Combined pre- and post-capillary pulmonary hypertension in left heart disease.

Patients with heart failure (HF) often have pulmonary hypertension (PH), which is mainly post-capillary; however, some of them also develop a pre-capillary component. The exact mechanisms leading to combined pre- and post-capillary PH are not yet clear, but the phenomenon seems to start from a passive transmission of increased pressure from the left heart to the lungs, and then continues with the remodeling of both the alveolar and vascular components through different pathways. More importantly, it is not yet clear which patients are predisposed to develop the disease. These patients have some characteristics similar to those with idiopathic pulmonary arterial hypertension (e.g., young age and frequent incidence in female gender), but they share cardiovascular risk factors with patients with HF (e.g., obesity and diabetes), with both reduced and preserved ejection fraction. Thanks to echocardiography parameters and newly introduced scores, more tools are available to distinguish between idiopathic pulmonary arterial hypertension and combined PH and to guide patients' management. It may be hypothesized to treat patients in whom the pre-capillary component is predominant with specific therapies such as those for idiopathic pulmonary arterial hypertension; however, no adequately powered trials of PH-specific treatment are available in combined PH. Early evidence of clinical benefit has been proven in some trials on phosphodiesterase type 5 inhibitors, while data on prostacyclin analogues, endothelin-1 receptor antagonists, and soluble guanylate cyclase stimulators are still controversial.

Tumour biomarkers: association with heart failure outcomes.

BACKGROUND: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. OBJECTIVES: To explore the association between tumour biomarkers and HF outcomes. METHODS: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumour biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1 and AFP. RESULTS: During a median follow-up of 21 months, 555 (27%) patients reached the primary end-point of all-cause mortality. CA125, CYFRA 21-1, CEA and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P < 0.001, P for trend < 0.001) and were, respectively, associated with a hazard ratio of 1.17 (95% CI 1.12-1.23; P < 0.0001), 1.45 (95% CI 1.30-1.61; P < 0.0001), 1.19 (95% CI 1.09-1.30; P = 0.006) and 1.10 (95% CI 1.05-1.16; P < 0.001) for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, haemoglobin and beta blocker). All tumour biomarkers (except AFP) had significant associations with secondary end-points (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a noninferior AUC compared with NT-proBNP (0.68) for all-cause mortality (P = 0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC = 0.71) improved the predictive value of the model for all-cause mortality (P = 0.0002 compared with NT-proBNP). CONCLUSIONS: Several established tumour biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumour biomarkers are also dysregulated in HF.

Relationship between endothelial dysfunction, videocapillaroscopy and circulating CD3+CD31+CXCR4+ lymphocytes in systemic lupus erythematosus without cardiovascular risk factors.

OBJECTIVE: The objective of this paper is to analyse whether digital capillary morphology, analysed by nailfold videocapillaroscopy (NVC), and the number of circulating CD3 + CD31 + CXCR4 + lymphocytes (angiogenic T cells) could be markers of endothelial dysfunction (ED) in systemic lupus erythematosus (SLE) without cardiovascular disease (CVD) and CV risk factors. METHODS: Nineteen consecutive SLE patients, according to Systemic Lupus International Collaborating Clinics Classification Criteria, with a disease duration less than five years, low disease activity, without CVD and CV risk factors (diabetes, chronic renal disease, uncontrolled systemic arterial hypertension, smoking, hypercholesterolemia, obesity), statin or beta-blocker use were enrolled. Each patient and sex- and age-matched healthy control (HC) underwent Doppler echocardiogram, an endothelial function study by peripheral arterial tonometry technique, NVC and peripheral blood immunophenotyping. RESULTS: SLE ED+ more frequently showed NVC abnormalities compared with HCs ( p < 0.0001) in terms of minor alterations ( p = 0.017), lower capillary numbers ( p = 0.0035) and major alterations. SLE ED + showed a higher rate of CD3 + CD31 + CXCR4 + lymphocytes compared with SLE ED- and with HCs. NVC + SLE showed a significantly reduced rate of total CD3 + cells, but a higher rate and absolute number of CD3 + CD31 + CXCR4 + , compared with NVC- SLE. CONCLUSION: NVC alterations are frequent in SLE without any CV risk factors and CVD. They are associated with ED and increased circulating CD3 + CD31 + CXCR4 + lymphocytes. These findings demonstrate a clear microvascular perturbation in patients with short disease duration, low disease activity and no CV risk factors.

Novel endotypes in heart failure: effects on guideline-directed medical therapy.

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains. Methods and results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort. Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

Ultrasound evaluation of left ventricular and aortic fibrosis after pre-eclampsia.

OBJECTIVES: Myocardial fibrosis is associated with adverse clinical outcome in adults. Our aim was to investigate using echocardiographic calibrated integrated backscatter (cIBS) the presence of myocardial and/or aortic fibrosis in asymptomatic women with a history of early-onset (EO) or late-onset (LO) pre-eclampsia (PE). METHODS: Thirty non-pregnant women whose most recent pregnancy was complicated by EO-PE, 30 with previous LO-PE pregnancy and 30 controls who had experienced only uncomplicated pregnancy previously were selected retrospectively from our electronic database and recalled between 6 months and 4 years after delivery. Data regarding gestational age (GA) and mean uterine artery (UtA) pulsatility index (PI) at diagnosis of PE were collected from their medical records. The women underwent cardiovascular assessment, during which the presence of fibrosis was investigated, by means of cIBS, at the basal interventricular septum (cIBSIVS ), the basal posterior wall (cIBSPW ) and the anterior wall of the ascending aorta, 3 cm above the valve (cIBSAO ). These findings were compared between the three patient groups. RESULTS: Using cIBS imaging, we found significant left ventricular (LV) fibrosis in women with a history of EO-PE compared with those with previous LO-PE pregnancy and controls (intergroup ANOVA P < 0.001 for cIBSIVS and P = 0.005 for cIBSPW ), whereas aortic fibrosis did not differ significantly among cases and controls. Stepwise multivariate regression analysis showed that LV fibrosis was associated independently with lower GA and higher mean UtA-PI at diagnosis of PE, while cIBSAO correlated with aortic diameters, stiffness and ventricular-arterial coupling. CONCLUSIONS: Women with a history of EO-PE show LV fibrosis in the short-medium term after delivery compared with women with previous LO-PE pregnancy and controls. LV fibrosis is associated with GA and mean UtA-PI at onset of PE. Larger studies using cardiac magnetic resonance imaging are needed to validate and confirm our findings. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.

INTRODUCTION: Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. METHODS AND RESULTS: BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05). CONCLUSION: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.

Endothelial dysfunction and vascular stiffness in women with previous pregnancy complicated by early or late pre-eclampsia.

OBJECTIVES: Pre-eclampsia (PE) is associated with an increased cardiovascular risk later in life. The persistence of endothelial dysfunction after delivery may represent the link between PE and cardiovascular disease. We aimed to evaluate endothelial function and arterial stiffness after delivery of pregnancy complicated by early-onset (EO) or late-onset (LO) PE and their correlation with gestational age and mean uterine artery pulsatility index at PE diagnosis and birth-weight percentile. METHODS: The study included 30 women with previous EO-PE, 30 with previous LO-PE and 30 controls with no previous PE. Participants were examined at between 6 months and 4 years after delivery. All included women were free from cardiovascular risk factors and drugs. Data on demographic and clinical characteristics during pregnancy were collected retrospectively from obstetrical charts. Endothelial function and arterial stiffness were assessed by peripheral arterial tonometry and pulse-wave analysis. RESULTS: All vascular parameters were significantly different, indicating circulatory impairment, in women with previous EO-PE. Women with previous LO-PE had higher vascular rigidity than did controls and all had normal values of reactive hyperemia index, although they were significantly lower when compared with those of controls. On multivariate analysis, gestational age and mean uterine artery pulsatility index at the time of PE diagnosis, and birth-weight percentile were all statistically related to the vascular indices studied, after correcting for confounding parameters. CONCLUSIONS: Women with previous pregnancy complicated by PE, in particular those with early-onset disease, showed persistent microcirculatory dysfunction, as suggested by a significant reduction in reactive hyperemia index value, and increased arterial stiffness. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Insights into cardiac alterations after pre-eclampsia: an echocardiographic study.

OBJECTIVES: To investigate cardiovascular (CV) performance status several years after early-onset (EO) or late-onset (LO) pre-eclampsia (PE), using echocardiography to assess myocardial strain and left ventricular (LV) torsional mechanics and ventricular-arterial coupling (VAC). METHODS: Thirty non-pregnant women with a previous singleton pregnancy complicated by EO-PE, 30 who had experienced LO-PE and 30 controls underwent echocardiography with two-dimensional (2D) speckle tracking between 6 months and 4 years after delivery and their findings were compared. All women were free from CV risk factors. VAC was defined as the ratio between aortic elastance (Ea) and LV end-systolic elastance (Ees). RESULTS: Women in the EO-PE group showed a persistent subclinical impairment in LV systole and a slight alteration in right ventricular function, with reductions in LV 2D strain (circumferential, radial and longitudinal) and right ventricular 2D strain and impairment of LV torsional mechanics, when compared both with women in the LO-PE group and with healthy controls. Although VAC was within the normal range in the whole study cohort, its individual components Ea and Ees were significantly altered more often in the EO-PE group than in both the LO-PE group and controls. All parameters investigated (except right ventricular 2D strain) were associated independently with gestational age at the time of diagnosis of PE. CONCLUSIONS: Women with a history of EO-PE are more likely to have subclinical impairment of systolic biventricular function than are those with a history of LO-PE and controls. The components of VAC (Ea and Ees) show subclinical alterations which are more significant in women with a history of EO-PE than in those with a history of LO-PE and controls, although VAC itself is maintained. Our study supports the use of closer CV monitoring in previously pre-eclamptic women, particularly those in whom PE was preterm. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Maternal cardiac function after HELLP syndrome: an echocardiography study.

OBJECTIVE: To evaluate maternal hemodynamics in asymptomatic women with a previous pregnancy affected by hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome and compare the findings to those of women with previous pre-eclampsia (PE) and controls with a previous uncomplicated pregnancy. METHODS: Women with a history of PE (n = 60) or HELLP syndrome (n = 49) and matched healthy controls (n = 60) underwent echocardiography at 6 months to 4 years after delivery, recording left ventricular (LV) dimensions, ejection fraction (LVEF) and mass, right ventricular (RV) tricuspid annular plane systolic excursion and fractional area change (FAC). Diastolic filling (E/A and E/E' ratios) and tissue Doppler imaging were evaluated for both ventricles and the myocardial performance index was calculated. RESULTS: Only women with previous HELLP syndrome showed significant LV concentric hypertrophy (20.4%). However, in both HELLP and PE groups, LV concentric remodeling (46.9% and 46.7%, respectively), diastolic dysfunction (expressed as altered E/A and E/E' ratios) and reduced LVEF (14.3% and 21.7%, respectively) were documented. RV variables did not differ significantly between cases and controls, except for FAC and E/E' ratio, which were slightly impaired in women with previous HELLP syndrome compared to those with previous PE (16.3% vs 10.0%, P = 0.04; 14.3% vs 3.3%, P = 0.03, respectively). CONCLUSIONS: The significant overlap of echocardiographic features in women with previous PE and HELLP syndrome suggests that these two conditions share the same pathophysiology. However, HELLP syndrome may lead to more severe cardiovascular remodeling in the short to medium term after delivery. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Maternal endothelial function and vascular stiffness after HELLP syndrome: a case-control study.

OBJECTIVES: To assess endothelial function and arterial stiffness in women with a previous pregnancy complicated by pre-eclampsia (PE) with hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome, and to compare these findings to those in women with previous PE but no HELLP and to those in controls with previous uncomplicated pregnancy, in order to investigate the influence of HELLP syndrome on subsequent cardiovascular impairment. METHODS: In this prospective single-center case-control study, we performed peripheral arterial tonometry (PAT) (using the EndoPAT method) and pulse-wave velocity (PWV) assessment in 109 women who had had a singleton pregnancy complicated by PE with (n = 49) or without (n = 60) HELLP syndrome, as well as in 60 controls with previous uncomplicated pregnancy, between 6 months and 4 years after delivery. The following EndoPAT and PWV indices were compared between groups: reactive hyperemia index (RHI), as an indication of endothelial function, and peripheral and aortic heart-rate-corrected augmentation indices (AIx) standardized for a heart rate of 75 bpm (AIx@75) and carotid-femoral pulse-wave velocity (cfPWV), as indications of arterial stiffness. RESULTS: PAT and arterial stiffness indices were significantly different between PE cases, with or without previous HELLP, and controls, except for carotid-femoral PWV. There were no significant differences among PE groups: women who had experienced HELLP and those with a history of PE without HELLP showed similar rates of RHI ≤ 1.67 (28.6% vs 18.3%, P = 0.254) and RHI ≤ 2.00 (61.2% vs 41.7%, P = 0.055), peripheral AIx@75 ≥ 17% (38.8% vs 30.0%, P = 0.417), aortic AIx@75 ≥ 35% (29.2% vs 20.0%, P = 0.461) and cfPWV × 0.8 > 9.6 m/s, which occurred in only three women, all in the group without previous HELLP (0% vs 5.0%, P = 0.251). On multivariate regression analysis, HELLP syndrome, intrauterine growth restriction (IUGR) and early-onset PE independently predicted endothelial dysfunction at 6 months to 4 years postpartum, after correcting for uterine artery pulsatility index, birth-weight percentile, and maternal blood pressure, age and body mass index. Women with both previous HELLP and early-onset IUGR had a significantly higher prevalence of endothelial dysfunction (P = 0.001). CONCLUSION: Similar vascular abnormalities were found in women previously affected by HELLP syndrome and those with previous PE without HELLP. However, a history of HELLP syndrome, IUGR and early-onset PE seems to identify a subgroup of women with a higher risk for future development of endothelial dysfunction. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Elastic properties of ascending aorta in women with previous pregnancy complicated by early- or late-onset pre-eclampsia.

OBJECTIVES: To evaluate the elastic properties of the ascending aorta in women with a previous pregnancy complicated by early-onset (EO) or late-onset (LO) pre-eclampsia (PE) and the correlation with gestational age (GA), systolic/diastolic blood pressure (SBP/DBP) and mean uterine artery pulsatility index (UtA-PI) at diagnosis of the disease as well as with birth weight of the neonate. METHODS: Thirty women who had a previous pregnancy complicated by EO-PE, 30 with a previous pregnancy complicated by LO-PE and 30 normal controls were selected retrospectively from our electronic database and then recalled for assessment from 6 months to 4 years after delivery. Data regarding GA, SBP/DBP and mean UtA-PI at the diagnosis of PE were obtained from medical records. At our assessment, aortic M-mode and tissue Doppler imaging (TDI) parameters were measured. Aortic diameters were assessed at end-diastole at four levels: Valsalva sinuses, sinotubular junction, tubular tract and aortic arch. Aortic compliance, distensibility, stiffness index (SI), Peterson's elastic modulus (EM), pulse-wave velocity and M-mode strain were calculated using standard formulae. Aortic expansion velocity, early and late diastolic retraction velocities and peak systolic tissue strain (TDI-ϵ) were determined. RESULTS: Aortic diameters at the four levels were significantly greater in both EO-PE and LO-PE groups than in controls. Aortic compliance and distensibility and TDI-ϵ were lower in EO-PE than in LO-PE (P = 0.001, P = 0.002 and P = 0.011, respectively) and controls (P = 0.037, P = 0.044 and P = 0.013, respectively). SI and EM were higher in EO-PE than in LO-PE (P = 0.001 and P < 0.001, respectively) and than in controls (P = 0.035 and P = 0.036, respectively). Multivariate analysis showed GA, DBP and UtA-PI at diagnosis of PE to be independent predictors of aortic elastic properties. CONCLUSIONS: Elastic properties of the ascending aorta were altered in women with a previous pregnancy complicated by EO-PE, but not in those with LO-PE. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Lower endothelial progenitor cell number, family history of cardiovascular disease and reduced HDL-cholesterol levels are associated with shorter leukocyte telomere length in healthy young adults.

BACKGROUND AND AIMS: Leukocyte telomere length (LTL) is a novel marker of cardiovascular (CV) risk. The aim of the study was to investigate the major determinants of LTL in a healthy young population at very low CV risk. METHODS AND RESULTS: LTL was determined in 82 healthy subjects (49M/33F; age37 ± 9yrs), normotensive and not taking any medication with different family history of cardiovascular disease (CVD) (24yes/58no). Fasting blood samples were drawn in all subjects for the determination of lipid profile, high sensitive C-reactive protein, uric acid, Plasminogen Activator Inhibitor-1 (PAI-1), LTL and Endothelial Progenitor Cell (EPC) number. LTL was assessed with a specific real-time PCR reaction in leukocyte DNA samples. LTL resulted inversely correlated with family history of CVD (t = 2.70; p = 0.009), age (r = -0.238; p = 0.032), waist circumference (r = -0.256; p = 0.02), triglycerides (r = -0.218; p = 0.049), PAI-1 (r = -0.288; p = 0.009) and directly correlated with HDL-cholesterol (r = 0.316; p = 0.004) and EPC number (r = 0.358; p = 0.002). At a multivariate analysis, family history of CVD (p = 0.013), EPC count (p = 0.003), and HDL-cholesterol (p = 0.017) were independently associated with LTL (r = 0.62). CONCLUSION: LTL is independently associated to CV risk factors also in healthy young adults.

Disconnect between the effects of serelaxin on renal function and outcome in acute heart failure.

BACKGROUND: We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes. METHODS: We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure. RESULTS: Improvement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64-2.15, p < 0.0001)], but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin [OR 0.70 (95% CI 0.60-0.83, p < 0.0001)] and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin [CVD HR 1.01 (0.99-1.04), ACM HR 1.01 (0.99-1.03), HF/renal failure hospitalization HR 0.99 (0.97-1.00)]. CONCLUSIONS: Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF. Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function.

Unusual arterial thrombotic events in Covid-19 patients.

INTRODUCTION: COVID-19 infection is commonly complicated with pro-thrombotic state and endothelial dysfunction. While several studies reported a high incidence of venous thromboembolic events. The occurrence of arterial thromboses are yet rarely described and could be underestimated. OBJECTIVES: To describe the clinical and biological characteristics of COVID-19 patients presenting with an associated arterial thromboembolic event. MATERIAL AND METHODS: We performed a retrospective multicentric study in 3 centers between France and Italy. All patients with a confirmed SARS-CoV-2 infection and arterial thromboembolic events were included in the analysis. RESULTS: From March 8th to April 25th 2020, we identified 20 patients (24 events) with arterial thromboembolic events over 209 admitted patients (9.6%) with severe COVID-19 infection. Arterial thrombotic events included acute coronary occlusions (n = 9), stroke (n = 6), limb ischemia (n = 3), splenic infarcts (n = 3), aortic thrombosis (n = 2) and occlusive mesenteric ischemia (n = 1). At the time of the event, 10/20 (50%) of patients received thromboprohylaxis, 2/20 (10%) were receiving treatment dose anticoagulation and 5/20 (25%) were receiving antiplatelet therapy. CONCLUSION: Our observations suggest that serious arterial thrombotic events might occur in Covid-19 patients. However, the exact incidence of such events and the best way to prevent them yet remains to be investigated.

Plasma homocysteine levels and late outcome in patients with unstable angina.

AIM OF THE STUDY: Previous studies have suggested that total plasma homocysteine (HCY) is an important cardiovascular risk factor because of its interaction with vascular smooth muscle cells, endothelium function, plasma lipoprotein, coagulation factors and platelets. The aim of this study was to evaluate a possible relationship between HCY levels and the severity of coronary artery disease (CAD) and its prognostic value in patients with unstable angina (UA). METHODS AND RESULTS: Ninety-four patients with UA were recruited and underwent coronary angiography and in some cases myocardial revascularization. The primary end point was the severity of CAD. The clinical end points were the recurrence of UA and the compositive end point of the occurrence of cardiac death and re-hospitalization due to acute coronary syndrome. HCY levels were shown to be poorly correlated with the severity of CAD. After 48 months' of follow-up, a graded relationship between HCY levels and recurrence of UA and compositive end point was found (p < 0.001). CONCLUSIONS: In the light of events occurring during the follow-up period, it was concluded that total plasma HCY is a strong predictor of recurrence of UA.

[Raised homocysteine plasma concentration in patients with heart failure: clinical significance]. / Elevate concentrazioni plasmatiche di omocisteina in pazienti affetti da insufficienza cardiaca: significato clinico.

UNLABELLED: Elevated plasma levels of homocysteine is associated with increased risk of thrombotic and atherosclerotic vascular disease. Several studies have demonstrated that hyper-homocysteinemia is an indipendent risk factor for vascular disease and is associated to heart failure. However there are no data regarding the association between homocysteine and various objective as well as subjective measures of heart failure. We hypothesized that plasma homocysteine is associated with clinical and echocardiographic signs of heart failure. On this ground we have analysed levels of homocysteine in patients with heart failure and possible correlation between these levels and clinical-functional pattern (NYHA class and ejection fraction). METHODS: Plasma homocysteine levels were determined in 123 patients with dilated cardiomyopathy (59 males, 64 females, mean age 67+/-10 years, mean EF 31+/-11% and mean NYHA 2.4+/-0.9, 47 idiopatic and 76 postischemic cardiomyopathy) and 85 healthy control subjects (homogeneus group for sex and age). Patients with chronic renal failure, vitamin B12 and folate deficiency or factors affecting homocysteine plasma levels were escluded from this study. Homocysteine levels were determined in coded plasma samples by immunoenzimatic methods. RESULTS: Patients with heart failure had a higher homocysteine level (mcg/L) than control subjects (21.72+/-10.28 vs 12.9+/-6.86, p<0,001) both postischemic (20.89+/-9.6 vs 12.9+/-6.86, p<0,001) and idiopatic cardiomiopathy (23.0+/-11.2 vs 12.9+/-6.86, p<0,001). A significant correlation was observed between homocysteine and NYHA functional class (p<0,001), age (p<0,001), creatinine (p<0,001), colesterol (p<0,05) while no correlations were observed with hemodynamic (HR, BP), functional (ejection fraction) and other metabolic parameters (triglycerides). Serum homocysteine was lowest in control and increased with increasing NYHA class. In idiopatic cardiomiopathy the correlation between homocysteine and NYHA functional class, creatinine (p<0,001), fibrinogen (p<0,05) was confirmed; in postischemic cardiomiopathy a significant correlation with creatinine and NYHA class (p<0,001) and with triglycerides (p<0,05) was also found. CONCLUSION: Plasma homocysteine was directly related to NYHA class. This observation may underline the strong relations of plasma homocysteine to congestive heart failure. Further research is indicated to evaluate a causal or non-causal mechanism for this association.

Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol.

BACKGROUND: Both metoprolol and carvedilol produce hemodynamic and clinical benefits in patients with chronic heart failure; carvedilol exerts greater antiadrenergic effects than metoprolol, but it is unknown whether this pharmacological difference results in hemodynamic and clinical differences between the 2 drugs. METHODS AND RESULTS: We randomized 150 patients with heart failure (left ventricular ejection fraction

PTX3, A prototypical long pentraxin, is an early indicator of acute myocardial infarction in humans.

BACKGROUND: Inflammation is an important component of ischemic heart disease. PTX3 is a long pentraxin whose expression is induced by cytokines in endothelial cells, mononuclear phagocytes, and myocardium. The possibility that PTX3 is altered in patients with acute myocardial infarction (AMI) has not yet been tested. METHODS AND RESULTS: Blood samples were collected from 37 patients admitted to the coronary care unit (CCU) with symptoms of AMI. PTX3 plasma concentrations, as measured by ELISA, higher than the mean+2 SD of age-matched controls (2.01 ng/mL) were found in 27 patients within the first 24 hours of CCU admission. PTX3 peaked at 7.5 hours after CCU admission, and mean peak concentration was 6.94+/-11.26 ng/mL. Plasma concentrations of PTX3 returned to normal in all but 3 patients at hospital discharge and were unrelated to AMI site or extent, Killip class at entry, hours from symptom onset, and thrombolysis. C-reactive protein peaked in plasma at 24 hours after CCU admission, much later than PTX3 (P<0.001). Patients >64 years old and women had significantly higher PTX3 concentrations at 24 hours (P<0.05). PTX3 was detected by immunohistochemistry in normal but not in necrotic myocytes. CONCLUSIONS: PTX3 is present in the intact myocardium, increases in the blood of patients with AMI, and disappears from damaged myocytes. We suggest that PTX3 is an early indicator of myocyte irreversible injury in ischemic cardiomyopathy.