Aim
Recent data suggest that guideline‐directed medical therapy of patients with heart failure (HF) with reduced ejection fraction (HFrEF) might improve clinical outcomes in patients with HF up to a ...left ventricular ejection fraction (LVEF) of 55–65%, whereas patients with higher LVEF do not seem to benefit. Recent data have shown that LVEF may have a U‐shaped relation with outcome, with poorer outcome also in patients with supranormal values. This suggests that patients with supranormal LVEF may be a distinctive group of patients.
Methods and results
RELAX‐AHF‐2 was a multicentre, placebo‐controlled trial on the effects of serelaxin on 180‐day cardiovascular (CV) mortality and worsening HF at day 5 in patients with acute HF. Echocardiograms were performed at hospital admission in 6128 patients: 155 (2.5%) patients were classified as HF with supranormal ejection fraction (HFsnEF; LVEF >65%), 1440 (23.5%) as HF with preserved ejection fraction (HFpEF; LVEF 50–65%), 1353 (22.1%) as HF with mildly reduced ejection fraction (HFmrEF; LVEF 41–49%) and 3180 (51.9%) as HFrEF (LVEF <40%). Patients with HFsnEF compared to HFpEF were more often women, had higher prevalence of non‐ischaemic HF, had lower levels of natriuretic peptides, were less likely to be treated with beta‐blockers and had higher blood urea nitrogen plasma levels. All‐cause mortality was not statistically different between groups, although patients with HFsnEF had the highest numerical rate. A declining trend was seen in the proportion of 180‐day deaths due to CV causes from HFrEF (290/359, 80.8%) to HFsnEF (14/24, 58.3%). The reverse was observed with death from non‐CV causes. No treatment effect of serelaxin was observed in any of the subgroups.
Conclusions
In this study, only 2.5% of patients were classified as HFsnEF. HFsnEF was primarily characterized by female sex, lower natriuretic peptides and a higher risk of non‐CV death.
Aim
Pathophysiological differences between patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction (EF) remain unclear. Therefore we used a phenomics approach, ...integrating selected proteomics data with patient characteristics and cardiac structural and functional parameters, to get insight into differential pathophysiological mechanisms and identify potential treatment targets.
Methods and results
We report data from a representative subcohort of the prospective Singapore Heart Failure Outcomes and Phenotypes (SHOP), including patients with HFrEF (EF <40%, n = 217), HFpEF (EF ≥50%, n = 213), and age‐ and sex‐matched controls without HF (n = 216). We measured 92 biomarkers using a proximity extension assay and assessed cardiac structure and function in all participants using echocardiography. We used multi‐block projection to latent structure analysis to integrate clinical, echocardiographic, and biomarker variables. Candidate biomarker targets were cross‐referenced with small‐molecule and drug databases. The total cohort had a median age of 65 years (interquartile range 60–71), and 50% were women. Protein profiles strongly discriminated patients with HFrEF (area under the curve AUC = 0.89) and HFpEF (AUC = 0.94) from controls. Phenomics analyses identified unique druggable inflammatory markers in HFpEF from the tumour necrosis factor receptor superfamily (TNFRSF), which were positively associated with hypertension, diabetes, and increased posterior and relative wall thickness. In HFrEF, interleukin (IL)‐8 and IL‐6 were possible targets related to lower EF and worsening renal function.
Conclusion
We identified pathophysiological mechanisms related to increased cardiac wall thickness parameters and potentially druggable inflammatory markers from the TNFRSF in HFpEF.
Study design and main study results. CA125, carbohydrate antigen 125; CTSL, cathepsin L; DKK1, Dickkopf‐related protein 1; HBEGF, heparin‐binding EGF‐like growth factor; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IL6, interleukin‐6; IL6R, interleukin‐6 receptor; IL8, interleukin‐8; LV, left ventricular; NGF, neurotrophic growth factor; PlGF, placental growth factor; TNFRSF, tumour necrosis factor receptor superfamily.
Aim
The comorbidities that collectively define metabolic syndrome are common in patients with heart failure. However, the role of metabolic syndrome in the pathophysiology of heart failure is not ...well understood. We therefore investigated the clinical and biomarker correlates of metabolic syndrome in patients with heart failure.
Methods and results
In 1103 patients with heart failure, we compared the biomarker expression using a panel of 363 biomarkers among patients with (n = 468 42%) and without (n = 635 58%) metabolic syndrome. Subsequently, a pathway overrepresentation analysis was performed to identify key biological pathways. Findings were validated in an independent cohort of 1433 patients with heart failure of whom 615 (43%) had metabolic syndrome. Metabolic syndrome was defined as the presence of three or more of five criteria, including central obesity, elevated serum triglycerides, reduced high‐density lipoprotein cholesterol, insulin resistance and hypertension. The most significantly elevated biomarkers in patients with metabolic syndrome were leptin (log2 fold change 0.92, p = 5.85 × 10−21), fatty acid‐binding protein 4 (log2 fold change 0.61, p = 1.21 × 10−11), interleukin‐1 receptor antagonist (log2 fold change 0.47, p = 1.95 × 10−13), tumour necrosis factor receptor superfamily member 11a (log2 fold change 0.35, p = 4.16 × 10−9), and proto‐oncogene tyrosine‐protein kinase receptor Ret (log2 fold change 0.31, p = 4.87 × 10−9). Network analysis identified 10 pathways in the index cohort and 6 in the validation cohort, all related to inflammation. The primary overlapping pathway in both the index and validation cohorts was up‐regulation of the natural killer cell‐mediated cytotoxicity pathway.
Conclusion
Metabolic syndrome is highly prevalent in heart failure and is associated with biomarkers and pathways relating to obesity, lipid metabolism and immune responses underlying chronic inflammation.
Albuminuria is common in patients with heart failure and associated with worse outcomes. The underlying pathophysiological mechanism of albuminuria in heart failure is still incompletely understood. ...The association of clinical characteristics and biomarker profile with albuminuria in patients with heart failure with both reduced and preserved ejection fractions were evaluated.
Two thousand three hundred and fifteen patients included in the index cohort of BIOSTAT-CHF were evaluated and findings were validated in the independent BIOSTAT-CHF validation cohort (1431 patients). Micro-albuminuria and macro-albuminuria were defined as urinary albumincreatinine ratio (UACR) 30 mg/gCr and 300 mg/gCr in spot urines, respectively. The prevalence of micro- and macro-albuminuria was 35.4 and 10.0, respectively. Patients with albuminuria had more severe heart failure, as indicated by inclusion during admission, higher New York Heart Association functional class, more clinical signs and symptoms of congestion, and higher concentrations of biomarkers related to congestion, such as biologically active adrenomedullin, cancer antigen 125, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (all P 0.001). The presence of albuminuria was associated with increased risk of mortality and heart failure (re)hospitalization in both cohorts. The strongest independent association with log UACR was found for log NT-proBNP (standardized regression coefficient 0.438, 95 confidence interval 0.350.53, P 0.001). Hierarchical clustering analysis demonstrated that UACR clusters with markers of congestion and less with indices of renal function. The validation cohort yielded similar findings.
In patients with new-onset or worsening heart failure, albuminuria is consistently associated with clinical, echocardiographic, and circulating biomarkers of congestion.
Heart failure (HF) is associated with cytokine activation and inflammation. Experimental evidence suggests that plasma interleukin-17 (IL-17) is associated with myocardial fibrosis and cardiac ...dysfunction in HF. IL-17D, a subtype of IL-17 originates from particular tissues such as the heart. However, there is very limited data on the IL-17 cytokine family in patients with HF. Therefore, we investigated the association between circulating IL-17D levels, clinical characteristics and outcome in a large cohort of patients with heart failure.
Plasma IL-17D was measured in 2032 patients with HF from 11 European countries using a proximity extension assay. The primary outcome was a composite of HF hospitalization or all-cause mortality. Patients with higher plasma IL-17D concentrations were more likely to have atrial fibrillation (AF), renal dysfunction and heart failure with preserved ejection fraction (HFpEF) and had higher plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations (all p < 0.001). IL-17D was not associated with interleukin-6 (IL-6) or C-reactive protein (CRP) concentrations. After adjustment for confounders in a multivariable Cox regression analysis, patients in the highest quartile of plasma IL-17D had a significantly increased risk of the composite outcome of HF hospitalization or all-cause mortality compared to patients in the lowest quartile Hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.05–1.57.
In patients with HF, elevated plasma IL-17D concentrations are associated with higher plasma NT-proBNP concentrations and a higher prevalence of AF and renal dysfunction. High IL-17D concentrations are independently associated with worse outcome.
•Patients with heart failure (HF) and high IL-17D concentrations are more likely to have atrial fibrillation and renal dysfunction•In patients with HF, elevated plasma IL-17D concentrations are associated with higher plasma NT-proBNP concentrations.
Several studies have shown that heart failure (HF) drug treatment seems to benefit patients with preserved ejection fraction (HFpEF) and a left ventricular ejection fraction (LVEF) up to 55–60% but ...not with higher LVEF. Certain HF drugs are now indicated in patients with HFpEF and a LVEF below normal. However, not much is known about patients with a normal LVEF. Therefore, we investigated the prevalence, clinical characteristics and outcome of patients with HF and a normal LVEF.
Normal LVEF was defined according to the Recommendations for Cardiac Chamber Quantification from the American Society of Echocardiography as a LVEF ≥62% for men and ≥ 64% for women. Preserved ejection fraction was defined as a LVEF ≥50% and reduced ejection fraction as a LVEF <50%. In the total cohort of 1568 studied patients with heart failure (mean age 73 years; 33.6% female) 57 patients (3.6%) had a normal LVEF. These patients least likely had a previous myocardial infarction (p < 0.001) or diabetes (p = 0.045), had the lowest Left Ventricular End Diastolic Diameter (p < 0.001), the highest rate of previous HF hospitalization in the last year (p = 0.015), the highest cardiac output (p < 0.001) and were most frequently women (p < 0.001). Patients with a normal LVEF had the lowest risk for the primary combined outcome of all-cause mortality and HF hospitalization.
Only 3.6% of patients with HF had a sex-adjusted normal LVEF. Despite the sex-adjusted cut-offs they were more frequently female with less ischemic heart disease, higher cardiac output and better clinical outcomes.
•Only 3.6% of patients with HF had a sex-adjusted normal LVEF.•Patients with a normal LVEF were most commonly women with less ischemic heart disease and diabetes.•They had the lowest risk for the primary combined outcome of all-cause mortality and HF hospitalization.
Hypohidrotic ectodermal dysplasia (HED) can be caused by mutations in the X-linked ectodysplasin A (ED1) gene or the autosomal ectodysplasin A-receptor (EDAR) and EDAR-associated death domain ...(EDARADD) genes. X-linked and autosomal forms are sometimes clinically indistinguishable. For genetic counseling in families, it is therefore important to know the gene involved. In 24 of 42 unrelated patients with features of HED, we found a mutation in ED1. ED1-negative patients were screened for mutations in EDAR and EDARADD. We found mutations in EDAR in 5 of these 18 patients. One mutation, p.Glu354X, is novel. In EDARADD, a novel variant p.Ser93Phe, probably a neutral polymorphism, was also found. Clinically, there was a difference between autosomal dominant and autosomal recessive HED patients. The phenotype in patients with mutations in both EDAR alleles was comparable to males with X-linked HED. Patients with autosomal dominant HED had features comparable to those of female carriers of X-linked HED. The teeth of these patients were quite severely affected. Hypohidrosis and sparse hair were also evident, but less severe. This study confirms Chassaing et al's earlier finding that mutations in EDAR account for approximately 25% of non-ED1-related HED. Mutations leading to a premature stop codon have a recessive effect except when the stop codon is in the last exon. Heterozygous missense mutations in the functional domains of the gene may have a dominant-negative effect with much variation in expression. Patients with homozygous or compound heterozygous mutations in the EDAR gene have a more severe phenotype than those with a heterozygous missense, nonsense or frame-shift mutation.
Transient activation of the renin-angiotensin system (RAS) induces irreversible renal damage causing sustained elevation in blood pressure (BP) in Cyp1a1-Ren2 transgenic rats. In our current study we ...hypothesized that activation of the AT1-receptor (AT1R) leads to a T-cell response causing irreversible impairment of renal function and hypertension. Cyp1a1-Ren2 rats harbor a construct for activation of the RAS by indole-3-carbinol (I3C). Rats were fed a I3C diet between 4-8 weeks of age to induce hypertension. Next, I3C was withdrawn and rats were followed-up for another 12 weeks. Additional groups received losartan (20 mg/kg/day) or hydralazine (100 mg/kg/day) treatment between 4-8 weeks. Rats were placed for 24h in metabolic cages before determining BP at week 8, 12 and 20. At these ages, subsets of animals were sacrificed and the presence of kidney T-cell subpopulations was investigated by immunohistochemistry and molecular marker analysis. The development of sustained hypertension was completely prevented by losartan, whereas hydralazine only caused a partial decrease in BP. Markers of renal damage: KIM-1 and osteopontin were highly expressed in urine and kidney samples of I3C-treated rats, even until 20 weeks of age. Additionally, renal expression of regulatory-T cells (Tregs) was highly increased in I3C-treated rats, whereas the expression of T-helper 1 (Th1) cells demonstrated a strong decrease. Losartan prevented these effects completely, whereas hydralazine was unable to affect these changes. In young Cyp1a1-Ren2 rats AT1R activation leads to induction of an immune response, causing a shift from Th1-cells to Tregs, contributing to the development of irreversible renal damage and hypertension.
AbstractBackgroundThe aim of this study was to examine the long-term effect of shortening after a midshaft clavicular fracture on strength deficiency in the shoulder. MethodThis study included 18 ...participants (14 males, 4 females) with a conservatively treated midshaft clavicular fracture. Mean age was 52.2 ± 13.8 years, range 32–76 years). The mean follow-up time was 13.5 ± 0.4 years. Participants filled in a QUICKDASH questionnaire and both clavicle lengths were measured using a caliper. The isometric strengths in internal rotation, external rotation and abduction of both arms were measured with a handheld dynamometer. ResultsAverage shortening of the clavicle in this group was 1.09 cm (SD 0.53). Nearly all strength measurements showed no significant difference between the shortened and the unaffected side. Multiple regression revealed a small (3N per mm length difference) but statistically significant relationship on external rotation between the relative extent of shortening of the clavicle, dominant side of the fracture and the isometric force difference between the unaffected and affected arm, F(2,15) = 5.746, p < .05, adj. R 2 = .358. Over 14 years there was a reduction in mean DASH-score of 4.4 (8.8 ± 12.3; current DASH = 4.4 ± 7.7) In this group, long term effects of clavicular shortening were small. Based on these results we conclude that on the long term clavicular shortening will not result in significant strength loss.
PDF
