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Oscar Plunde,1,2 Anders Franco-Cereceda,3,4 Magnus Bäck1,4 1Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden; 2Novo Nordisk A/S, Medical & Science, Copenhagen, Denmark; 3Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 4Heart and Vascular Center, Karolinska University Hospital, Stockholm, SwedenCorrespondence: Oscar Plunde, Department of Medicine, Solna, Karolinska Institutet, 17164 Stockholm, Sweden, Tel +46 8-524 800 00, Email oscar.persson@ki.seBackground: Cardio-ankle vascular index (CAV) is a measure of systemic arterial stiffness and has been shown to increase after aortic valve surgery. However, change in CAVI-derived pulse wave morphology has not previously been addressed.Case Study: A 72-year-old female was transferred to a large center for heart valve interventions for evaluation of her aortic stenosis. Few co-morbidities were detected on medical history, other than previous radiation treatment for breast cancer, and no signs of other concomitant cardiovascular disease. The patient was accepted for surgical aortic valve replacement due to severe aortic valve stenosis and arterial stiffness was assessed with CAVI, as part of an ongoing clinical study. The pre-operative CAVI was 4.7 which after surgery increased almost 100% to 9.35. In tandem, the slope of systolic upstroke pulse morphology captured from brachial cuffs was changed from a prolonged flattened pattern to a steeper.Conclusion: After aortic valve replacement surgery due to aortic valve stenosis, in addition to increased CAVI-derived measures of arterial stiffness, the slope of the CAVI-derived upstroke pulse wave morphology changes to a steeper slope. This finding could have implications in the future of aortic valve stenosis screening and utilization of CAVI.Keywords: arterial stiffness, cardio-ankle vascular index, pulse wave morphology, aortic valve stenosis

AIMS: Long-chain polyunsaturated fatty acids (PUFAs) generate diverse bioactive lipid mediators, which tightly regulate vascular inflammation. The effects of omega-3 PUFA supplementation in cardiovascular prevention however remain controversial. In addition to direct dietary intake, fatty acid desaturases (FADS) determine PUFA levels. Increased arterial stiffness represents an independent predictor of mortality and cardiovascular events. The aim of the present study was to determine the association of PUFA intake, FADS1 genotype, and FADS expression with arterial stiffness. METHODS AND RESULTS: A cross-sectional population-based cohort study of 1464 participants without overt cardiovascular disease was conducted. Dietary intake was assessed using a food frequency questionnaire. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV), and the FADS1 locus variant was determined. Blood cell transcriptomics was performed in a subset of 410 individuals. Pulse wave velocity was significantly associated with the FADS1 locus variant. Differential associations between PWV and omega-3 PUFA intake were observed depending on the FADS1 genotype. High omega-3 PUFA intake attenuated the FADS1 genotype-dependent associations. Carriers of the minor FADS1 locus variant exhibited increased expression of FADS2, which is associated with PWV. CONCLUSION: Taken together, these findings point to FADS1 genotype-dependent associations of omega-3 PUFA intake on subclinical cardiovascular disease. These findings may have implications for identifying responders and non-responders to omega-3 PUFA supplementation and open up for personalized dietary counselling in cardiovascular prevention.

Cardiovascular disease is the most common cause of death world-wide where atherosclerosis is the main culprit and aortic valve disease accounts about two percent of all CVD deaths. Atherosclerosis is a lipid and inflammation driven disease that share many features with aortic valve stenosis (AVS). Globally, the prevalence of AVS has been estimated to over 10 million patients and the incidence to over 12 500 new cases annually which is likely increasing due to increased longevity, yet no medical treatment is available. A link between atherosclerosis and AVS has previously been established by overlapping prevalence and common pathobiological hallmarks including lipid infiltration, inflammation, and calcification. Recent genetic studies have demonstrated several loci in which single nucleotide polymorphisms are associated with both diseases. However, there is also evidence pointing to separate etiologies including disease specific genetic risk factors, histopathological differences, and isolated clinical presentation. The aim of this thesis was to establish the interplay between atherosclerosis and AVS. A physiologic part was covered in Article I, specific mechanisms in Article II-IV and molecular epidemiology in Article IV. In Article I, arterial stiffness was determined in a cohort with ascending aortic dilatation and/or aortic valve disease before and after cardiac surgery. Arterial stiffness correlates with atherosclerotic cardiovascular disease and aggravates the increased left ventricular stress in AVS. Cardio-ankle vascular index (CAVI) measures arterial stiffness from the heart to the ankle and was lower in subjects with AVS compared with aortic regurgitation and ascending aortic dilation, before surgery, despite being older. In contrast, aortic stiffness assessed by carotid femoral pulse wave velocity (cfPWV) was not different between the groups. After surgery, CAVI but not cfPWV increased in patients with AVS but remained unchanged in patients undergoing aort

Oscar Plunde,1,2 Magnus Bäck1,2 1Translational Cardiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 2Department of Cardiology, Karolinska University Hospital, Stockholm, SwedenCorrespondence: Magnus Bäck, Department of Cardiology, Karolinska University Hospital, M85, Stockholm, 141 86, Sweden, Tel +46 8 585 800 00, Email magnus.back@ki.seAbstract: The most common cause for interventional valve treatment is aortic stenosis. A cardinal symptom of aortic stenosis is heart failure due to the increased load exerted on the left ventricle. However, the left ventricular load is not solely determined based on the degree of aortic stenosis but is also impacted by arterial stiffness. The combined load can be determined by valvulo-arterial impedance (Zva), which is associated with poor outcome in aortic stenosis. We recently demonstrated low measures of systemic arterial stiffness in patients with aortic stenosis, and that arterial stiffness was increased after surgical aortic valve replacement. The results indicated a masked arterial stiffness in aortic stenosis when using methods incorporating peripheral arterial segments. Available studies using several different methods to assess arterial stiffness in relatively small aortic stenosis cohorts examined before and after either surgical or transcatheter aortic valve replacement/intervention have generated contradictory results. In this commentary, we present a detailed literature review to explore how different methods and measures of arterial stiffness in aortic stenosis capture or not, a masked arterial stiffness in aortic stenosis and possible reasons for the observed results. Future studies validating a non-invasive reproducible method to assess arterial stiffness in aortic stenosis patients could potentially lead to an implementation in pre-interventional risk assessment for aortic stenosis.Keywords: aortic stenosis, arterial stiffness, pulse wave velocity, cardio ankle vascular index, valv

Background: Aortic stenosis (AS) contributes to cardiovascular mortality and morbidity but disease mechanisms remain largely unknown. Recent evidence associates a single nucleotide polymorphism rs174547 within theFADS1gene, encoding FADS1 (fatty acid desaturase 1), with risk of several cardiovascular outcomes, including AS.FADS1encodes a rate-limiting enzyme for omega-3 and omega-6 fatty acid metabolism. The aim of this study was to decipher the local transcriptomic and lipidomic consequences of rs174547 in tricuspid aortic valves from patients with AS. Methods: Expression quantitative trait loci study was performed using data from Illumina Human610-Quad BeadChip, Infinium Global Screening Arrays, and Affymetrix Human Transcriptome 2.0 arrays in calcified and noncalcified aortic valve tissue from 58 patients with AS (mean age, 74.2; SD, 5.9). Fatty acid content was assessed in aortic valves from 25 patients with AS using gas chromatography.Delta 5 and Delta 6 desaturase activity was assessed by the product-to-precursor ratio. Results: The minor C-allele of rs174547, corresponding to the protective genotype for AS, was associated with higher FADS2 mRNA levels in calcified valve tissue, whereas FADS1 mRNA and other transcripts in proximity of the single nucleotide polymorphism were unaltered. In contrast, the FADS1 Delta 5-desaturase activity and the FADS2 Delta 6-desaturase activity were decreased. Finally, docosahexaenoic acid was decreased in calcified tissue compared with non-calcified tissue and C-allele carriers exhibited increased docosahexaenoic acid levels. Overall desaturase activity measured with omega-3 fatty acids was higher in C-allele carriers. Conclusions: The association between the FADS1 genotype and AS may implicate effects on valvular fatty acids.