Phenotyping congestion in acute heart failure by renal flow and right heart to pulmonary circulation coupling.

AIMS: In acute heart failure (AHF), kidney congestion is basic to treatment and prognosis. Its aetiology is manifold and quite unexplored in details mainly regarding the right heart to pulmonary circulation (Pc) coupling. We investigated the right heart to kidney interrelationship by Doppler renal flow pattern, right atrial dynamics, and right ventricular (RV) function to Pc coupling in AHF. METHODS AND RESULTS: In 119 AHF patients, echocardiographic and renal Doppler data were analysed. Univariate and multivariate regression models were performed to define the determinants of a quantitative parameter of renal congestion, the renal venous stasis index (RVSI). When grouped according to different intra-renal venous flow patterns, no differences were observed in haemodynamics and baseline renal function. Nonetheless, patients with renal Doppler evidence of congestion showed a reduced RV function [tricuspid annular plane systolic excursion (TAPSE), S'-wave velocity, and fractional area change], impaired RV to Pc coupling [TAPSE/pulmonary artery systolic pressure (PASP) ratio], and right atrial peak longitudinal strain (RAPLS), along with signs of volume overload [increased inferior vena cava (IVC) diameters and estimated right atrial pressure]. Univariate and multivariate regression analyses confirmed TAPSE/PASP, RAPLS, and IVC diameter as independent determinants of the RVSI. RVSI was the only variable predicting the composite outcome (cardiac death, heart failure hospitalization, and haemodialysis). An easy-to-use echo-derived right heart score of four variables provided good accuracy in identifying kidney congestion. CONCLUSIONS: In AHF, the renal venous flow pattern combined with a right heart study phenotypes congestion and clinical evolution. Keys to renal flow disruption are an impaired right atrial dynamics and RV-Pc uncoupling. Integration of four right heart echocardiographic variables may be an effective tool for scoring the renal congestive phenotype in AHF.

Left Atrial Dynamics During Exercise in Mitral Regurgitation of Primary and Secondary Origin: Pathophysiological Insights by Exercise Echocardiography Combined With Gas Exchange Analysis.

OBJECTIVES: The aim of this study was to identify the pattern of exercise left atrial (LA) dynamics, its gas exchange correlates, and prognosis in mitral regurgitation (MR) of primary and secondary origin. BACKGROUND: The adaptive response and clinical significance of LA function during exercise in MR is undefined. METHODS: A total of 196 patients with MR (81 with primary MR, 115 with secondary MR) and 54 control subjects underwent exercise stress echocardiography and cardiopulmonary exercise testing with LA function assessment. Patients with MR were divided into 4 groups according to etiology and severity using a cutoff of 3+. RESULTS: LA dynamics was studied using speckle-tracking echocardiography. Compared with control subjects, patients with MR had a lower LA strain and strain rate at rest. Exercise LA strain and LA strain rate progressively worsened from primary MR <3+ through secondary MR ≥3+. In primary MR, some reserve in exercise LA strain and LA strain rate was observed, but not in secondary MR. In secondary MR, LA strain at rest and during exercise (18.1 ± 5.7 s-1, 18.3 ± 6.9 s-1, 18.6 ± 5.5 s-1, 13.9 ± 3.8 s-1) and peak oxygen consumption (11.7 ± 3 ml/min/kg) were decreased compared with the other groups. In secondary MR ≥3+, the slope of ventilation versus carbon dioxide was higher compared with the other groups: 35.1 (interquartile range [IQR]: 29.0 to 44.2) compared with control subjects: 26.5 (IQR: 24.4 to 29.0); patients with primary MR <3+ (26.9; IQR: 24.0 to 31.9); those with primary MR >3+ (25.5; IQR: 23.4 to 29.0); and those with secondary MR <3+ (29.5; IQR: 26.5 to 33.7) (p < 0.05 for all). A progressive impairment in exercise LA mechanics combined with limited cardiac output increase and right ventricular-to-pulmonary circulation uncoupling was observed from primary to secondary MR. LAS during exercise was predictive of all-cause mortality and hospitalization for heart failure. CONCLUSIONS: In MR of any origin, exercise LA reservoir and pump function are impaired. For similar MR extent, secondary MR exhibits worse atrial function, resulting in the lowest exercise performance, limited cardiac output increase, impaired right ventricular-to-pulmonary circulation coupling, and the highest event rate.

TNNT2 Missplicing in Skeletal Muscle as a Cardiac Biomarker in Myotonic Dystrophy Type 1 but Not in Myotonic Dystrophy Type 2.

Cardiac involvement is one of the most important manifestations of the multisystemic phenotype of patients affected by myotonic dystrophy (DM) and represents the second cause of premature death. Molecular mechanisms responsible for DM cardiac defects are still unclear; however, missplicing of the cardiac isoform of troponin T (TNNT2) and of the cardiac sodium channel (SCN5A) genes might contribute to the reduced myocardial function and conduction abnormalities seen in DM patients. Since, in DM skeletal muscle, the TNNT2 gene shows the same aberrant splicing pattern observed in cardiac muscle, the principal aim of this work was to verify if the TNNT2 aberrant fetal isoform expression could be secondary to myopathic changes or could reflect the DM cardiac phenotype. Analysis of alternative splicing of TNNT2 and of several genes involved in DM pathology has been performed on muscle biopsies from patients affected by DM type 1 (DM1) or type 2 (DM2) with or without cardiac involvement. Our analysis shows that missplicing of muscle-specific genes is higher in DM1 and DM2 than in regenerating control muscles, indicating that these missplicing could be effectively important in DM skeletal muscle pathology. When considering the TNNT2 gene, missplicing appears to be more evident in DM1 than in DM2 muscles since, in DM2, the TNNT2 fetal isoform appears to be less expressed than the adult isoform. This evidence does not seem to be related to less severe muscle histopathological alterations that appear to be similar in DM1 and DM2 muscles. These results seem to indicate that the more severe TNNT2 missplicing observed in DM1 could not be related only to myopathic changes but could reflect the more severe general phenotype compared to DM2, including cardiac problems that appear to be more severe and frequent in DM1 than in DM2 patients. Moreover, TNNT2 missplicing significantly correlates with the QRS cardiac parameter in DM1 but not in DM2 patients, indicating that this splicing event has good potential to function as a biomarker of DM1 severity and it should be considered in pharmacological clinical trials to monitor the possible effects of different therapeutic approaches on skeletal muscle tissues.

RV Contractile Function and its Coupling to Pulmonary Circulation in Heart Failure With Preserved Ejection Fraction: Stratification of Clinical Phenotypes and Outcomes.

OBJECTIVES: This study sought to investigate how right ventricular (RV) contractile function and its coupling with pulmonary circulation (PC) stratify clinical phenotypes and outcome in heart failure preserved ejection fraction (HFpEF) patients. BACKGROUND: Pulmonary hypertension and RV dysfunction are key hemodynamic abnormalities in HFpEF. METHODS: Three hundred eighty seven HFpEF patients (mean age 64 ± 12 years, 59% females, left ventricular ejection fraction 59 ± 7%) underwent RV and pulmonary hemodynamic evaluation by echocardiography (entire population) and right heart catheterization (219 patients). Patients were investigated by tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP) relationship and stratified according to TAPSE/PASP ratio tertiles (1: <0.35; 2: 0.35 to 0.57; 3: >0.57). Specifically, TAPSE/PASP ratio was taken as a noninvasive index of RV to PC coupling based on the correlation with invasively evaluated RV systolic elastance/arterial elastance (r = 0.35; p < 0.0001). RESULTS: Groups had similar prevalence of comorbidities except for a higher prevalence of atrial fibrillation and kidney dysfunction in tertile 1. Progressively increasing levels of natriuretic peptides, worse systemic and pulmonary hemodynamics, abnormal exercise aerobic capacity and ventilatory inefficiency were observed from the highest to lowest TAPSE/PASP tertile. TASPE/PASP correlated with pulmonary artery compliance (r = 0.69; p < 0.0001). Remarkably, the tertile 1 group distributed along the worse portion of the curve at lower pulmonary artery compliance and higher pulmonary vascular resistances. In addition, the TAPSE/PASP ratio emerged as an independent predictor of worse outcomes. CONCLUSIONS: A thorough assessment of RV-PC coupling and RV contractile function stratify HFpEF phenotypes at different level of risk. These observations shift the interest toward therapeutic strategies that may benefit the right heart as primary unmet need in the complex pathophysiology of the HFpEF syndrome.

Mitral regurgitation in heart failure: insights from CPET combined with exercise echocardiography.

AIMS: In heart failure patients with reduced ejection fraction (HFrEF), exercise-induced functional mitral regurgitation (MR) may affect functional capacity and outcome. We sought to study functional and cardiac phenotypes of HFrEF patients according to the MR degree. METHODS AND RESULTS: We performed rest and exercise echocardiography (Ex-Echo), simultaneously combined with cardiopulmonary exercise test (CPET), in 102 HFrEF patients, identifying 3 groups: non-severe (ERO <20 mm2) MR (group A), exercise-induced severe (ERO ≥20 mm2) MR (group B), and rest severe MR (group C). Patients were tracked for the composite end point of death and heart failure hospitalization. Group B (ERO: rest= 14 ± 5 mm2, Ex= 28 ± 6 mm2; P = < 0.001) had a functional impairment (workload = 56 ± 21 vs. 50 ± 17 watts, P = 0.42; peak VO2 = 11.8 ± 3.2 vs. 11.5 ± 3.0 mL/Kg/min, P = 0.70) similar to Group C (ERO: rest = 29 ± 7 mm2, Ex = 42 ± 7 mm2, P = < 0.001), associated with comparable advanced left ventricle remodelling (end diastolic indexed volume = 107 ± 34 vs. 115 ± 30 mL/m2, P = 0.27), characterized by exercise-induced pulmonary hypertension (PH) (Ex systolic pulmonary pressures = 63 ± 16 mmHg). Group C showed the worse cardiac phenotype (right ventricle dilatation, dysfunction, and rest PH) with severe ventilatory impairment (VE/VCO2 = 41.2 ± 11) compared with Groups A and B. Moreover, Group C had the higher rate of death and HF hospitalization. CONCLUSIONS: In HFrEF patients, severe dynamic MR produces functional limitation similar to rest severe MR, characterized by dynamic PH. Rest severe MR reflects the most advanced bi-ventricular remodelling associated with rest PH, the most unfavourable ventilatory profile, and the worst mid-term outcome.

Pulmonary Hypertension in Heart Failure Patients: Pathophysiology and Prognostic Implications.

Pulmonary hypertension (PH) due to left heart disease (LHD), i.e., group 2 PH, is the most common reason for increased pressures in the pulmonary circuit. Although recent guidelines incorporate congenital heart disease in this classification, left-sided heart diseases of diastolic and systolic origin including valvular etiology are the vast majority. In these patients, an increased left-sided filling pressure triggers a multistage hemodynamic evolution that ends into right ventricular failure through an initial passive increase in pulmonary artery pressure complicated over time by pulmonary vasoconstriction, endothelial dysfunction, and remodeling of the small-resistance pulmonary arteries. Regardless of the underlying left heart pathology, when present, PH-LHD is associated with more severe symptoms, worse exercise tolerance, and outcome, especially when right ventricular dysfunction and failure are part of the picture. Compared with group 1 and other forms of pulmonary arterial hypertension, PH-LHD is more often seen in elderly patients with a higher prevalence of cardiovascular comorbidities and most, if not all, of the features of metabolic syndrome, especially in case of HF preserved ejection fraction. In this review, we provide an update on current knowledge and some potential challenges about the pathophysiology and established prognostic implications of group 2 PH in patients with HF of either preserved or reduced ejection fraction.

Group 2 PH: Medical Therapy.

Pulmonary hypertension (PH) secondary to left heart disease, classified as Group 2, is a widely underestimated target of therapy. Prevention and treatment of initial subclinical stages are not valued as a priority in the management of this chronic disease population, whereas attention is high for PH consequences in patients with advanced heart failure (HF) requiring a left ventricular mechanical assist device or heart transplant candidates. Even so, there is a growing interest toward the evidence of a clinical and prognostic role of PH in the elderly populations and in HF with preserved ejection fraction (HFpEF). Certainly, along with a prevalence definition not yet defined, the search for effective pharmacological approaches that might favorably affect the aging process and the natural history of HFpEF from earlier stages is not an easy task. Pharmacological studies that have tested some traditional pulmonary arterial hypertension approved drugs (i.e., prostanoids and endothelin-1 receptor blockers) primarily in PH and HF with reduced ejection fraction have not been positive, especially because of concomitant side effects, i.e., systemic hypotension, fluid retention and hepatic toxicity. In recent years, interest has moved toward drugs overexpressing the nitric oxide (NO)-cyclic guanosine monophosphate pathway with recent availability of well-tolerated selective pulmonary vasodilators, such as phosphodiesterase type 5 inhibitors and guanylate cyclase stimulators. Single center studies performed with these drugs have shown good tolerability and safety profile providing alternating hemodynamic results mainly because of recruitment of patients at different stages of the pulmonary vascular disease. Nonetheless, the overexpression of NO pathway appears to remain the most solid background for targeting lung microvessel dysfunction and treating RV dysfunction since the earliest stages of the disease.

Right Ventricular Contractile Reserve and Pulmonary Circulation Uncoupling During Exercise Challenge in Heart Failure: Pathophysiology and Clinical Phenotypes.

OBJECTIVES: Right ventricular (RV) exercise contractile reserve (RVECR), its phenotypes, and its functional correlates are among the unresolved issues with regard to the role of the right ventricle in heart failure (HF) syndrome, and understanding these issues constitutes the objective of this study. BACKGROUND: Although the role of the right ventricle in HF syndrome might be fundamental, the pathophysiology of the failing right ventricle has not been extensively investigated. METHODS: Ninety-seven patients with HF (mean age 64 years, 70% men, mean left ventricular ejection fraction 33 ± 10%) underwent maximal exercise stress echocardiographic and cardiopulmonary exercise testing. RVECR and RV-to-pulmonary circulation (PC) coupling were assessed using the length-force relationship (tricuspid annular plane systolic excursion [TAPSE] vs. pulmonary artery systolic pressure) and the slope of mean pulmonary artery pressure versus cardiac output. On the basis of TAPSE, patients were categorized into 3 groups: those with TAPSE at rest ≥16 mm (group A, n = 60) and those with TAPSE at rest <16 mm, who were divided according to median TAPSE at peak exercise (15.5 mm) into 2 subgroups (group B, ≥15.5 mm, n = 19; group C, <15.5 mm, n = 18). RESULTS: Although they had similar left ventricular ejection fractions and rest RV impairment, compared with patients in group C, those in group B showed some degree of RVECR (upward shift of the length-force relationship), better RV-to-PC coupling (lower mean pulmonary artery pressure vs. cardiac output slope), and greater ventilatory efficiency (lower slope of minute ventilation to carbon dioxide output). Rest mitral regurgitation and net changes in pulmonary artery systolic pressure were the variables retained in the best regression model as correlates of RVECR. CONCLUSIONS: In patients with HF, RVECR unmasks different phenotypes. Impaired RV function at rest might not invariably lead to unfavorable RVECR and exercise RV-to-PC coupling. Testing these variables appears useful even in more advanced stages of HF to define various clinical conditions and, most likely, to define different levels of risk.

Prevalence and characterization of exercise oscillatory ventilation in apparently healthy individuals at variable risk for cardiovascular disease: A subanalysis of the EURO-EX trial.

INTRODUCTION: There has been a greater appreciation of several variables obtained by cardiopulmonary exercise testing (CPX). Exercise oscillatory ventilation (EOV) is a CPX pattern that has gained recognition as an ominous marker of poor prognosis in cardiac patients. The purpose of the present study is to characterize whether such an abnormal ventilatory pattern may also be detected in apparently healthy subjects and determine its clinical significance. METHODS: The study involved 510 subjects (mean age 60 ± 14 years; 49% male) with a broad cardiovascular (CV) risk factor profile who underwent CPX. RESULTS: The population was divided into two groups according to the presence (17%) or absence of EOV. Subjects with EOV were significantly older and a higher percentage was female. Risk factor profile and medication use was significantly different between subgroups, indicating subjects with EOV had a worse CV risk factor profile and were prescribed CV-focused preventive medications at a significantly higher frequency. Subjects with EOV had comparatively poorer CPX performance and gas exchange phenotype. Multivariate binary logistic regression analysis found being female was the strongest predictor of EOV (odds ratio: 2.77, 95% confidence interval (CI): 1.66-4.61, p < 0.001). A diagnosis of diabetes (odds ratio: 2.40, 95% CI: 1.34-4.15.2, p < 0.001) added significant value for predicting EOV and was retained in the regression. The likelihood for EOV for subjects who were female and diagnosed with diabetes was 3.71 (95% CI 1.88-7.30, p < 0.001). CONCLUSIONS: This is the first study to examine EOV prevalence and characterization in apparently healthy persons with results supporting an in-depth definition of abnormal exercise phenotypes.

Cardiopulmonary Exercise Testing in Heart Failure.

A growing body of literature has underscored the value of ventilatory gas exchange techniques during exercise testing (commonly termed cardiopulmonary exercise testing, or CPX) and their applications in the management of patients with heart failure (HF). The added precision provided by this technology is useful in terms of understanding the physiology and mechanisms underlying exercise intolerance in HF, quantifying the response to therapy, evaluating disability, making activity recommendations, and quantifying the response to exercise training. Importantly, a wealth of data has been published in recent years on the prognostic utility of CPX in patients with HF. These studies have highlighted the concept that indices of ventilatory inefficiency, such as the VE/VCO2 slope and oscillatory breathing, are particularly powerful in stratifying risk in HF. This article provides an overview of the clinical utility of CPX in patients with HF, including the applications of ventilatory inefficiency during exercise, the role of the pulmonary system in HF, respiratory muscle performance (RMP), and the application of CPX as part of a comprehensive clinical and exercise test evaluation.

Past, present, and future rehabilitation practice patterns for patients with heart failure: the European perspective.

The recent European Society of Cardiology position paper strongly advises participation of patients with stable heart failure (HF) in structured exercise training (ET) programs, and in most recent years considerable efforts have been put into standardization of exercise prescription. Up to now, 3 ET modalities are proposed for HF populations with variable combinations and extent of effects: (1) endurance aerobic (continuous and interval); (2) strength/resistance; (3) respiratory. Irrespective of ET modalities, most of the studies have clearly demonstrated significant improvements in exercise physiology (ie, oxygen consumption, muscle function, and ventilation), quality of life, and left ventricular function.

Predictors of abnormal heart rate recovery in patients with heart failure reduced and preserved ejection fraction.

BACKGROUND: Heart rate recovery (HRR) is becoming an important prognostic maker in heart failure (HF), but very little is known about the underlying mechanisms responsible for its clinical efficacy. Therefore, we examined echocardiographic and exercise (submaximal and maximal) characteristics to gain a better appreciation of HRR and factors responsible for the development of abnormal HRR in patients with both heart failure reduced ejection fraction (HFrEF) and heart failure preserved ejection fraction (HFpEF). METHODS: Cardiopulmonary exercise testing (CPX), a 6-minute walk test (6MWT), and resting 2D echocardiography were randomly performed in 240 HF patients (200 HFrEF, 40 HFpEF) after which HRR was measured. HRR was defined as the difference between heart rate at peak exercise and 1 minute following test termination. RESULTS: Bivariate correlation analyses found significant relationships among most CPX and 6MWT measurements with the highest correlations between 6MWT HRR and 6MWT peak HR (r = 0.65; p < 0.001) and CPX HRR and CPX HRreserve (r = 0.63; p < 0.001). The relationship between 6MWT HRR and CPX HRR was very good (r = 0.91; p < 001). Multivariate logistic regression of submaximal and maximal exercise found 6MWT peak HR and exercise oscillatory ventilation (EOV), respectively, were the strongest predictors (p < 0.001) of abnormal HRR. The E/E' was a significant predictor (p < 0.001) of abnormal HRR, but EOV was the strongest predictor of abnormal HRR (OR = 6.5). CONCLUSIONS: HRR after both CPX and the 6MWT is significantly related to many exercise and echocardiographic measures with the most significant predictors of abnormal HRR being related to indices of cardiorespiratory performance in patients with HFrEF and HFpEF.

Cardiopulmonary exercise testing reflects similar pathophysiology and disease severity in heart failure patients with reduced and preserved ejection fraction.

BACKGROUND: We are unaware of any previous investigation that has compared the relationship of key cardiopulmonary exercise testing (CPX) variables to various measures of pathophysiology between heart failure-reduced ejection fraction (HFrEF) and HF-preserved ejection fraction (HFpEF) cohorts that are well matched with respect to baseline characteristics and their exercise response, which is the purpose of the present study. METHODS: Thirty-four patients with HFpEF were randomly matched to 34 subjects with HFrEF according to age and sex as well as peak oxygen consumption (VO2), ventilatory efficiency (VE/VCO2 slope), and exercise oscillatory ventilation (EOV). In addition to CPX, patients also underwent echocardiography with tissue Doppler imaging (TDI) and assessment of N-terminal pro-B-type natriuretic peptide (NT-proBNP). RESULTS: When matched for age, sex, and CPX variables, the HFrEF and HFpEF cohorts had similar echocardiography with TDI and NT-proBNP values, indicating comparable disease severity. In addition, the correlations between key CPX measures (peak VO2 and VE/VCO2 slope) and echocardiography with TDI and NT-proBNP measures were similar between HFrEF and HFpEF groups. Of note, the correlation between the VE/VCO2 slope and pulmonary artery systolic pressure and NT-proBNP was highly significant in both groups (r ≥ 0.65, p < 0.01). Moreover, subjects with EOV in both groups had a significantly higher PASP (∼47 vs. ∼35 mmHg, p < 0.05). CONCLUSIONS: The results of the current study indicate CPX equally represents disease severity in HFrEF and HFpEF patients. This is a novel finding supporting the key role of CPX in the clinical follow-up of HF patients irrespective of LVEF and cardiac phenotype.

Heart rate recovery after the 6 min walk test rather than distance ambulated is a powerful prognostic indicator in heart failure with reduced and preserved ejection fraction: a comparison with cardiopulmonary exercise testing.

AIMS: Heart rate recovery (HRR) appears to be a robust prognostic marker in heart failure (HF). When using the 6 min walk test (6MWT) in HF, distance ambulated is generally the reference prognostic variable. We hypothesized that HRR after the 6MWT would be a better prognostic measure than distance ambulated. METHODS AND RESULTS: A 6MWT and cardiopulmonary exercise testing (CPX) were randomly performed in 258 HF patients [216 HF with reduced EF (HFrEF) and 42 HF preserved EF (HFpEF)], after which HRR was measured. HRR was defined as the difference between heart rate at peak exercise and 1 min following test termination. Patients were assessed for major cardiac events during a mean follow-up period of 22.8 ± 22.1 months. There were 50 major cardiac events during the tracking period. Univariate Cox regression analysis results identified HRR after both the 6MWT and CPX as a significant (P < 0.001) predictor of adverse events. Multivariate Cox regression analysis revealed that dichotomized HRR after the 6MWT and CPX was the strongest predictor of survival (χ(2) 61.1 and 53.8, respectively; P < 0.001), with LVEF (residual χ(2) 6.1, P < 0.05) adding significant prognostic value to the 6MWT model and ventilatory efficiency (the VE/VCO2 slope) (residual χ(2) 6.6, P < 0 .05) adding significant prognostic value to the CPX model. CONCLUSIONS: HRR after the 6MWT is a powerful prognosticator that performs similarly to HRR after maximal exercise. If confirmed in subsequent studies, 6MWT HRR should replace 6MWT distance as the reference criterion 6MWT measure to consider when grading cardiovascular risk in HF patients.

Treatment for pulmonary hypertension of left heart disease.

OPINION STATEMENT: Pulmonary hypertension (PH) secondary to left heart disease is a largely underestimated target of therapy. Except for a specific focus on PH consequences in patients with advanced heart failure (HF) receiving a left ventricular mechanical assist device or candidates for transplantation, prevention and treatment of initial subclinical forms of PH are not considered a priority in the management of this chronic disease population. Nonetheless, there is recent growing evidence supporting a clinical and prognostic role of PH in the elderly and in HF with preserved ejection fraction (pEF). Studies have defined PH-HFpEF as a new entity typically defining the evolving nature of disease. Although the prevalence of PH in these populations is not well-defined, the potential for effective pharmacological approaches that might impact the natural history of the disease starting from earlier stages is promising. However, it should be recognized that pharmacological studies performed to date with traditional pulmonary vasodilators in cohorts with HF and left-sided PH have not been positive, primarily because of concomitant systemic hypotension and hepatic side effects. This evidence along with the lack of studies specifically performed in the elderly and HFpEF often lead Guidelines to give neutral recommendations or even arbitrary assumptions. Recent availability of selective well-tolerated pulmonary vasodilators, such as phosphodiesterase type 5 (PDE5) inhibitors, however, seem to offer a solid background for treating left-sided PH at both early and later stages of the disease process.

Exercise oscillatory breathing and NT-proBNP levels in stable heart failure provide the strongest prediction of cardiac outcome when combining biomarkers with cardiopulmonary exercise testing.

BACKGROUND: N-Terminal pro-brain natriuretic peptide (NT-proBNP) and cardiopulmonary exercise testing (CPET)-derived variables are gold standards for assessing prognosis in heart failure (HF) patients. We sought to refine cardiac events prediction by performing a combined analysis of NT-proBNP with markers of exercise ventilatory efficiency. METHODS AND RESULTS: A total of 260 stable HF patients underwent measurements of plasma NT-proBNP levels before, at peak exercise, and at 1-minute CPET recovery phase along with peak oxygen uptake (VO(2)), ventilation to CO(2) production (VE/VCO(2)) slope, and exercise periodic breathing (EPB) determinations. After a median follow-up period of 20.6 months, there were 54 cardiac-related deaths. Univariate analysis including NT-proBNP at rest, at peak exercise, and at 1 minute recovery, peak VO(2), VE/VCO(2) slope, and EPB showed NT-proBNP to be the strongest independent predictor with equivalent performance for rest, peak, and recovery levels. Thus, only NT-proBNP at rest was considered (Harrel C 0.783, 95% confidence interval [CI] 0.722-0.844) with VE/VCO(2) slope (Harrel C 0.720, 95% CI 0.646-0.794), EPB (Harrel C 0.685, 95% CI 0.619-0.751), and peak VO(2) (Harrel C 0.618, 95% CI 0.533-0.704). With bivariate stepwise analyses, NT-proBNP along with EPB emerged as the strongest prognosticators (Harrel C 0.800, 95% CI 0.737-0.862). CONCLUSIONS: In the refinement for robust outcome predictors in HF patients, NT-proBNP levels together with EPB led to the most powerful definition. VE/VCO(2) slope and peak VO(2) did not provide any prognostic adjunct. A biomarker/CPET approach seems very promising to warrant the continuous implementation in the prognostic work-up of HF patients.

Nutrient withdrawal rescues growth factor-deprived cells from mTOR-dependent damage.

Deregulated nutrient signaling plays pivotal roles in body ageing and in diabetic complications; biochemical cascades linking energy dysmetabolism to cell damage and loss are still incompletely clarified, and novel molecular paradigms and pharmacological targets critically needed. We provide evidence that in the retrovirus-packaging cell line HEK293-T Phoenix, massive cell death in serum-free medium is remarkably prevented or attenuated by either glucose or aminoacid withdrawal, and by the glycolysis inhibitor 2-deoxy-glucose. A similar protection was also elicited by interference with mitochondrial function, clearly suggesting involvement of energy metabolism in increased cell survival. Oxidative stress did not account for nutrient toxicity on serum-starved cells. Instead, nutrient restriction was associated with reduced activity of the mTOR/S6 Kinase cascade. Moreover, pharmacological and genetic manipulation of the mTOR pathway modulated in an opposite fashion signaling to S6K/S6 and cell viability in nutrient-repleted medium. Additionally, stimulation of the AMP-activated Protein Kinase concomitantly inhibited mTOR signaling and cell death, while neither event was affected by overexpression of the NAD+ dependent deacetylase Sirt-1, another cellular sensor of nutrient scarcity. Finally, blockade of the mTOR cascade reduced hyperglycemic damage also in a more pathophysiologically relevant model, i.e. in human umbilical vein endothelial cells (HUVEC) exposed to hyperglycemia. Taken together these findings point to a key role of the mTOR/S6K cascade in cell damage by excess nutrients and scarcity of growth-factors, a condition shared by diabetes and other ageing-related pathologies.

Mammalian life-span determinant p66shcA mediates obesity-induced insulin resistance.

Obesity and metabolic syndrome result from excess calorie intake and genetic predisposition and are mechanistically linked to type II diabetes and accelerated body aging; abnormal nutrient and insulin signaling participate in this pathologic process, yet the underlying molecular mechanisms are incompletely understood. Mice lacking the p66 kDa isoform of the Shc adaptor molecule live longer and are leaner than wild-type animals, suggesting that this molecule may have a role in metabolic derangement and premature senescence by overnutrition. We found that p66 deficiency exerts a modest but significant protective effect on fat accumulation and premature death in lepOb/Ob mice, an established genetic model of obesity and insulin resistance; strikingly, however, p66 inactivation improved glucose tolerance in these animals, without affecting (hyper)insulinaemia and independent of body weight. Protection from insulin resistance was cell autonomous, because isolated p66KO preadipocytes were relatively resistant to insulin desensitization by free fatty acids in vitro. Biochemical studies revealed that p66shc promotes the signal-inhibitory phosphorylation of the major insulin transducer IRS-1, by bridging IRS-1 and the mTOR effector p70S6 kinase, a molecule previously linked to obesity-induced insulin resistance. Importantly, IRS-1 was strongly up-regulated in the adipose tissue of p66KO lepOb/Ob mice, confirming that effects of p66 on tissue responsiveness to insulin are largely mediated by this molecule. Taken together, these findings identify p66shc as a major mediator of insulin resistance by excess nutrients, and by extension, as a potential molecular target against the spreading epidemic of obesity and type II diabetes.

High-resolution imaging of redox signaling in live cells through an oxidation-sensitive yellow fluorescent protein.

We present the application of a redox-sensitive mutant of the yellow fluorescent protein (rxYFP) to image, with elevated sensitivity and high temporal and spatial resolution, oxidative responses of eukaryotic cells to pathophysiological stimuli. The method presented, based on the ratiometric quantitation of the distribution of fluorescence by confocal microscopy, allows us to draw real-time "redox maps" of adherent cells and to score subtle changes in the intracellular redox state, such as those induced by overexpression of redox-active proteins. This strategy for in vivo imaging of redox signaling circumvents many of the technical limitations currently encountered in the study of complex redox-based phenomena and promises to contribute substantially to this expanding area of signal transduction.