Abstract Introduction Advanced heart failure is a malignant disease characterized by a debilitating late course, with increasingly frequent hospitalisations and high rate of mortality. Levosimendan, ...an inodilator developed for the treatment of acutely decompensated chronic heart failure, has been recently proposed also as a repetitive treatment of advanced heart failure. Several studies on the use of levosimendan in this settings report mortality data. Independent meta-analyses on the effect on mortality of repetitive or intermittent levosimendan administration in advanced heart failure has been published but were criticized in regard to the selection of the studies. Meanwhile new data became available. We therefore updated the selection of studies and re-analyzed all the available data. Methods & results Data from seven randomized trial and a total of 438 adult patients using intermittent levosimendan in a cardiological setting were included in the present analysis. The average follow-up period was 8 ± 3.8 months. The use of levosimendan was associated with a significant reduction in mortality at the longest follow-up available 41 of 257 (16%) in the levosimendan group vs. 39 of 181 (21.5%) in the control arm, OR = 0.54 (95% CI 0.32–0.91), p for effect = 0.02, p for heterogeneity = 0.64, I2 = 0%. Conclusions The updated results suggest that repetitive or intermittent levosimendan administration in advanced heart failure is associated with a significant reduction in mortality at the longest follow-up available. There is therefore a strong rationale for a randomized clinical trial with adequate power on mortality.
Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator. This study evaluated the haemodynamic effect and safety of cinaciguat added to standard therapy in patients with acute ...decompensated heart failure (ADHF).
In this placebo-controlled, phase IIb study (NCT00559650), 139 patients admitted with ADHF, pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, left ventricular ejection fraction <40%, and a pre-existing need for invasive haemodynamic monitoring were randomized 2:1 to cinaciguat:placebo (continuous i.v. infusion). The dose was titrated for 8 h and maintained for 16-40 h (starting dose: 100 μg/h). At 8 h, mean PCWP changed from 25.7 ± 5.0 mmHg by -7.7 mmHg with cinaciguat and from 25.0 ± 5.3 mmHg by -3.7 mmHg with placebo (P < 0.0001). The mean right atrial pressure changed from 12.4 ± 5.3 mmHg by -2.7 mmHg with cinaciguat and from 11.8 ± 4.9 mmHg by -0.6 mmHg with placebo (P= 0.0019). Cinaciguat also decreased the pulmonary and systemic vascular resistance and the mean arterial pressure, and increased the cardiac index (all P < 0.0001 vs. placebo). Systolic blood pressure changed by -21.6 ± 17.0 mmHg with cinaciguat and -5.0 ± 14.5 mmHg with placebo. Adverse events were experienced by 71 and 45% of patients receiving cinaciguat and placebo, respectively. No adverse effects on the 30-day mortality were seen; however, the trial was stopped prematurely due to an increased occurrence of hypotension at cinaciguat doses ≥200 µg/h.
Cinaciguat unloaded the heart in patients with ADHF. However, high doses were associated with hypotension.
Background: Acute coronary syndrome (ACS) patients are widely treated with long-term beta-blocker therapy after cardiac event. Especially for low-risk patients, the benefits of beta-blockers on ...survival and the optimal therapy duration remain unclear. We investigated the effect of adherence to beta-blockers on long-term survival of ACS patients.
Methods and results: A total of 1855 consecutive ACS patients who underwent angiography and survived 30 days after were followed for a median of 8.6 years. During follow-up, 30.1% (n = 558) of patients died. Adherence was assessed as yearly periods covered by medication purchases and investigated as a dynamic time-dependent variable in Cox proportional hazards models. In a univariable model, non-adherence to beta-blockers was associated with higher all-cause mortality (Hazard ratio HR 2.99, 95% confidence interval CI 2.50−3.57; p < .001). Results were similar in multivariable models on both overall survival (HR 1.84, 95% CI 1.51−2.24; p < .001) and on 1-year landmark survival (HR 1.74, 95% CI 1.41−2.14; p < .001). In subgroup analyses, the increase in all-cause mortality was consistent among low-risk patients (HR 1.60, 95% CI 1.16−2.21; p = .004).
Conclusion: Poor adherence to beta-blockers is associated with increased long-term mortality among ACS patients. Even low-risk patients seem to benefit from long-term beta-blocker therapy.
Key messages
Adherence to secondary prevention medications diminishes drastically over the years after an ACS event.
Non-adherence to β-blockers is associated with increased long-term mortality of ACS patients, and the effect on survival extends beyond the first year after an ACS event.
Our follow-up was exceptionally lengthy with median follow-up period of 8.6 years.
Summary Background Comparison of patients with coronary heart disease and controls in genome-wide association studies has revealed several single nucleotide polymorphisms (SNPs) associated with ...coronary heart disease. We aimed to establish the external validity of these findings and to obtain more precise risk estimates using a prospective cohort design. Methods We tested 13 recently discovered SNPs for association with coronary heart disease in a case-control design including participants differing from those in the discovery samples (3829 participants with prevalent coronary heart disease and 48 897 controls free of the disease) and a prospective cohort design including 30 725 participants free of cardiovascular disease from Finland and Sweden. We modelled the 13 SNPs as a multilocus genetic risk score and used Cox proportional hazards models to estimate the association of genetic risk score with incident coronary heart disease. For case-control analyses we analysed associations between individual SNPs and quintiles of genetic risk score using logistic regression. Findings In prospective cohort analyses, 1264 participants had a first coronary heart disease event during a median 10·7 years' follow-up (IQR 6·7–13·6). Genetic risk score was associated with a first coronary heart disease event. When compared with the bottom quintile of genetic risk score, participants in the top quintile were at 1·66-times increased risk of coronary heart disease in a model adjusting for traditional risk factors (95% CI 1·35–2·04, p value for linear trend=7·3×10−10 ). Adjustment for family history did not change these estimates. Genetic risk score did not improve C index over traditional risk factors and family history (p=0·19), nor did it have a significant effect on net reclassification improvement (2·2%, p=0·18); however, it did have a small effect on integrated discrimination index (0·004, p=0·0006). Results of the case-control analyses were similar to those of the prospective cohort analyses. Interpretation Using a genetic risk score based on 13 SNPs associated with coronary heart disease, we can identify the 20% of individuals of European ancestry who are at roughly 70% increased risk of a first coronary heart disease event. The potential clinical use of this panel of SNPs remains to be defined. Funding The Wellcome Trust; Academy of Finland Center of Excellence for Complex Disease Genetics; US National Institutes of Health; the Donovan Family Foundation.
The aim was to study the prognostic value of plasma ceramides (Cer) as cardiovascular death (CV death) markers in three independent coronary artery disease (CAD) cohorts.
Corogene study is a ...prospective Finnish cohort including stable CAD patients (n = 160). Multiple lipid biomarkers and C-reactive protein were measured in addition to plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1). Subsequently, the association between high-risk ceramides and CV mortality was investigated in the prospective Special Program University Medicine-Inflammation in Acute Coronary Syndromes (SPUM-ACS) cohort (n = 1637), conducted in four Swiss university hospitals. Finally, the results were validated in Bergen Coronary Angiography Cohort (BECAC), a prospective Norwegian cohort study of stable CAD patients. Ceramides, especially when used in ratios, were significantly associated with CV death in all studies, independent of other lipid markers and C-reactive protein. Adjusted odds ratios per standard deviation for the Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio were 4.49 (95% CI, 2.24-8.98), 1.64 (1.29-2.08), and 1.77 (1.41-2.23) in the Corogene, SPUM-ACS, and BECAC studies, respectively. The Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio improved the predictive value of the GRACE score (net reclassification improvement, NRI = 0.17 and ΔAUC = 0.09) in ACS and the predictive value of the Marschner score in stable CAD (NRI = 0.15 and ΔAUC = 0.02).
Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently used lipid markers. This may improve the identification of high-risk patients in need of more aggressive therapeutic interventions.
Abstract
Aims
Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High ...plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization.
Methods and results
We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture.
Conclusion
Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD.
Aim
Chronic periodontitis has an episodic and multifactorial character, with fluctuations in bacterial burden, inflammatory response, and tissue destruction. We investigated the association of ...selected salivary biomarkers with periodontal parameters and validated the use of a novel salivary diagnostic approach, the cumulative risk score (CRS), in detection of periodontitis in subjects with angiographically verified coronary artery disease diagnosis.
Materials and Methods
The concentrations of matrix metalloproteinase (MMP)‐8, interleukin (IL)‐1β, and Porphyromonas gingivalis were analysed from saliva of 493 subjects. The subjects participated in a detailed clinical and radiographic oral examination. The CRS index, combining the three salivary biomarkers, was calculated for each subject.
Results
High salivary concentrations of MMP‐8, IL‐1β, and P. gingivalis were associated with deepened periodontal pockets and alveolar bone loss, and MMP‐8 and IL‐1β with bleeding on probing. The CRS index had a stronger association with moderate to severe periodontitis (OR 6.13; 95% CI 3.11–12.09) than any of the markers alone.
Conclusions
Salivary concentrations of MMP‐8, IL‐1β, and P. gingivalis are associated with various clinical and radiographic measures of periodontitis. The CRS index, combining the three salivary biomarkers, is associated with periodontitis more strongly than any of the markers alone regardless of the coronary artery disease status of the patients.
Ectopic accumulation of fat accompanies visceral obesity with detrimental effects. Lipid oversupply to cardiomyocytes leads to cardiac steatosis, and in animal studies lipotoxicity has been ...associated with impaired left ventricular (LV) function. In humans, studies have yielded inconclusive results. The aim of the study was to evaluate the role of epicardial, pericardial and myocardial fat depots on LV structure and function in male subjects with metabolic syndrome (MetS).
A study population of 37 men with MetS and 38 men without MetS underwent cardiovascular magnetic resonance and proton magnetic spectroscopy at 1.5 T to assess LV function, epicardial and pericardial fat area and myocardial triglyceride (TG) content.
All three fat deposits were greater in the MetS than in the control group (p <0.001). LV diastolic dysfunction was associated with MetS as measured by absolute (471 mL/s vs. 667 mL/s, p = 0.002) and normalized (3.37 s⁻¹ vs. 3.75 s⁻¹, p = 0.02) LV early diastolic peak filling rate and the ratio of early diastole (68% vs. 78%, p = 0.001). The amount of epicardial and pericardial fat correlated inversely with LV diastolic function. However, myocardial TG content was not independently associated with LV diastolic dysfunction.
In MetS, accumulation of epicardial and pericardial fat is linked to the severity of structural and functional alterations of the heart. The role of increased intramyocardial TG in MetS is more complex and merits further study.
Aim
We aimed to study how lipopolysaccharide (LPS) in saliva and serum associates with each other, periodontal microbial burden, periodontitis and coronary artery disease (CAD).
Materials and methods
...The used Parogene cohort comprised N = 505 Finnish adults. Coronary diagnosis was acquired by coronary angiography, and the main outcomes were as follows: no significant CAD (n = 123), stable CAD (n = 184) and acute coronary syndrome (n = 169). Periodontitis was defined according to clinical and radiographic examinations. Levels for 75 strains of subgingival bacteria were determined by checkerboard DNA–DNA hybridization. Saliva and serum LPS activity was analysed by Limulus amebocyte lysate assay.
Results
The level of 11 bacterial strains, which were mainly oral and respiratory Gram‐negative species, associated with salivary LPS levels in an age‐ and gender‐adjusted linear regression. A total of 4.9% of the serum LPS, that is endotoxemia, variation was explainable by saliva LPS among patients with periodontitis (n = 247, R2 = .049, Pearson's r = .222, p < .001). Endotoxemia associated with stable CAD in a confounder adjusted multinomial logistic regression model (OR 1.99, 95% CI 1.04–3.81, p = .039, 3rd tertile).
Conclusions
In particular in periodontitis patients, subgingival microbial burden contributes to endotoxemia. LPS is a possible molecular mediator between periodontitis and CAD.
Natriuretic peptide (NP) levels (B-type natriuretic peptide (BNP) and N-terminal proBNP) are now widely used in clinical practice and cardiovascular research throughout the world and have been ...incorporated into most national and international cardiovascular guidelines for heart failure. The role of NP levels in state-of-the-art clinical practice is evolving rapidly. This paper reviews and highlights ten key messages to clinicians:
NP levels are quantitative plasma biomarkers of heart failure (HF).
NP levels are accurate in the diagnosis of HF.
NP levels may help risk stratify emergency department (ED) patients with regard to the need for hospital admission or direct ED discharge.
NP levels help improve patient management and reduce total treatment costs in patients with acute dyspnoea.
NP levels at the time of admission are powerful predictors of outcome in predicting death and re-hospitalisation in HF patients.
NP levels at discharge aid in risk stratification of the HF patient.
NP-guided therapy may improve morbidity and/or mortality in chronic HF.
The combination of NP levels together with symptoms, signs and weight gain assists in the assessment of clinical decompensation in HF.
NP levels can accelerate accurate diagnosis of heart failure presenting in primary care.
NP levels may be helpful to screen for asymptomatic left ventricular dysfunction in high-risk patients.
Published by Elsevier B.V. on behalf of European Society of Cardiology.
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