Improving early diagnosis of cardiovascular disease in patients with type 2 diabetes and COPD: protocol of the RED-CVD cluster randomised diagnostic trial.

INTRODUCTION: The early stages of chronic progressive cardiovascular disease (CVD) generally cause non-specific symptoms that patients often do not spontaneously mention to their general practitioner, and are therefore easily missed. A proactive diagnostic strategy has the potential to uncover these frequently missed early stages, creating an opportunity for earlier intervention. This is of particular importance for chronic progressive CVDs with evidence-based therapies known to improve prognosis, such as ischaemic heart disease, atrial fibrillation and heart failure.Patients with type 2 diabetes or chronic obstructive pulmonary disease (COPD) are at particularly high risk of developing CVD. In the current study, we will demonstrate the feasibility and effectiveness of screening these high-risk patients with our early diagnosis strategy, using tools that are readily available in primary care, such as symptom questionnaires (to be filled out by the patients themselves), natriuretic peptide measurement and electrocardiography. METHODS AND ANALYSIS: The Reviving the Early Diagnosis-CVD trial is a multicentre, cluster randomised diagnostic trial performed in primary care practices across the Netherlands. We aim to include 1300 (2×650) patients who participate in a primary care disease management programme for COPD or type 2 diabetes. Practices will be randomised to the intervention arm (performing the early diagnosis strategy during the routine visits that are part of the disease management programmes) or the control arm (care as usual). The main outcome is the number of newly detected cases with CVDs in both arms, and the subsequent therapies they received. Secondary endpoints include quality of life, cost-effectiveness and the added diagnostic value of family and reproductive history questionnaires and three (novel) biomarkers (high-sensitive troponin-I, growth differentiation factor-15 and suppressor of tumourigenicity 2). Finally newly initiated treatments will be compared in both groups. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Ethical Committee of the University Medical Center Utrecht, the Netherlands. Results are expected in 2022 and will be disseminated through international peer-reviewed publications. TRIAL REGISTRATION NUMBER: NTR7360.

Randomised controlled trial into the role of ramipril in fibrosis reduction in rheumatic heart disease: the RamiRHeD trial protocol.

INTRODUCTION: Rheumatic heart disease (RHD) is a major burden in developing countries and accounts for 80% of all people living with the disease, where it causes most cardiovascular morbidity and mortality in children and young adults. Chronic inflammation and fibrosis of heart valve tissue due to chronic inflammation in RHD will cause calcification and thickening of the impacted heart valves, especially the mitral valve. This fibrogenesis is enhanced by the production of angiotensin II by increased transforming growth factor ß expression and later by the binding of interleukin-33, which is known to have antihypertrophic and antifibrotic effects, to soluble sST2. sST2 binding to this non-natural ligand worsens fibrosis. Therefore, we hypothesise that ACE inhibitors (ACEIs) would improve rheumatic mitral valve stenosis. METHODS AND ANALYSIS: This is a single-centre, double-blind, placebo-controlled, randomised clinical trial with a pre-post test design. Patients with rheumatic mitral stenosis and valve dysfunction will be planned for cardiac valve replacement operation and will be given ramipril 5 mg or placebo for a minimum of 12 weeks before the surgery. The expression of ST2 in the mitral valve is considered to be representative of cardiac fibrosis. Mitral valve tissue will be stained by immunohistochemistry to ST2. Plasma ST2 will be measured by ELISA. This study is conducted in the Department of Cardiology and Vascular Medicine, Universitas Indonesia, National Cardiac Center Harapan Kita Hospital, Jakarta, Indonesia, starting on 27 June 2019. ETHICS AND DISSEMINATION: The performance and dissemination of this study were approved by the ethics committee of National Cardiovascular Center Harapan Kita with ethical code LB.02.01/VII/286/KEP.009/2018. TRIAL REGISTRATION NUMBER: NCT03991910.

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.

Application of speCtraL computed tomogrAphy to impRove specIficity of cardiac compuTed tomographY (CLARITY study): rationale and design.

INTRODUCTION: Anatomic stenosis evaluation on coronary CT angiography (CCTA) lacks specificity in indicating the functional significance of a stenosis. Recent developments in CT techniques (including dual-layer spectral detector CT [SDCT] and static stress CT perfusion [CTP]) and image analyses (including fractional flow reserve [FFR] derived from CCTA images [FFRCT] and deep learning analysis [DL]) are potential strategies to increase the specificity of CCTA by combining both anatomical and functional information in one investigation. The aim of the current study is to assess the diagnostic performance of (combinations of) SDCT, CTP, FFRCT and DL for the identification of functionally significant coronary artery stenosis. METHODS AND ANALYSIS: Seventy-five patients aged 18 years and older with stable angina and known coronary artery disease and scheduled to undergo clinically indicated invasive FFR will be enrolled. All subjects will undergo the following SDCT scans: coronary calcium scoring, static stress CTP, rest CCTA and if indicated (history of myocardial infarction) a delayed enhancement acquisition. Invasive FFR of ≤0.80, measured within 30 days after the SDCT scans, will be used as reference to indicate a functionally significant stenosis. The primary study endpoint is the diagnostic performance of SDCT (including CTP) for the identification of functionally significant coronary artery stenosis. Secondary study endpoint is the diagnostic performance of SDCT, CTP, FFRCT and DL separately and combined for the identification of functionally significant coronary artery stenosis. ETHICS AND DISSEMINATION: Ethical approval was obtained. All subjects will provide written informed consent. Study findings will be disseminated through peer-reviewed conference presentations and journal publications. TRIAL REGISTRATION NUMBER: NCT03139006; Pre-results.