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Supplemental material, sj-pdf-1-jao-10.1177_03913988211003912 for A novel intra-ventricular assist device enhances cardiac performance in normal and acutely failing isolated porcine hearts by Daniël IM van Dort, Jos Thannhauser, Wim J Morshuis, Guillaume SC Geuzebroek and Dirk J Duncker in The International Journal of Artificial Organs

Supplemental material, sj-pdf-1-jao-10.1177_03913988211003912 for A novel intra-ventricular assist device enhances cardiac performance in normal and acutely failing isolated porcine hearts by Daniël IM van Dort, Jos Thannhauser, Wim J Morshuis, Guillaume SC Geuzebroek and Dirk J Duncker in The International Journal of Artificial Organs

Additional file 4 Supplementary Figure 4. The mRNA expression level of cell-type-specific markers. Genes labeled red and blue were significantly up- and downregulated in patients versus controls (p < 0.05).

Additional file 13. Supplementary Table 7. Overview of included samples in H3K27ac ChIP-seq, RNAPII ChIP-seq, and RNA-seq experiments.

Additional file 5. Supplementary Figure 5. Gene Ontology (GO) analysis of genes annotated to DARs using ToppFun. a Molecular function enrichment for hyperacetylated regions, b Biological process for hyperacetylated regions, c Cellular component for hyperacetylated regions, d Molecular function for hypoacetylated regions, e Biological process for hypoacetylated regions, f Cellular component for hypoacetylated regions.

Additional file 12. Supplementary Table 6. a An overview of general information of all included human cardiac samples. b An overview of detailed clinical parameters of the included AS patients.

Key points Familial hypercholesterolaemia (FH) causes vascular dysfunction involving reduced nitric oxide (NO) bioavailability and limits exercise-induced vasodilatation in the systemic, but not pulmonary, vasculature. The mechanism(s) underlying blunted exercise-induced systemic vasodilatation in FH are unclear but may involve enhanced endothelin-1 (ET-1)-mediated vasoconstriction resulting from lessened NO-dependent inhibition. In a chronically instrumented swine model of FH, ET-1 receptor inhibition in vivo did not restore systemic exercise-induced vasodilatation but rather revealed a reduced role for ET-1 in regulating systemic and pulmonary vascular tone at rest and during exercise associated with reduced circulating ET-1 in FH swine. In contrast, isolated skeletal muscle arterioles from FH swine exhibited enhanced ET-1 sensitivity due to reduced NO with no change in smooth muscle ET receptor expression. These results increase understanding of FH-associated vascular dysfunction by revealing a novel reduction in ET production and resultant attenuation of ET-dependent vascular tone in vivo in FH. Vascular dysfunction has been associated with familial hypercholesterolaemia (FH), a severe form of hyperlipidaemia. We recently demonstrated that swine with FH exhibit reduced exercise-induced systemic, but not pulmonary, vasodilatation involving reduced nitric oxide (NO) bioavailability. Since NO normally limits endothelin (ET) action, we examined the hypothesis that reduced systemic vasodilatation during exercise in FH swine results from increased ET-mediated vasoconstriction. Systemic and pulmonary vascular responses to exercise were examined in chronically instrumented normal and FH swine in the absence and presence of the ETA/B receptor antagonist tezosentan. Intrinsic reactivity to ET was further assessed in skeletal muscle arterioles. FH swine exhibited similar to 9-fold elevation in total plasma cholesterol versus normal swine. Similar to our recent findings, systemic, not pulmonary, vasodilatation during exercise was reduced in FH swine. Blockade of ET receptors caused marked systemic vasodilatation at rest and during exercise in normal swine that was significantly reduced in FH swine. The reduced role of ET in FH swine in vivo was not the result of decreased arteriolar ET responsiveness, as responsiveness was increased in isolated arterioles. Smooth muscle ET receptor protein content was unaltered by FH. However, circulating plasma ET levels were reduced in FH swine. ET receptor antagonism caused pulmonary vasodilatation at rest and during exercise in normal, but not FH, swine. Therefore, contrary to our hypothesis, FH swine exhibit a generalised reduction in the role of ET in regulating vascular tone in vivo probably resulting from reduced ET production. This may represent a unique vascular consequence of severe familial hypercholesterolaemia.

The epidemic of obesity is recognized as one of the most important public health problems facing the world today. According to 2014 World Health Organization (WHO) data,1 39% of adults worldwide are overweight (body mass index, BMI ≥ 25 kg/m2) and 13% of adults are obese (BMI ≥ 30 kg/m2). Thus, more than half a billion adults worldwide are classified as obese. The prevalence of obesity varies by geographical region, gender and income level. The highest prevalence is found in the USA (61% overweight, 27% obese), closely followed by Europe (59% overweight, 23% obese), with the lowest prevalence in South–East Asia (22% overweight, and 5% obese). In Europe, the vast majority of countries have an overweight prevalence of more than 60%.1 Asians generally have a higher percentage of body fat than Caucasians of the same age, sex and BMI. Even below the usual cut-off of BMI = 25 kg/m2 Asian people seem to be at increased risk for type 2 diabetes.2 This may have implications for obesity diagnostic criteria. Indeed, the proposed optimal BMI cut-off values by WHO in Asian populations seems to vary from 22 to 25 kg/m2 based on the ethnic background. A Consensus Statement for Diagnosis of Obesity, Abdominal Obesity and the Metabolic Syndrome for Asian Indians has suggested the following BMI cut-off values: normal BMI = 18.0–22.9 kg/m2; overweight = 23.0–24.9 kg/m2; and obesity > 25 kg/m2.3 Thus it is indeed debatable whether uniform BMI cut-off values to diagnose obesity and/or for cardiovascular risk stratification purposes can be use worldwide. The use of additional anthropometric measurements e.g. waist-circumference or CT based quantification of abdominal/subcutaneous fat volume could help to better delineate obesity and risk parameters and to implement preventive strategies against obesity in each specific ethnic scenario.

Histological specimen and textbook schematics evoke static pictures of vascular networks. However, the concept of a static system is grossly misleading as vessels and their arrangement into networks exhibit a high degree of adaptation in vessel tone and vessel wall structure.1–3 These adaptive responses include the fast adjustment of vessel diameter by changes in smooth muscle tone, the slower changes of structural vessel diameter, the addition or removal of vessels by angiogenesis (sprouting/splitting), or vascular pruning ( Figure 1 ). It is relevant to distinguish physiological adaptation, maintaining an adequate state of perfusion as well as perfusion reserve, from mal-adaptation, which may occur in the context of pathological conditions, such as a persistent increase in blood pressure. There are also differences between regulatory mechanisms in larger vessels (e.g. remodelling at the site of epicardial stenosis) and those in the microcirculation. Even within the microcirculation vascular control mechanisms are highly dependent on vessel size and type and the extent of changes in vasomotor tone and structure seem to increase with decreasing vessel size.4,5 Adaptive processes in the microcirculation are increasingly emerging as being crucial for maintenance of physiological function and for the development of relevant pathological conditions. This part of the coronary circulation, exhibiting that functional and structural plasticity requires more attention in both basic and clinical science as the basis to develop improved diagnostic and therapeutic approaches. Consequently, the present review will focus on adaptive events occurring in the coronary microcirculation which is beyond the domain of catheter investigation and intravascular imaging. Figure 1 Dynamics of vascular adaptation at various time scale (angioadaptation).57 While tone provides a rapid mechanism to adjust perfusion …