month changes in %LVEDVi were significant smaller in the doxycycline group than in the control group [0.4% (IQR: -16.0 to 14.2%) vs.13.4% (IQR: -7.9 to 29.3%); P = 0.012], as well as infarct size [5.5% (IQR: 0 to 18.8%) vs. 10.4% (IQR: 0.3 to 29.9%) P = 0.052], and infarct severity [0.53 (IQR: 0.43-0.62) vs. 0.44 (IQR: 0.29-0.60), P = 0.014], respectively. CONCLUSION: In patients with acute STEMI and LV dysfunction, doxycycline reduces the adverse LV remodelling for comparable definite myocardial infarct size (NCT00469261).

BNP in mitral valve restrictive annuloplasty for ischemic mitral regurgitation.

Restrictive annuloplasty with undersized mitral rings is used to correct functional mitral regurgitation (MR) in patients with ischemic left ventricular dysfunction. Seventeen patients with severe coronary artery disease, previous myocardial infarction, moderate/severe functional MR and heart failure symptoms were prospectively evaluated. All patients received CABG associated with restrictive annuloplasty. Preoperatively and 6 months after the operation, clinical evaluation, echocardiography and blood sampling for BNP measurement were performed. Operative mortality occurred in 1 patient. MR degree decreased from 3.8+/-0.3 to 1.0+/-0.7 (p<0.01), LVEF increased from 36+/-11% to 43+/-8% (p<0.05), left ventricular end diastolic diameters changed from 54.7+/-5.2 mm to 51.5+/-5.8 mm (p=0.51). NYHA class improved from 2.94+/-1.02 to 1.21+/-0.42 (p<0.01). Mean plasma BNP levels decreased from 471+/-248 pmol/l to 55.6+/-52.8 pmol/l (p<0.05). Restrictive mitral annuloplasty is a safe procedure to be associated to CABG operation. We demonstrated mid-term reduction of BNP plasma values after MR correction thus suggesting the effectiveness of surgical treatment in modifying natural history of the disease.

The 212A variant of the APJ receptor gene for the endogenous inotrope apelin is associated with slower heart failure progression in idiopathic dilated cardiomyopathy.

BACKGROUND: Idiopathic dilated cardiomyopathy (IDC) has multiple genetic and acquired causes. Apelin is an endogenous peptide that increases cardiac inotropism through his APJ receptor. No data are available concerning the APJ gene mutations responsible for IDC or on the role of APJ receptor gene variants in predicting heart failure (HF) progression. METHODS AND RESULTS: We prospectively evaluated 202 consecutive patients with IDC and 202 matched controls: 90 were screened for APJ gene mutations and all 202 were genotyped for G212A and A445C APJ receptor polymorphisms. No mutations were found within the coding or untranslated regions of the APJ receptor, and no differences in allelic or genotype frequencies were observed comparing patients with a healthy control population. The correlations between APJ receptor polymorphisms and HF progression were assessed. During a median follow-up of 37 months, 35 patients experienced HF progression. Univariate analysis showed that patients carrying at least 1 copy of 212A had a significantly lower risk for HF-related events than those who were homozygous for the G212 variant, and multivariate analysis confirmed that it was significantly related to a more favorable prognosis. CONCLUSIONS: APJ is unlikely to be a gene causing IDC, but the independent correlation between the 212A allele and a better prognosis suggests that it might act as a modifier gene.

Beta1- and beta2-adrenergic receptor polymorphisms affect susceptibility to idiopathic dilated cardiomyopathy.

OBJECTIVE: Beta1- and beta2-adrenergic receptors (ARs) play a pivotal role in myocardial function. We investigated whether functionally relevant polymorphisms within the genes encoding for these receptors indicate susceptibility to idiopathic dilated cardiomyopathy (DCM). METHODS: This case-control association study involved 189 patients with DCM and 378 gender- and age-matched control subjects. All of the subjects were characterised by polymerase chain reaction-restriction fragment length polymorphism analysis in terms of Ser49Gly and Arg389Gly polymorphisms in the beta1-AR, and the 5' leader cistron Arg19Cys, Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms in the beta2-AR. Genotype, allele and haplotype frequencies were analysed. RESULTS: Univariate analysis showed that the distribution of genotype and allele frequencies of the beta1-Ser49Gly, beta1-Arg389Gly and beta2-Arg16Gly polymorphisms was significantly different between the patients and controls, and the beta1-Gly49/beta1-Arg389 haplotype was significantly more represented in the patients. Multivariate analysis showed that only the beta1-Gly49 variant (odds ratio 1.91; 95% confidence interval 1.24-2.95; P = 0.003) and beta2-Gly16Gly genotype (odds ratio 1.58; 95% confidence interval 1.10-2.26; P = 0.013) carriers were at significantly higher risk of developing DCM. CONCLUSIONS: In our population from southern Italy, the Gly49 allele of the beta1-AR and the Gly16Gly genotype of the beta2-AR were significantly and independently associated with the DCM phenotype, thus suggesting their role in favouring susceptibility to the disease.

Ventricular repolarization dynamicity provides independent prognostic information toward major arrhythmic events in patients with idiopathic dilated cardiomyopathy.

OBJECTIVES: The purpose of this work was to evaluate whether ventricular repolarization dynamicity predicts major arrhythmic events in patients with idiopathic dilated cardiomyopathy (DCM). BACKGROUND: Arrhythmic risk stratification in patients with DCM is still an open issue. Ventricular repolarization analysis should provide relevant information, but QT interval and QT dispersion failed in predicting arrhythmic risk. METHODS: The following parameters were evaluated in 179 consecutive DCM patients without history of sustained ventricular tachycardia (VT) and/or ventricular fibrillation (VF) at enrollment: QRS duration, QT interval corrected for heart rate, and QT dispersion at electrocardiogram (ECG); left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter at echocardiogram; and nonsustained ventricular tachycardia (NSVT), heart rate variability (standard deviation of RR intervals), and ventricular repolarization dynamicity as measured by means of 24-h ECG monitoring, by calculating the slope of linear regression analysis of QT end and RR intervals (QTe-slope) and the value of mean QT end corrected for heart rate. RESULTS: During a mean follow-up of 39 months, 9 patients died suddenly and 15 experienced VT and/or VF. At multivariate analysis, LVEF (p = 0.047), NSVT (p = 0.022), and QTe-slope (p = 0.034) were significantly associated with arrhythmic events. Among the patients with a low LVEF, NSVT and/or steeper QTe-slope identified a subgroup at highest arrhythmic risk. CONCLUSIONS: In patients with DCM, QT dynamicity is independently associated with the occurrence of major arrhythmic events and improves the predictive accuracy of stratifying arrhythmic risk of these patients.

Ischemic mitral regurgitation: pathophysiology, diagnosis and surgical treatment.

Ischemic mitral valve regurgitation often complicates acute myocardial infarction and also represents a negative prognostic factor for long-term survival in patients undergoing surgical myocardial revascularization. While severe mitral regurgitation should always be corrected during a coronary artery bypass operation, the decision making is more difficult in patients with a mild-to-moderate degree of regurgitation. Recent studies and experimental protocols have elucidated the pathophysiological mechanisms leading to mitral regurgitation with great interest in annular modifications and subvalvular alterations. These data suggest that new and integrated surgical approaches that address annuloplasty ring sizing, ring type selection and tethering phenomenon (i.e., chordal cutting, 'edge-to-edge' technique and left-ventricular plasty techniques) are required for a safer and durable valve repair. Transthoracic and transesophageal echocardiography are useful in determining the etiology and the degree of mitral regurgitation, to assess mitral deformation and to measure indexes of global and regional left-ventricular remodeling. Stress echocardiography may unmask higher degrees of mitral regurgitation. More data are needed in order to confirm the promising and interesting preliminary experimental findings of magnetic resonance imaging in diagnosis and clinical evaluation of ischemic mitral regurgitation.

SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene.

BACKGROUND: Brugada syndrome is associated with a high risk of sudden cardiac death and is caused by mutations in the cardiac voltage-gated sodium channel gene. Previously, the R282H-SCN5A mutation in the sodium channel gene was identified in patients with Brugada syndrome. In a family carrying the R282H-SCN5A mutation, an asymptomatic individual had a common H558R-SCN5A polymorphism and the mutation on separate chromosomes. Therefore, we hypothesized that the polymorphism could rescue the mutation. METHODS AND RESULTS: In heterologous cells, expression of the mutation alone did not produce sodium current. However, coexpressing the mutation with the polymorphism produced significantly greater current than coexpressing the mutant with the wild-type gene, demonstrating that the polymorphism rescues the mutation. Using immunocytochemistry, we demonstrated that the R282H-SCN5A construct can traffic to the cell membrane only in the presence of the H558R-SCN5A polymorphism. Using fluorescence resonance energy transfer and protein fragments centered on H558R-SCN5A, we demonstrated that cardiac sodium channels preferentially interact when the polymorphism is expressed on one protein but not the other. CONCLUSIONS: This study suggests a mechanism whereby the Brugada syndrome has incomplete penetrance. More importantly, this study suggests that genetic polymorphisms may be a potential target for future therapies aimed at rescuing specific dysfunctional protein channels.

Alpha- and beta-adrenergic receptor polymorphisms in hypertensive and normotensive offspring.

BACKGROUND: The offspring of hypertensive families are characterized by higher arterial blood pressure values and a depressed autonomic control of heart rate. The present study aimed to verify whether these differences are associated with a different genotype distribution of functionally relevant polymorphisms of the alpha- and beta-adrenergic receptor (AR) genes. METHODS: We selected 109 age- and sex-matched young normotensive subjects with (FH+, n = 56) and without (FH-, n = 53) a family history of hypertension who underwent evaluation of arterial pressure; 24-h electrocardiogram monitoring to assess time-domain parameters of autonomic heart rate control [i.e. mean RR interval (NN), SD of RR intervals (SDNN) and mean square root of the differences of consecutive RR intervals (rMSSD)]; spectral baroreflex sensitivity measurement; and echo-Doppler to assess diastolic function and left ventricular mass. They were also characterized for the following polymorphisms by means of polymerase chain reaction-restriction fragment polymorphism analysis: Arg492Cys in the alpha1a-AR; Del301-303 in the alpha2b-AR; Ser49Gly and Arg389Gly in the beta1-AR; and the 5' leader cistron Arg19Cys, Arg16Gly and Gln27Glu in the beta2-AR. RESULTS: FH+ individuals showed a higher systolic pressure, a lower SDNN and a greater isovolumic relaxation time compared to normotensive offspring. No differences were found between the two groups when genotype distribution of the studied polymorphisms was considered. Subjects carrying alpha1a-AR Cys492 allelic variant showed lower values of NN, SDNN and rMSSD, independent of age, gender and body mass index. CONCLUSIONS: The functionally relevant polymorphisms of alpha2b-, beta1- and beta2-AR genes are not associated with a family history of essential hypertension. The Arg492Cys polymorphism of the alpha1a-AR gene, although not associated with a family history of hypertension, was strongly related to autonomic control of heart rate.

Prognostic value of brain natriuretic peptide in the management of patients receiving cardiac resynchronization therapy.

OBJECTIVE: To evaluate the role of brain natriuretic peptide (BNP) in predicting the progression of heart failure (HF) after cardiac resynchronization therapy (CRT). BACKGROUND: It has been shown that BNP predicts the prognosis and can guide the treatment of HF. METHODS: We studied 50 consecutive patients (61+/-10 years, 23 male) with HF (8 with ischaemic cardiomyopathy), NYHA class III, left bundle branch block, left ventricular ejection fraction (LVEF) 91.5 pg/ml had 89% sensitivity, 59% specificity, and negative and positive predictive values of 96% and 33%, respectively, for HF progression after 12 months. CONCLUSIONS: HF patients with high BNP values after 1 month of CRT have worse prognosis during follow-up. Therefore, in these patients other therapeutic options should be considered.

Independent and incremental prognostic value of endogenous ouabain in idiopathic dilated cardiomyopathy.

Increased circulating levels of endogenous ouabain (EO) have been observed in some heart failure patients, but their long term clinical significance is unknown. This study investigated the prognostic value of EO for worsening heart failure among 140 optimally treated patients (age 50+/-14 years; 104 male; NYHA class 1.9+/-0.7) with idiopathic dilated cardiomyopathy. Plasma EO was determined by RIA and by liquid chromatography mass spectrometry, values were linearly correlated (r = 0.89) in regression analysis. During follow-up (13+/-5 months), heart failure progression was defined as worsening clinical condition leading to one or more of the following: sustained increase in conventional therapies, hospitalization, cardiac transplant, or death. NYHA functional class, age, LVEF, peak VO2 and plasma levels of EO were predictive for heart failure progression. Heart failure worsened 1.5 fold (HR: 1.005; 95% CI: 1.001-1.007; p<0.01) for each 100 pmol/L increase in plasma EO. Moreover, those patients with higher plasma EO values had an odds ratio of 5.417 (95% CI: 2.044-14.355; p<0.001) for heart failure progression. Following multivariate analysis, LVEF, NYHA class and plasma EO remained significantly linked with clinical events. This study provides the first evidence that circulating EO is a novel, independent and incremental marker that predicts the progression of heart failure.