Multimodality ImAging of Cardiovascular Dysfunction : risk factors, diagnostics and treatment options

Cardiovascular diseases are a major cause of mortality worldwide, and includes all diseases of the heart and circulation. Despite improvements in knowledge and treatment options over the last decades, it remains one of the leading causes of disability and death. The underlying mechanisms vary depending on the disease in question. Some of these risk factors can be avoided, controlled, treated or modified such as high cholesterol, high blood pressure and obesity. While others, such as family history and gender, cannot be avoided and their emphasis lies on monitoring and treatment. In this thesis, the role of DNA damage, atherosclerosis and the renin angiotensin system, factors that modulate cardiovascular damage and disease, are investigated and discussed. Additionally, the effect of nutritional and therapeutic interventions is explored

Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

Aneurysm-osteoarthritis syndrome characterized by unpredictable aortic aneurysm formation, is caused by SMAD3 mutations. SMAD3 is part of the SMAD2/3/4 transcription factor, essential for TGF-β-activated transcription. Although TGF-β-related gene mutations result in aneurysms, the underlying mechanism is unknown. Here, we examined aneurysm formation and progression in Smad3−/− animals. Smad3−/− animals developed aortic aneurysms rapidly, resulting in premature death. Aortic wall immunohistochemistry showed no increase in extracellular matrix and collagen accumulation, nor loss of vascular smooth muscle cells (VSMCs) but instead revealed medial elastin disruption and adventitial inflammation. Remarkably, matrix metalloproteases (MMPs) were not activated in VSMCs, but rather specifically in inflammatory areas. Although Smad3−/− aortas showed increased nuclear pSmad2 and pErk, indicating TGF-β receptor activation, downstream TGF-β-activated target genes were not upregulated. Increased pSmad2 and pErk staining in pre-aneurysmal Smad3−/− aortas implied that aortic damage and TGF-β receptor-activated signaling precede aortic inflammation. Finally, impaired downstream TGF-β activated transcription resulted in increased Smad3−/− VSMC proliferation. Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibil

Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema

Background: In this study we set out to investigate the clinically observed relationship between chronic obstructive pulmonary disease (COPD) and aortic aneurysms. We tested the hypothesis that an

AT1-receptor blockade, but not renin inhibition, reduces aneurysm growth and cardiac failure in fibulin-4 mice

Aims: Increasing evidence supports a role for the angiotensin II-AT 1 -receptor axis in aneurysm development. Here, we studied whether counteracting this axis via stimulation of AT 2 receptors is beneficial. Such stimulation occurs naturally during AT 1 -receptor blockade with losartan, but not during renin inhibition with aliskiren. Methods and results: Aneurysmal homozygous fibulin-4 R/R mice, displaying a four-fold reduced fibulin-4 expression, were treated with placebo, losartan, aliskiren, or the β-blocker propranolol from day 35 to 100. Their phenotype includes cystic media degeneration, aortic regurgitation, left ventricular dilation, reduced ejection fraction, and fractional shortening. Although losartan and aliskiren reduced hemodynamic stress and increased renin similarly, only losartan increased survival. Propranolol had no effect. No drug rescued elastic fiber fragmentation in established aneurysms, although losartan did reduce aneurysm size. Losartan also increased ejection fraction, decreased LV diameter, and reduced cardiac pSmad2 signaling. None of these effects were seen with aliskiren or propranolol. Longitudinal micro-CT measurements, a novel method in which each mouse serves as its own control, revealed that losartan reduced LV growth more than aneurysm growth, presumably because the heart profits both from the local (cardiac) effects of losartan and its effect