IMPRESS

2021

In the past decade, there has been significant progress in understanding sex- and gender-based differences in cardiovascular diseases (CVD). However, this knowledge remains scattered across medical literature, highlighting the need for a centralized platform accessible to healthcare professionals, scientists, policymakers, and patients. The IMPRESS consortium aims to establish a knowledge platform focused on gathering, summarizing, and prioritizing existing knowledge related to sex- and gender-specific aspects of CVD. This initiative seeks to promote the implementation of existing knowledge into clinical practice, identify knowledge gaps, and inform policymakers about areas requiring additional attention.

In substantial portions of women with symptoms of myocardial ischemia, obstructive disease in the epicardial coronary arteries is absent. Currently, such women undergo multiple diagnostic tests, which do not always result in a conclusive diagnosis. IMPRESS seeks to reduce missed and delayed diagnoses of heart diseases in women, improving cardiovascular care outcomes nationwide. The knowledge platform will serve as a national resource, fostering collaboration and supporting the adoption of sex- and gender-sensitive practices in cardiovascular medicine.

The Research
IMPRESS consolidates existing knowledge, fosters research, and implements findings into practice wherever possible (for example by creating a Decision Support Tool for primary care and for cardiologists). Within the IMPRESS consortium, the following studies are being conducted:

Delphi study: delayed or missed diagnosis of heart disease
Silent heart attacks: causes, symptoms, and risk factors of silent myocardial infarctions
UMCU-IMPRESS pilot study: undetected coronary microvascular disease (CMD)
Peripheral-Flow: LASCA technique in CMD
Dutch registry of coronary function tests

The origin

In the past decade, the understanding of sex- and gender differences in CVD has considerably improved. However, relevant evidence is scattered throughout the medical literature. There is a need to make this information easily accessible to health care professionals, scientists, policy makers and patients. Implementation of existing knowledge in clinical practice will then be promoted, knowledge gaps identified, and policy makers informed on the areas that need additional attention. This is also of high importance to the Dutch Heart Foundation, which therefore funded the IMPRESS consortium; a collaboration between several DCVA partners; the Nederlandse Vereniging voor Cardiologie (NVVC), WCN, Netherlands Heart Institute (NLHI), ZonMw and the Dutch Heart Foundation, supported by the DCVA.

Collaborators

Contact person:

Taieve Stoops

taive.stoops@heart-institute.nl

Principal investigators

Prof. Dr. H. den Ruijter (Hester)

H.M.denRuijter-2@umcutrecht.nl

Prof. Dr. ir. H. Boersma (Eric)

h.boersma@erasmusmc.nl

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Cardiomyopathies, caused by genetic mutations affecting cardiac muscle components, pose significant economic and societal burdens due to their hereditary nature and early onset. Despite known genetic defects, predicting disease progression remains challenging due to extreme clinical variability. Recent research indicates that cardiomyopathy mutations induce metabolic stress, exacerbated by factors like obesity, which can accelerate disease progression. The Double Dose hypothesis suggests that targeting metabolic stress may offer preventive or curative strategies for these conditions.
The Focus
The Double Dose Consortium aims to understand how cardiomyopathy-causing mutations lead to structural changes in cardiomyocytes. This interdisciplinary effort combines experts in preclinical research, clinical genetics, health technology assessment, and clinical care focused on cardiomyopathy in both children and adults.
The Research
The consortium combines experts in preclinical research, clinical genetics, health technology assessment and clinical researchers with a strong clinical focus on cardiomyopathy in children and adults. These experts investigate how obesity and muscle adiposity contribute to vascular and cardiac muscle dysfunction in mutation carriers through the analysis of clinical data, patient samples, and experimental models. They will also study the mechanisms underlying ultrastructural changes in cardiomyocytes caused by these mutations, leading to impaired metabolism, contraction, relaxation defects, and disrupted cellular communication within the heart.
Utilizing extensive patient cohorts and ongoing studies, the consortium aims to optimize care for cardiomyopathy patients by assessing the cost-effectiveness of diagnostics and clinical interventions. They plan to translate findings on metabolic alterations into clinical trials targeting treatments that reduce metabolic stress. The Double Dose program will establish biobanks containing serum, tissue, and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to provide mechanistic insights into cardiomyopathy pathophysiology and improve diagnosis and care.
Origin
This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation, together with Stichting Hartedroom. The consortium is a continuation of the Dosis consortium, in which the interaction between mutation and external factors was investigated. They found that cardiomyopathy-mutations induce metabolic stress and that secondary metabolic stress, such as obesity accelerates disease progression.
 

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Praetorian-covid

2020

The SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the acute respiratory distress syndrome (ARDS). The reninangiotensin-system (RAS) plays an important role in the development of ARDS, with ACE2 (angiotensin-converting enzyme 2) being a key enzyme within this. The virus's spike protein binds to ACE2, facillitating cellular internalization. Downregulation of ACE2 results in the excessive accumulation of angiotensin II, which in turn increases pulmonary vascular permeability through stimulation of the angiotensin II type 1a receptor (AT1R), thereby exacerbating lung pathology associated with decreased ACE2 activity. Currently available AT1R blockers (ARBs) such as valsartan, have shown potential to block this pathological process mediated by angiotensin II.
The Focus
The primary aim of the PRAETORIAN-COVID trial is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death of COVID-19 patients.
The Research
Participants receiving active treatment are administered valsartan at a dosage titrated to blood pressure, with a maximum of 160 mg twice daily. Participants receiving placebo are provided with a matching placebo. The treatment duration was 14 days or until reaching the primary endpoint, or until hospital discharge, if applicable within 14 days.Two complementary mechanisms underpin the potential efficacy of angiotensin II type 1 receptor blockers (ARBs) in preventing acute respiratory distress syndrome (ARDS) and reducing morbidity and mortality:

ARBs block excessive angiotensin-mediated activation of the AT1R.
ARBs upregulate ACE2 expression, leading to reduced angiotensin II levels and increased production of the protective vasodilator angiotensin 1–7.

Given these mechanisms, ARBs show promise in preventing ARDS development, potentially reducing the need for intensive care unit (ICU) admission and mechanical ventilation, and ultimately lowering mortality rates associated with SARS-CoV-2 infection.

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