Association of mild kidney dysfunction with diastolic dysfunction and heart failure with preserved ejection fraction.

AIMS: We aim to investigate the association between kidney dysfunction and left ventricular diastolic dysfunction parameters and heart failure with preserved ejection fraction (HFpEF) and whether this is sex-specific. METHODS AND RESULTS: We included participants from the HELPFul observational study. Outpatient clinical care data, including echocardiography, and an expert panel judgement on HFpEF was collected. Estimated glomerular filtration rate (eGFR) was calculated by creatinine and cystatin C without race. The association between eGFR with E/e', left ventricular mass index, relative wall thickness, and stage C/D heart failure was tested by multivariable adjusted regression models, stratified by sex, reporting odds ratios and 95% confidence intervals (95% confidence interval). We analysed 880 participants, mean age 62.9 (standard deviation: 9.3) years, 69% female. Four hundred six participants had mild (37.6%) kidney dysfunction (eGFR: 60-89 mL/min/1.73 m2 ) or moderate (8.5%) kidney dysfunction (eGFR: 30-59 mL/min/1.73 m2 ). HFpEF was significantly more prevalent in participants with mild and moderate kidney dysfunction (10.3% and 16.0%, respectively) than participants with normal kidney function (3.4%). A lower kidney function was associated with higher E/e' and higher relative wall thickness values. Participants with moderate kidney dysfunction had a higher likelihood of American College of Cardiology/American Heart Association stage C/D HF (odds ratio: 2.07, 95% confidence interval: 1.23, 3.49) than participants with normal kidney functions. CONCLUSIONS: Both mild and moderate kidney dysfunction are independently associated with left ventricular diastolic dysfunction parameters and HFpEF. This association is independent of sex and strongest for moderate kidney dysfunction. Considering mild-to-moderate kidney dysfunction as risk factor for HFpEF may help identify high-risk groups benefiting most from early intervention.

Plasma Proteomic Patterns Show Sex Differences in Early Concentric Left Ventricular Remodeling.

BACKGROUND: Concentric remodeling (cRM) can precede heart failure with preserved ejection fraction (HFpEF), a condition prevalent in women. METHODS: Patients (n=60 593, 54.2% women) visiting outpatient clinics of Cardiology Centers of the Netherlands were analyzed for cRM, HFpEF development, and mortality risk. We studied risk factors for relative wall thickness both sex-stratified and in women and men combined. Biomarker profiling was performed (4534 plasma proteins) in a substudy involving 557 patients (65.4% women) to identify pathways involved in cRM. RESULTS: cRM was present in 23.5% of women and 27.6% of men and associated with developing HFpEF (HR, 2.15 [95% CI, 1.51-2.99]) and mortality risk (HR, 1.09 [95% CI, 1.00-1.19]) in both sexes. Age, heart rate, and hypertension were statistically significantly stronger risk factors for relative wall thickness in women than men. Higher circulating levels of IFNA5 (interferon alpha-5) were associated with higher relative wall thickness in women only. Pathway analysis revealed differential pathway activation by sex and increased expression of inflammatory pathways in women. CONCLUSIONS: cRM is prevalent in approximately 1 in 4 women and men visiting outpatient cardiology clinics and associated with HFpEF development and mortality risk in both sexes. Known risk factors for cRM were more strongly associated in women than men. Proteomic analysis revealed inflammatory pathway activation in women, with a central role for IFNA5. Differential biologic pathway activation by sex in cRM may contribute to the female predominance of HFpEF and holds promise for identification of new therapeutic avenues for prevention and treatment of HFpEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT001747.

The HFA-PEFF score identifies 'early-HFpEF' phenogroups associated with distinct biomarker profiles.

AIMS: The HFA-PEFF score was developed to optimize diagnosis and to aid in early recognition of heart failure (HF) with preserved ejection fraction (HFpEF) in patients who present with HF-like symptoms. Recognizing early-HFpEF phenogroups is essential to better understand progression towards overt HFpEF and pave the way for early intervention and treatment. Whether the HFA-PEFF domain scores can identify 'early-HFpEF' phenogroups remains unknown. The aims of this pilot study are to (i) identify distinct phenogroups by cluster analysis of HFA-PEFF domain scores in subjects that present with HF-like symptoms and (ii) study whether these phenogroups may be associated with distinct blood proteome profiles. METHODS AND RESULTS: Subjects referred to the Cardiology Centers of the Netherlands, location Utrecht, with non-acute possibly cardiac-related symptoms (such as dyspnoea or fatigue) were prospectively enrolled in the HELPFul cohort (N = 507) and were included in the current analysis. Inclusion criteria for this study were (i) age ≥ 45 years and (ii) a left ventricular ejection fraction (LVEF) ≥ 50%, in the absence of a history of HF, coronary artery disease, congenital heart disease, or any previous cardiac interventions. Multinominal-based clustering with latent class model using the HFA-PEFF domain scores (functional, structural, and biomarker scores) as input was used to detect distinct phenotypic clusters. For each bootstrapping run, the 92 Olink proteins were analysed for their association with the identified phenogroups. Four distinct phenogroups were identified in the current analysis (validated by bootstrapping 1000×): (i) no left ventricular diastolic dysfunction (no LVDD, N = 102); (ii) LVDD with functional left ventricular (LV) abnormalities (N = 204); (iii) LVDD with functional and structural LV abnormalities (N = 204); and (iv) LVDD with functional and structural LV abnormalities and elevated BNP (N = 107). The HFA-PEFF total score risk categories significantly differed between the phenogroups (P < 0.001), with an increase of the HFA-PEFF score from Phenogroup 1 to 4 (low/intermediate/high HFA-PEFF risk score: Phenogroup 1: 88%/12%/0%; Phenogroup 2: 9%/91%/0%; Phenogroup 3: 0%/92%/8%; Phenogroup 4: 5%/83%/12%). Thirty-two out of the 92 Olink protein biomarkers significantly differed among the phenogroups. The top eight biomarkers-N-terminal prohormone brain natriuretic peptide, growth differentiation factor-15, matrix metalloproteinase-2, osteoprotegerin, tissue inhibitor of metalloproteinase-4, chitinase-3-like protein 1, insulin-like growth factor-binding protein 2, and insulin-like growth factor-binding protein 7-are mainly involved in inflammation and extracellular matrix remodelling, which are currently proposed key processes in HFpEF pathophysiology. CONCLUSIONS: This study identified distinct phenogroups by using the HFA-PEFF domain scores in ambulant subjects referred for HF-like symptoms. The newly identified phenogroups accompanied by their circulating biomarkers profile might aid in a better understanding of the pathophysiological processes involved during the early stages of the HFpEF syndrome.

Sex-specific microRNAs in women with diabetes and left ventricular diastolic dysfunction or HFpEF associate with microvascular injury.

Left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF) are microcirculation defects following diabetes mellitus (DM). Unrecognized HFpEF is more prevalent in women with diabetes compared to men with diabetes and therefore sex-specific diagnostic strategies are needed. Previously, we demonstrated altered plasma miRs in DM patients with microvascular injury [defined by elevated plasma Angiopoietin-2 (Ang-2) levels]. This study hypothesized the presence of sex-differences in plasma miRs and Ang-2 in diabetic (female) patients with LVDD or HFpEF. After a pilot study, we assessed 16 plasma miRs in patients with LVDD (n = 122), controls (n = 244) and female diabetic patients (n = 10). Subsequently, among these miRs we selected and measured plasma miR-34a, -224 and -452 in diabetic HFpEF patients (n = 53) and controls (n = 52). In LVDD patients, miR-34a associated with Ang-2 levels (R2 0.04, R = 0.21, p = 0.001, 95% CI 0.103-0.312), with plasma levels being diminished in patients with DM, while women with an eGFR < 60 ml/min and LVDD had lower levels of miR-34a, -224 and -452 compared to women without an eGFR < 60 ml/min without LVDD. In diabetic HFpEF women (n = 28), plasma Ang-2 levels and the X-chromosome located miR-224/452 cluster increased compared to men. We conclude that plasma miR-34a, -224 and -452 display an association with the microvascular injury marker Ang-2 and are particularly targeted to women with LVDD or HFpEF.

Increased circulating IgG levels, myocardial immune cells and IgG deposits support a role for an immune response in pre- and end-stage heart failure.

The chronic inflammatory response plays an important role in adverse cardiac remodelling and the development of heart failure (HF). There is also evidence that in the pathogenesis of several cardiovascular diseases, chronic inflammation is accompanied by antibody and complement deposits in the heart, suggestive of a true autoimmune response. However, the role of antibody-mediated immune responses in HF progression is less clear. We assessed whether immune cell infiltration and immunoglobulin levels are associated with HF type and disease stage, taking sex differences into account. We found IgG deposits and increased infiltration of immune cells in the affected myocardium of patients with end-stage HF with reduced ejection fraction (HFrEF, n = 20). Circulating levels of IgG1 and IgG3 were elevated in these patients. Furthermore, the percentage of transitional/regulatory B cells was decreased (from 6.9% to 2.4%) compared with healthy controls (n = 5). Similarly, increased levels of circulating IgG1 and IgG3 were observed in men with left ventricular diastolic dysfunction (LVDD, n = 5), possibly an early stage of HF with preserved EF (HFpEF). In conclusion, IgG deposits and infiltrates of immune cells are present in end-stage HFrEF. In addition, both LVDD patients and end-stage HFrEF patients show elevated levels of circulating IgG1 and IgG3, suggesting an antibody-mediated immune response upon cardiac remodelling, which in the early phase of remodelling appear to differ between men and women. These immunoglobulin subclasses might be used as marker for pre-stage HF and its progression. Future identification of auto-antigens might open possibilities for new therapeutic interventions.

Discovery of biomarkers for the presence and progression of left ventricular diastolic dysfunction and HEart faiLure with Preserved ejection Fraction in patients at risk for cardiovascular disease: rationale and design of the HELPFul case-cohort study in a Dutch cardiology outpatient clinic.

INTRODUCTION: Left ventricular diastolic dysfunction (LVDD) is a common condition in both sexes that may deteriorate into heart failure (HF) with preserved ejection fraction (pEF), although this seems to happen more often in women than in men. Both LVDD and HFpEF often go unrecognised, necessitating the discovery of biomarkers that aid both the identification of individuals with LVDD at risk of developing HF and identification of individuals most likely to benefit from treatment. METHODS AND ANALYSIS: HELPFul is an ongoing case-cohort study at a Dutch cardiology outpatient clinic enrolling patients aged 45 years and older without history of cardiovascular disease, who were referred by the general practitioner for cardiac evaluation. We included a random sample of patients and enriched the cohort with cases (defined as an E/e' ≥8 measured with echocardiography). Information about medical history, cardiovascular risk factors, electrocardiography, echocardiography, exercise test performance, common carotid intima-media thickness measurement and standard cardiovascular biomarkers was obtained from the routine care data collected by the cardiology outpatient clinic. Study procedure consists of extensive venous blood collection for biobanking and additional standardised questionnaires. Follow-up will consist of standardised questionnaires by mail and linkage to regional and national registries. We will perform cardiac magnetic resonance imaging and coronary CT angiography in a subgroup of patients to investigate the extent of macrovascular and microvascular coronary disease. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Review Board of the University Medical Center Utrecht. Results will be disseminated through national and international conferences and in peer-reviewed journals in cardiovascular disease. TRIAL REGISTRATION: NTR6016;Pre-results.

Opportunistic screening models for high-risk men and women to detect diastolic dysfunction and heart failure with preserved ejection fraction in the community.

BACKGROUND: The prevalence of undetected left ventricular diastolic dysfunction is high, especially in the elderly with comorbidities. Left ventricular diastolic dysfunction is a prognostic indicator of heart failure, in particularly of heart failure with preserved ejection fraction and of future cardiovascular and all-cause mortality. Therefore we aimed to develop sex-specific diagnostic models to enable the early identification of men and women at high-risk of left ventricular diastolic dysfunction with or without symptoms of heart failure who require more aggressive preventative strategies. DESIGN: Individual patient data from four primary care heart failure-screening studies were analysed (1371 participants, excluding patients classified as heart failure and left ventricular ejection fraction <50%). METHODS: Eleven candidate predictors were entered into logistic regression models to be associated with the presence of left ventricular diastolic dysfunction/heart failure with preserved ejection fraction in men and women separately. Internal-external cross-validation was performed to develop and validate the models. RESULTS: Increased age and ß-blocker therapy remained as predictors in both the models for men and women. The model for men additionally consisted of increased body mass index, moderate to severe shortness of breath, increased pulse pressure and history of ischaemic heart disease. The models performed moderately and similarly well in men (c-statistics range 0.60-0.75) and women (c-statistics range 0.51-0.76) and the performance improved significantly following the addition of N-terminal pro b-type natriuretic peptide (c-statistics range 0.61-0.80 in women and 0.68-0.80 in men). CONCLUSIONS: We provide an easy-to-use screening tool for use in the community, which can improve the early detection of left ventricular diastolic dysfunction/heart failure with preserved ejection fraction in high-risk men and women and optimise tailoring of preventive interventions.

The prevalence of left ventricular diastolic dysfunction and heart failure with preserved ejection fraction in men and women with type 2 diabetes: A systematic review and meta-analysis.

OBJECTIVE: Type 2 diabetes is a risk factor for the development of left ventricular diastolic dysfunction and heart failure with preserved ejection fraction. Our aim was to provide a summary estimate of the prevalence of left ventricular diastolic dysfunction and heart failure with preserved ejection fraction in type 2 diabetes patients and to investigate sex disparities. METHODS AND RESULTS: A systematic search of the databases Medline and Embase was conducted for studies reporting the prevalence of left ventricular diastolic dysfunction or heart failure with preserved ejection fraction among type 2 diabetes patients. Studies were only included if echocardiography was performed. Prevalence estimates were pooled using random-effects meta-analysis. A total of 28 studies were included. Data on the prevalence of left ventricular diastolic dysfunction were available in 27 studies. The pooled prevalence for left ventricular diastolic dysfunction in the hospital population (2959 type 2 diabetes participants) and in the general population (2813 type 2 diabetes participants) was 48% [95% confidence interval: 38%-59%] and 35% (95% confidence interval: 24%-46%), respectively. Heterogeneity was high in both populations, with estimates ranging from 19% to 81% in the hospital population and from 23% to 54% in the general population. For women and men, the pooled prevalence estimates of left ventricular diastolic dysfunction were 47% (95% confidence interval: 37%-58%) and 46% (95% confidence interval: 37%-55%), respectively. Only two studies presented the prevalence of heart failure with preserved ejection fraction; 8% (95% confidence interval: 5%-14%) in a hospital population and 25% (95% confidence interval: 21%-28%) in the general population [18% in men (mean age: 73.8; standard deviation: 8.6) and 28% in women (mean age: 74.9; standard deviation: 6.9)]. CONCLUSION: The prevalence of left ventricular diastolic dysfunction among type 2 diabetes patients is similarly high in men and women, while heart failure with preserved ejection fraction seems to be more common in women than men, at least in community people with type 2 diabetes.