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Aortic stenosis (AS) is the most common valvular heart disease and most prevalent in the elderly. In the latest decades, a new method for replacement of the aortic valve: transcatheter aortic valve implantation (TAVI) has been introduced. This has enabled treatment of patients who were earlier not candidates for surgery, and has also led to a shift towards TAVI from open surgery for many patients with symptomatic AS. The aims of this thesis were to examine clinical outcomes after TAVI since its implementation in Sweden. In Study I we analysed the burden of disease after TAVI with focus on causes of hospitalisation, hospitalisation patterns and predictors of repeated hospitalisation. We identified that hospitalisations are common and from various indications. Heart failure was the most prevalent diagnosis and efforts should be made to reduce the burden of heart failure hospitalisations. In Study II we performed an external validation of an existing prediction model of risk for short-term hospitalisations after TAVI. The model underperformed in a Swedish setting and it is therefore not recommended for clinical use in its current state. The findings highlight the challenges of developing reliable models that are valid after transportation into a new setting. In Study III we investigated regional differences in availability to TAVI in Sweden with focus on regional procedure rates, short-term mortality and waiting times. The findings indicated no major regional differences. Hence, despite that Sweden is a geographically large and sparsely populated country the current system with a few specialised TAVI centres seems sufficient for providing national coverage of TAVI procedures. In Study IV we examined the need for and indications for coronary interventions after TAVI. We concluded that most patients do not need interventions after TAVI and in case an intervention is needed, the outcome is in a majority of cases successful, even though the success rates are lower than in

The human heart and lungs constitute an intricate and dynamic system. Various clinical physiological examinations can be used to evaluate cardio-pulmonary function and identify abnormalities. Thus, it is important to understand how normal physiology presents, to be able to identify pathological findings. To distinguish normal from abnormal findings in a patient population compared to healthy controls, adequate, accurate and up-to-date reference materials are required. There is currently a lack of well-established sex and age specific reference materials that clearly state boundaries of normality for electrocardiography (ECG) variables. For lung function examinations there are several different reference materials available, being discordant between ethnicities. In addition, the relation between lung function, age, sex, and height has generally been difficult to model in an optimal way. This highlights the need for more adequate sex-specific models regarding age- and height-dependency of spirometry variables. Heart rate variability (HRV) is a method for evaluating the autonomic nervous system (ANS) and its influence on heart rate and blood pressure. Autonomic disturbances are characterized by an imbalance between the sympathetic and the parasympathetic nervous systems. It is well known that decreased HRV is associated with increased mortality. Autonomic imbalances are also associated with various pathological conditions, of which rheumatoid arthritis (RA) and ischemic heart disease (IHD) are studied in this thesis. The purpose of this thesis was to describe the properties of different clinical physiological examinations and to investigate reference values relating to cardiovascular and pulmonary function in healthy individuals regarding age and sex. In addition, the aim was to assess the relationship between HRV, RA and CVD both cross sectionally and longitudinally. In a subjectively healthy population (n=219) of varying age, there were age and sex-dependent diffe

Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice. In cardiac surgery, the negative influence of AF on short- and long-term outcomes has made concomitant ablation procedures more common. The indications, clinical aspects, results, risks, and benefits of the additional surgical ablation are still valuable topics for discussion. This compilation thesis consists of four papers aiming to investigate some of the clinical, biochemical, and echocardiographic aspects of surgical ablation for AF (Cox-Maze IV) when performed concomitant to mitral valve surgery (MVS). Through a retrospective, case-control, single-center study, we described the impact of the Cox-Maze IV procedure added to MVS with focus on postoperative heart failure (paper I). Cryoenergy (cryo) and radiofrequency (RF) are the two different energy sources mainly used in Cox-Maze IV for AF ablation. To achieve linear scars in the atrial wall, the RF procedure uses heat damage, whereas the cryo method freezes down to -150°C. Through a prospective, randomized, longitudinal, controlled study, we compared the biochemical responses of the two ablative methods in concomitant MVS and the release of enzymes expressing myocardial injury, as well as inflammatory, cell stress, and apoptosis-specific proteins. We could show that cryo results in a larger release of markers for myocardial damage but has no impact on the early inflammatory response (paper II). Extended scar lesions resulting after maze may influence atrial function. As the left atrium plays a key role in the altered cardiac hemodynamics in AF, an echocardiographic analysis of the effects of the Cox-Maze IV procedure concomitant to MVS on the left atrium was carried out. The impacts of the two energy sources (cryo and RF) on left atrial remodeling and function had not been compared previously. Their direct effect on left atrial remodeling and mechanical function were assessed 1 year after surgery in patients with restored sinus rh, Förmaksflimmer (FF) är den vanligaste arytmin som ses i klinisk praxis. Inom hjärtkirurgi har den negativa inverkan på kort- och långtidsutfall för patienter med FF gjort samtidiga ablationsprocedurer vanligare. Indikationerna, de kliniska aspekterna, resultaten, riskerna och fördelarna med den extra kirurgiska ablationen är fortfarande under diskussion. Den aktuella avhandligen består av fyra artiklar som syftar till att undersöka några av de kliniska, biokemiska och ekokardiografiska aspekterna av kirurgisk ablation vid förmaksflimmer (Cox-Maze IV) när det utförs samtidigt med mitralisklaffkirurgi. I en retrospektiv fallkontrollstudie beskrev vi effekten av Cox-Maze IVproceduren som tillägg till mitralisklaffkirurgin med fokus på postoperativ hjärtsvikt (första artikeln). Kryo och Radiofrekvens är de två olika energikällorna som huvudsakligen används vid Cox-Maze IV för FF-ablation. För att uppnå ärrlinjer i förmaksväggen använder Radiofrekvens-proceduren värmeskada, medan Kryo-metoden fryser ner vävnader till minus 150º C grader Celsius. En jämförelse av de biokemiska svaren presenteras mellan de två ablativa metoderna vid samtidig mitralisklaffkirurgi. Frisättningen av biokemiska markörer som uttrycker myokardskada samt inflammatoriska, cellstress- och apoptosspecifika (celldödsspecifika) proteiner rapporteras. Genom en prospektiv randomiserad longitudinell kontrollerad studie kunde vi visa att Kryo hade en större frisättning av hjärtskademarkörer, men ingen inverkan på tidig inflammatorisk respons (andra artikeln). Ärrskador som uppstår efter Cox-Maze IV kan påverka förmaksfunktionen. Eftersom det vänstra förmaket spelar en nyckelroll vid förmaksflimmer förändrade hemodynamiken, genomfördes en ekokardiografisk analys av effekterna av Cox-Maze IV-proceduren samtidigt med mitralisklaffkirurgi på vänster förmak. Effekten av de två energikällorna (Kryo och Radiofrekvens) på vänster förmaks remodeling och funktion har inte jämförts tidigare på ett prospektivt sätt.

Red blood cells (RBCs) mediate cardioprotection via nitric oxide-like bioactivity, but the signaling and the identity of any mediator released by the RBCs remains unknown. We investigated whether RBCs exposed to hypoxia release a cardioprotective mediator and explored the nature of this mediator. Perfusion of isolated hearts subjected to ischemia-reperfusion with extracellular supernatant from mouse RBCs exposed to hypoxia resulted in improved postischemic cardiac function and reduced infarct size. Hypoxia increased extracellular export of cyclic guanosine monophosphate (cGMP) from mouse RBCs, and exogenous cGMP mimicked the cardioprotection induced by the supernatant. The protection induced by hypoxic RBCs was dependent on RBC-soluble guanylate cyclase and cGMP transport and was sensitive to phosphodiesterase 5 and activated cardiomyocyte protein kinase G. Oral administration of nitrate to mice to increase nitric oxide bioactivity further enhanced the cardioprotective effect of hypoxic RBCs. In a placebo-controlled clinical trial, a clear cardioprotective, soluble guanylate cyclase-dependent effect was induced by RBCs collected from patients randomized to 5 weeks nitrate-rich diet. It is concluded that RBCs generate and export cGMP as a response to hypoxia, mediating cardioprotection via a paracrine effect. This effect can be further augmented by a simple dietary intervention, suggesting preventive and therapeutic opportunities in ischemic heart disease.

OBJECTIVES: The aim included investigation of the associations between sedentary (SED), low-intensity physical activity (LIPA), moderate-to-vigorous intensity PA (MVPA) and the prevalence of subclinical atherosclerosis in both coronaries and carotids and the estimated difference in prevalence by theoretical reallocation of time in different PA behaviours. DESIGN: Cross-sectional. SETTING: Multisite study at university hospitals. PARTICIPANTS: A total of 22 670 participants without cardiovascular disease (51% women, 57.4 years, SD 4.3) from the population-based Swedish CArdioPulmonary bioImage study were included. SED, LIPA and MVPA were assessed by hip-worn accelerometer. PRIMARY AND SECONDARY OUTCOMES: Any and significant subclinical coronary atherosclerosis (CA), Coronary Artery Calcium Score (CACS) and carotid atherosclerosis (CarA) were derived from imaging data from coronary CT angiography and carotid ultrasound. RESULTS: High daily SED (>70% ≈10.5 hours/day) associated with a higher OR 1.44 (95% CI 1.09 to 1.91), for significant CA, and with lower OR 0.77 (95% CI 0.63 to 0.95), for significant CarA. High LIPA (>55% ≈8 hours/day) associated with lower OR for significant CA 0.70 (95% CI 0.51 to 0.96), and CACS, 0.71 (95% CI 0.51 to 0.97), but with higher OR for CarA 1.41 (95% CI 1.12 to 1.76). MVPA above reference level, >2% ≈20 min/day, associated with lower OR for significant CA (OR range 0.61-0.67), CACS (OR range 0.71-0.75) and CarA (OR range 0.72-0.79). Theoretical replacement of 30 min of SED into an equal amount of MVPA associated with lower OR for significant CA, especially in participants with high SED 0.84 (95% CI 0.76 to 0.96) or low MVPA 0.51 (0.36 to 0.73). CONCLUSIONS: MVPA was associated with a lower risk for significant atherosclerosis in both coronaries and carotids, while the association varied in strength and direction for SED and LIPA, respectively. If causal, clinical implications include avoiding high levels of daily SED and low le

Background: Current evidence suggests that use of intracoronary imaging during percutaneous coronary intervention (PCI) of the left main coronary artery (LMCA) reduces mortality. However, there is a scarcity of data on the overall role of intracoronary imaging, particularly in other non-LMCA proximal coronary artery lesions. We aimed to investigate the association of use of intracoronary imaging on outcome in proximal lesions treated with PCI. Methods: The Swedish Coronary Angiography and Angioplasty Registry was used to identify all proximal coronary artery lesions treated with stent implantation between June 11, 2013, and January 16, 2021. Proximal coronary artery lesions (LMCA, proximal left anterior descending artery, left circumflex artery, and right coronary artery) assessed by intracoronary imaging before and/or after stent implantation were matched to control lesions treated based on angiography alone using propensity score matching. The primary end point was target lesion revascularization with PCI, and secondary end points included all-cause mortality and definite stent thrombosis within 3 years. Results: Among the 3623 matched pairs, intracoronary imaging was associated with significantly lower risk of target lesion revascularization, 3.7% vs 4.7%; hazard ratio (HR), 0.77; 95% CI, 0.61-0.97; P = .025, and all-cause mortality, 9.1% vs 12.8%; HR, 0.70; 95% CI, 0.61-0.81; P < .001, with no difference in definite stent thrombosis. Conclusions: The use of intracoronary imaging in proximal coronary artery lesions is associated with lower rates of repeat revascularization and better survival. The results appear to be primarily driven by improved outcome of LMCA lesions. These results reinforce the role of intracoronary imaging in assessing and treating proximal coronary lesions., This work was supported by The Swedish Heart-Lung Foundation, Knut and Alice Wallenberg Foundation, ALF, Skane University Hospital funds, Märta Winkler Foundation, Thorsten Westerströms Foundation,and the Anna-Lisa and Sven-Eric Lundgren Foundation for Medical Research.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals that have been linked to increased cholesterol levels and thus may have a role in the development of cardiovascular disease (CVD). OBJECTIVES: To investigate associations between PFAS exposure and incident CVD (a combined CVD end-point consisting of myocardial infarction, ischemic stroke, or heart failure) in two independent population-based cohorts in Sweden. In addition, we performed a meta-analysis also including results from previous studies. METHODS: In 2,278 subjects aged 45-75 years from the EpiHealth study, the risk of incident CVD in relation to relative plasma levels of perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) was investigated. Associations between plasma levels of six PFAS and incident CVD were also examined in the PIVUS-study (n = 1,016, all aged 70 years). In addition, a meta-analysis was performed including three previous prospective studies, together with the results from the present study. RESULTS: There were no overall statistically significant associations between levels of the different PFAS and incident CVD, neither in EpiHealth nor in PIVUS. However, there was a significant sex interaction for PFOS in EpiHealth (p = 0.008), and an inverse association could be seen only in men (Men, HR: 0.68, 95 % CI: 0.52, 0.89) (Women, HR: 1.13, 95 % CI: 0.82, 1.55). A meta-analysis of five independent studies regarding PFOA and incident CVD showed a risk ratio (RR) of 0.80 (CI: 0.66, 0.94) when high levels were compared to low levels. CONCLUSIONS: This longitudinal study using data from two population-based cohort studies in Sweden did not indicate any increased risk of incident CVD for moderately elevated PFAS levels. A meta-analysis of five independent cohort studies rather indicated a modest inverse association between PFOA levels and incident CVD, further supporting that increasing PFAS levels are not linked to

Background The majority of patients survive the acute phase of myocardial infarction (MI) but have an increased risk of recurrent cardiovascular disease (CVD) events. To be regularly physically active or change activity level is associated with a lower risk of all-cause mortality. The objective was to explore to what extent physical activity (PA) levels or change in PA levels during the first year post-MI was associated with any recurrent nonfatal CVD events and specific CVD events (eg, MI, ischemic stroke, and vascular dementia). Methods and Results This cohort study among MI survivors was based on Swedish national registries between 2005 and 2020. PA levels were self-rated at 2 and 12 months post-MI, and patients were classified into remaining physically inactive, increasing, decreasing, or remaining active. A total of 6534 nonfatal CVD events occurred during 6 years of follow-up among the 47 153 included patients. In fully adjusted analyses, the risk of any nonfatal CVD event was lower (P<0.05) among patients remaining active (37%), increasing (22%), or decreasing (18%) PA level compared with remaining inactive. Compared with remaining inactive, the risk of recurring MI and stroke was lower (P>0.05) among remaining active (41% versus 52%, respectively), increasing (20% versus 35%, respectively), or decreasing PA level (24% versus 34%, respectively). For vascular dementia, patients remaining physically active had an 80% lower risk compared with remaining inactive (P<0.05). Conclusions Remaining physically active or change in PA levels during the first year post-MI was associated with a lower risk of recurrent nonfatal CVD events. This emphasizes the importance of supporting patients to continue to be or become physically active.

AIMS: Central to the practice of precision medicine in percutaneous coronary intervention (PCI) is a risk-stratification tool to predict outcomes following the procedure. This study is intended to assess machine learning (ML)-based risk models to predict clinically relevant outcomes in PCI and to support individualized clinical decision-making in this setting. METHODS AND RESULTS: Five different ML models [gradient boosting classifier (GBC), linear discrimination analysis, Naïve Bayes, logistic regression, and K-nearest neighbours algorithm) for the prediction of 1-year target lesion failure (TLF) were trained on an extensive data set of 35 389 patients undergoing PCI and enrolled in the global, all-comers e-ULTIMASTER registry. The data set was split into a training (80%) and a test set (20%). Twenty-three patient and procedural characteristics were used as predictive variables. The models were compared for discrimination according to the area under the receiver operating characteristic curve (AUC) and for calibration. The GBC model showed the best discriminative ability with an AUC of 0.72 (95% confidence interval 0.69-0.75) for 1-year TLF on the test set. The discriminative ability of the GBC model for the components of TLF was highest for cardiac death with an AUC of 0.82, followed by target vessel myocardial infarction with an AUC of 0.75 and clinically driven target lesion revascularization with an AUC of 0.68. The calibration was fair until the highest risk deciles showed an underestimation of the risk. CONCLUSION: Machine learning-derived predictive models provide a reasonably accurate prediction of 1-year TLF in patients undergoing PCI. A prospective evaluation of the predictive score is warranted. REGISTRATION: Clinicaltrial.gov identifier is NCT02188355., Funding Agency:Terumo Europe NV, Leuven, Belgium

INTRODUCTION: There is no consensus on the impact of coronary artery disease in patients undergoing transcatheter aortic valve implantation. Therefore, the objective of this study was, in a single-center setting, to evaluate the five-year outcome of transcatheter aortic valve implantation patients with or without coronary artery disease. METHODS: All transcatheter aortic valve implantation patients between 2009 and 2019 were included and grouped according to the presence or absence of coronary artery disease. The primary endpoint, five-year all-cause mortality, was evaluated using Cox regression adjusted for age, sex, procedure years, and comorbidities. Comorbidities interacting with coronary artery disease were evaluated with interaction tests. In-hospital complications was the secondary endpoint. RESULTS: In total, 176 patients had aortic stenosis and concomitant coronary artery disease, while 170 patients had aortic stenosis only. Mean follow-up was 2.2±1.6 years. There was no difference in the adjusted five-year all-cause mortality between transcatheter aortic valve implantation patients with and without coronary artery disease (hazard ratio 1.00, 95% confidence interval 0.59-1.70, P=0.99). In coronary artery disease patients, impaired renal function, peripheral arterial disease, or ejection fraction < 50% showed a significant interaction effect with higher five-year all-cause mortality. No significant differences in complications between the groups were found. CONCLUSION: Five-year mortality did not differ between transcatheter aortic valve implantation patients with or without coronary artery disease. However, in patients with coronary artery disease and impaired renal function, peripheral arterial disease, or ejection fraction < 50%, we found significantly higher five-year all-cause mortality.

Humans show a population-level preference for using the right hand. The fighting hypothesis is an influential theory that suggests that left-handedness persists because its rarity provides a surprise advantage in fighting interactions, and that left-handedness is less frequent because it has a health cost. However, evidence for the health cost of left-handedness is unsubstantiated, leaving the greater frequency of right-handers unexplained. Research indicates that homicide may have been common in early hominins. We propose that the hand used to hold a weapon by early hominins could have influenced the outcome of a fight, due to the location of the heart and aorta. A left-handed unilateral grip exposes the more vulnerable left hemithorax towards an opponent, whereas a right-hand unilateral grip exposes the less vulnerable right hemithorax. Consequently, right-handed early ancestors, with a preference for using the right forelimb in combat, may have had a lower risk of a mortal wound, and a fighting advantage. This would explain their greater frequency. In accordance with the original fighting hypothesis, we also suggest that left-handed fighters have a surprise advantage when they are rare, explaining their persistence. We discuss evidence for the modified fighting hypothesis, its predictions, and ways to test the theory.

INTRODUCTION: Atrial fibrillation (AF) is a major risk factor for ischaemic stroke and transient ischaemic attack (TIA), and AF detection can be challenged by asymptomatic and paroxysmal presentation. Long-term ECG monitoring after ischaemic stroke or TIA is recommended by all major societies in cardiology and cerebrovascular medicine as a secondary prophylactic measure. However, data on stroke reduction are lacking, and the recommendations show significant diversity. METHODS AND ANALYSIS: AF SPICE is a multicentre, national, investigator-initiated, randomised, parallel-group, register-based trial comparing extended ECG monitoring versus standard ECG monitoring in patients admitted with ischaemic stroke or TIA, with a composite endpoint of stroke, all-cause-mortality and intracerebral bleeding. Patients aged ≥70 years without previous AF will be randomised 1:1 to control (standard ECG monitoring) or intervention (extended ECG monitoring). In the control arm, patients will undergo 48±24 hours (ie, a range of 24-72 hours) of continuous ECG monitoring according to national recommendations. In the intervention arm, patients will undergo 14+14 days of continuous ECG monitoring 3 months apart using an ECG patch device, which will provide an easy-accessed, well-tolerated 14-day continuous ECG recording. All ECG patch recordings will be read in a core facility. In cases of AF detection, oral anticoagulation will be recommended if not contraindicated. A pilot phase has been concluded in 2022, which will transcend into the main trial during 2023-2026, including approximately 30 stroke units. The sample size was calculated to be 3262 patients. The primary outcome will be collected from register data during a 36-month follow-up. ETHICS AND DISSEMINATION: Ethical approval has been provided by the Swedish Ethical Review Authority, reference 2021-02770. The trial will be conducted according to the ethical principles of the Declaration of Helsinki and national regulatory standards.

BACKGROUND AND AIMS: Patients with long atrial high-rate episodes (AHRE) ≥ 24 hours and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared to no anticoagulation in these patients. METHODS: This secondary prespecified analysis of NOAH-AFNET 6 examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared to placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and ECG-diagnosed atrial fibrillation. RESULTS: AHRE ≥24 hours were present at baseline in 259/2389 patients enrolled in NOAH-AFNET 6 (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc score 4). Clinical characteristics were not different from patients with shorter AHRE. During a median follow-up of 1.8 years, the primary outcome occurred in 9/132 patients with AHRE ≥24 hours (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). AHRE duration did not interact with the efficacy (p-interaction = 0.65) or safety (p-interaction = 0.98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 hours developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; p < 0.001). CONCLUSIONS: This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk.

Influenza vaccination reduces the risk of adverse cardiovascular events.The IAMI trial randomly assigned 2571 patients with acute myocardial infarction (AMI) to receive influenza vaccine or saline placebo during their index hospital admission. It was conducted at 30 centers in 8 countries from October 1, 2016 to March 1, 2020. In this post-hoc exploratory sub-study, we compare the trial outcomes in patients receiving early season vaccination (n = 1188) and late season vaccination (n = 1344).The primary endpoint wasthe composite of all-cause death, myocardial infarction (MI), or stent thrombosis at 12 months. Thecumulative incidence of the primary and key secondary endpoints by randomized treatment and early or late vaccination was estimated using the Kaplan-Meier method. In the early vaccinated group, the primary composite endpoint occurred in 36 participants (6.0%) assigned to influenza vaccine and 49 (8.4%) assigned to placebo (HR 0.69; 95% CI 0.45 to 1.07), compared to 31 participants (4.7%) assigned to influenza vaccine and 42 (6.2%) assigned to placebo (HR 0.74; 95% CI 0.47 to 1.18) in the late vaccinated group (P = 0.848 for interaction on HR scale at 1 year). We observed similar estimates for the key secondary endpoints of all-cause death and CV death. There was no statistically significant difference in vaccine effectiveness against adverse cardiovascular events by timing of vaccination. The effect of vaccination on all-cause death at one year was more pronounced in the group receiving early vaccination (HR 0.50; 95% CI, 0.29 to 0.86) compared late vaccination group (HR 0.75; 35% CI, 0.40 to 1.40) but there was no statistically significant difference between these groups (Interaction P = 0.335). In conclusion,there is insufficient evidence from the trial to establish whether there is a difference in efficacy between early and late vaccinationbut regardless of vaccination timing we strongly recommended influenza vaccination in all patients with cardiovascular

Background and Aims: Peripheral arterial disease (PAD) is a clinical manifestation of atherosclerosis, affecting arteries in the leg. Based on their symptoms and severity, PAD patients are characterized into three sub-groups: asymptomatic, intermittent claudication (IC) and critical limb ischemia (CLI). Despite its high prevalence, PAD remains under diagnosed and the role of immune cells in PAD pathophysiology remains poorly understood. In this study, we characterized the innate immune responses in PAD patients compared to healthy controls. Methods: Blood samples were collected from 14 patients with PAD (IC) and 30 healthy controls, to assess the phenotype of monocytes and neutrophils by using 10-colour flow cytometry. Phagocytosis assay was performed with labelled E.coli particles. Mann-Whitney U non-parametrical test was used for statistical comparison between PAD patients and healthy controls. Results: A significant higher proportion of leukocytes (p<0.05) and neutrophils (p<0.01) was observed in PAD patients compared to healthy controls, whereas monocyte subsets showed no significant differences. Interestingly, neutrophils showed a significantly impaired phagocytosis capability (p<0.05) and reduced expression of myeloperoxidase (MPO) (p<0.05) in PAD patients compared to healthy controls. Conclusions: Taken together these results, suggest that PAD patients have an increased proportion of neutrophils in circulation, with impaired phagocytosis capability, compared to healthy controls.

Background and Aims: Cells within atherosclerotic lesions have a higher glutamine demand than cells in healthy vessel although glutaminase, the enzyme converting glutamine to glutamate, is significantly downregulated in human carotid lesions. This may suggest rewiring of glutamine metabolic pathways in atherosclerotic lesions, caused by infiltrating immune cells and or their cytokines. Here we aimed at exploring the enzymes and transporters involved in glutamine metabolism in human carotid atherosclerotic tissues and aortic smooth muscle cells (hAoSMCs) exposed to interferon gamma. Methods: Protein and mRNA from interferon gamma-treated hAoSMCs were subjected to Western blot or qRT-PCR for quantification of enzymes and transporters involved in glutamine metabolism. H2DCFDA probe was utilized for detection of intracellular reactive oxygen species (ROS) using flow cytometry. The expression of these enzymes and transporters was also evaluated in human carotid lesions (GEO accession: GSE43292). Results: Interferon-treated hAoSMCs display a significantly lower expression of glutaminase followed by an increase in the expression of glutamine transporters, glutamine synthetase and glutamine-fructose-6-phosphate transaminase-1 (GFPT1). The level of ROS and the expression of enzymes involved in de novo synthesis of glutathione are elevated in interferon-treated cells. A similar expression pattern for these genes, expect for GFPT1, is also evident in human carotid lesions where glutaminase mRNA shows a strong positive correlation with SMC markers and a strong negative correlation with macrophage markers. Conclusions: Glutamine metabolism is disrupted in human carotid lesions and interferon gamma alters glutamine metabolism in hAoSMCs, which may favor the production of UDP-GlcNAc and reactive oxygen species.

Background: Deferral of coronary revascularization is safe whether guided by instantaneous wave-free ratio (iFR) or by fractional flow reserve (FFR). We aimed to assess long-term outcomes in patients deferred from revascularization based on iFR or FFR in a large real-world population. Methods: From 2013 through 2017, 201,933 coronary angiographies were registered in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). We included all patients (n = 11,324) with at least 1 coronary lesion deferred from PCI during an index procedure using iFR (>0.89; n = 1998) or FFR (>0.80; n = 9326). The primary outcome was major adverse cardiac events (MACE) defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization. A multivariable-adjusted Cox proportional hazards model was used, with analysis for interaction of prespecified subgroups. Results: Patients presented with stable angina pectoris (iFR 46.9% vs FFR 48.6%), unstable angina or non–ST-elevation myocardial infarction (iFR 37.7% vs FFR 33.1%), ST-elevation myocardial infarction (iFR 1.9% vs FFR 1.6%), and other indications (iFR 12.5% vs FFR 15.7%). The median follow-up was 2 years for both iFR and FFR groups. At the conclusion of the study, the cumulative MACE risks were 26.7 for the iFR group and 25.9% for FFR group. In the adjusted analysis, no difference was found between the 2 groups (adjusted hazard ratio: iFR vs FFR, 0.947; 95% CI, 0.84-1.08; P = 39). Consistent with the overall findings, the prespecified subgroups showed no interaction with the FFR/iFR results. Conclusions: Deferral of revascularization showed similar long-term safety whether based on iFR or on FFR.

OBJECTIVES: The aim included investigation of the associations between sedentary (SED), low-intensity physical activity (LIPA), moderate-to-vigorous intensity PA (MVPA) and the prevalence of subclinical atherosclerosis in both coronaries and carotids and the estimated difference in prevalence by theoretical reallocation of time in different PA behaviours. DESIGN: Cross-sectional. SETTING: Multisite study at university hospitals. PARTICIPANTS: A total of 22 670 participants without cardiovascular disease (51% women, 57.4 years, SD 4.3) from the population-based Swedish CArdioPulmonary bioImage study were included. SED, LIPA and MVPA were assessed by hip-worn accelerometer. PRIMARY AND SECONDARY OUTCOMES: Any and significant subclinical coronary atherosclerosis (CA), Coronary Artery Calcium Score (CACS) and carotid atherosclerosis (CarA) were derived from imaging data from coronary CT angiography and carotid ultrasound. RESULTS: High daily SED (>70% ≈10.5 hours/day) associated with a higher OR 1.44 (95% CI 1.09 to 1.91), for significant CA, and with lower OR 0.77 (95% CI 0.63 to 0.95), for significant CarA. High LIPA (>55% ≈8 hours/day) associated with lower OR for significant CA 0.70 (95% CI 0.51 to 0.96), and CACS, 0.71 (95% CI 0.51 to 0.97), but with higher OR for CarA 1.41 (95% CI 1.12 to 1.76). MVPA above reference level, >2% ≈20 min/day, associated with lower OR for significant CA (OR range 0.61-0.67), CACS (OR range 0.71-0.75) and CarA (OR range 0.72-0.79). Theoretical replacement of 30 min of SED into an equal amount of MVPA associated with lower OR for significant CA, especially in participants with high SED 0.84 (95% CI 0.76 to 0.96) or low MVPA 0.51 (0.36 to 0.73). CONCLUSIONS: MVPA was associated with a lower risk for significant atherosclerosis in both coronaries and carotids, while the association varied in strength and direction for SED and LIPA, respectively. If causal, clinical implications include avoiding high levels of daily SED and low le

Red blood cells (RBCs) mediate cardioprotection via nitric oxide-like bioactivity, but the signaling and the identity of any mediator released by the RBCs remains unknown. We investigated whether RBCs exposed to hypoxia release a cardioprotective mediator and explored the nature of this mediator. Perfusion of isolated hearts subjected to ischemia-reperfusion with extracellular supernatant from mouse RBCs exposed to hypoxia resulted in improved postischemic cardiac function and reduced infarct size. Hypoxia increased extracellular export of cyclic guanosine monophosphate (cGMP) from mouse RBCs, and exogenous cGMP mimicked the cardioprotection induced by the supernatant. The protection induced by hypoxic RBCs was dependent on RBC-soluble guanylate cyclase and cGMP transport and was sensitive to phosphodiesterase 5 and activated cardiomyocyte protein kinase G. Oral administration of nitrate to mice to increase nitric oxide bioactivity further enhanced the cardioprotective effect of hypoxic RBCs. In a placebo-controlled clinical trial, a clear cardioprotective, soluble guanylate cyclase-dependent effect was induced by RBCs collected from patients randomized to 5 weeks nitrate-rich diet. It is concluded that RBCs generate and export cGMP as a response to hypoxia, mediating cardioprotection via a paracrine effect. This effect can be further augmented by a simple dietary intervention, suggesting preventive and therapeutic opportunities in ischemic heart disease.

AIM: To investigate the association between change in cardiorespiratory fitness (CRF) and cardiovascular disease (CVD)-related and all-cause hospital admission, and explore if the association varies dependent on prior admission, baseline CRF, sex, and age. METHODS: 91,140 adult participants (41.5% women) with two examinations from occupational health profile assessments between 1986 and 2019 were included (mean 3.2-years between examinations). CRF was assessed as maximal oxygen consumption and estimated through a submaximal cycle test. CRF change was defined as annual percentage change in relative CRF (mL*min-1*kg-1) and further divided into "decliners" (<-1%), "maintainers" (-1%; 1%), and "increasers" (>1%). Hospital admissions were followed over a mean of 7-years. Natural cubic splines and Cox's proportional hazards model were applied. Additionally, prevented fraction for the population was calculated. RESULTS: Increase in CRF was associated with lower risk of CVD [HR = 0.99] and all-cause hospital admission [HR = 0.99], after multilevel-adjustment for confounders and change in smoking, diet, and stress. Compared to a decline, maintenance of CRF was associated with 9% and 7% lower risk of CVD and all-cause admission, respectively. Increase in CRF reduced the risk with 13% and 11%, and for individuals with prior admission, with 20% and 14%. The burden of CVD and all-cause admission was 6% and 5% lower than if the whole cohort had declined CRF, with large potential cost-savings. CONCLUSIONS: Efforts to maintain or improve CRF should be included in disease preventive strategies, regardless of change in other lifestyle-related risk factors. Preventing the age-associated decline in CRF can lessen healthcare utilization and costs.

Background The majority of patients survive the acute phase of myocardial infarction (MI) but have an increased risk of recurrent cardiovascular disease (CVD) events. To be regularly physically active or change activity level is associated with a lower risk of all-cause mortality. The objective was to explore to what extent physical activity (PA) levels or change in PA levels during the first year post-MI was associated with any recurrent nonfatal CVD events and specific CVD events (eg, MI, ischemic stroke, and vascular dementia). Methods and Results This cohort study among MI survivors was based on Swedish national registries between 2005 and 2020. PA levels were self-rated at 2 and 12 months post-MI, and patients were classified into remaining physically inactive, increasing, decreasing, or remaining active. A total of 6534 nonfatal CVD events occurred during 6 years of follow-up among the 47 153 included patients. In fully adjusted analyses, the risk of any nonfatal CVD event was lower (P<0.05) among patients remaining active (37%), increasing (22%), or decreasing (18%) PA level compared with remaining inactive. Compared with remaining inactive, the risk of recurring MI and stroke was lower (P>0.05) among remaining active (41% versus 52%, respectively), increasing (20% versus 35%, respectively), or decreasing PA level (24% versus 34%, respectively). For vascular dementia, patients remaining physically active had an 80% lower risk compared with remaining inactive (P<0.05). Conclusions Remaining physically active or change in PA levels during the first year post-MI was associated with a lower risk of recurrent nonfatal CVD events. This emphasizes the importance of supporting patients to continue to be or become physically active.

Cardiovascular diseases (CVD) rank among the leading global causes of mortality. Early detection and diagnosis are paramount in minimizing their impact. The application of ML and DL in classifying the occurrence of cardiovascular diseases holds significant potential for reducing diagnostic errors. This research endeavors to construct a model capable of accurately predicting cardiovascular diseases, thereby mitigating the fatality associated with CVD. In this paper, the authors introduce a novel approach that combines an artificial intelligence network (AIN)-based feature selection (FS) technique with cutting-edge DL and ML classifiers for the early detection of heart diseases based on patient medical histories. The proposed model is rigorously evaluated using two real-world datasets sourced from the University of California. The authors conduct extensive data preprocessing and analysis, and the findings from this study demonstrate that the proposed methodology surpasses the performance of existing state-of-the-art methods, achieving an exceptional accuracy rate of 99.99%. © 2023 IGI Global. All rights reserved., Funding: The Researchers Supporting Project (No. RSPD2023R609), King Saud University, Riyadh, Saudi Arabia.

Background: According to the current guidelines, evidence of the effects of transcatheter closure in patients aged ≥60 years with an atrial shunt and cryptogenic stroke is still limited. Methods: Using Swedish health registries, patients aged ≥60 years who had previously developed a cryptogenic cerebrovascular event and undergone transcatheter closure were identified. Patients with atrial fibrillation were excluded, and the remaining patients were propensity score-matched with patients of the same age and risk profile who had only undergone medical treatment and with controls from the general population. They were then followed up until 2017 (mean period of 7.1 ±3.9 years). Results: In total, 100 patients of the intervention group were matched with 100 patients of the medical treatment group and with 100 controls and followed up. The hazard ratio for a recurrent ischemic stroke in the intervention group compared with the medical treatment group was 0.8 (95% confidence interval, 0.3–2.1), and that compared with the controls was 2.3 (95% confidence interval, 0.6–8.9). Atrial fibrillation occurred at the same rate in the two treatment groups (odds ratio, 0.8; 95% confidence interval, 0.4–1.7). However, patients in the intervention group developed vascular disease at a lower rate (odds ratio, 0.5; 95% confidence interval, 0.25–0.85). Conclusions: Patients aged ≥60 years with cryptogenic stroke may undergo transcatheter closure of an atrial shunt after thorough screening for other potential causes of stroke. The incidence of vascular disease seems to be mitigated in these patients relative to medically treated patients. © 2023 The Authors. Published by Elsevier B.V., Funding: This work was supported by the Swedish state under an agreement between the Swedish government and county councils, the ALF agreement (Grant Number: 236,611), and the Swedish Heart-Lung Foundation (Grant Numbers: 20,090,724 and 20180644).

The evolution of clinical decision support (CDS) tools has been improved by usage of new technologies, yet there is an increased need to develop user-friendly, evidence-based, and expert-curated CDS solutions. In this paper, we show with a use-case how interdisciplinary expertise can be combined to develop CDS tool for hospital readmission prediction of heart failure patients. We also discuss how to make the tool integrated in clinical workflow by understanding end-user needs and have clinicians-in-the-loop during the different development stages. © 2023 European Federation for Medical Informatics (EFMI) and IOS Press.

Background: According to the current guidelines, evidence of the effects of transcatheter closure in patients aged ≥60 years with an atrial shunt and cryptogenic stroke is still limited. Methods: Using Swedish health registries, patients aged ≥60 years who had previously developed a cryptogenic cerebrovascular event and undergone transcatheter closure were identified. Patients with atrial fibrillation were excluded, and the remaining patients were propensity score-matched with patients of the same age and risk profile who had only undergone medical treatment and with controls from the general population. They were then followed up until 2017 (mean period of 7.1 ±3.9 years). Results: In total, 100 patients of the intervention group were matched with 100 patients of the medical treatment group and with 100 controls and followed up. The hazard ratio for a recurrent ischemic stroke in the intervention group compared with the medical treatment group was 0.8 (95% confidence interval, 0.3–2.1), and that compared with the controls was 2.3 (95% confidence interval, 0.6–8.9). Atrial fibrillation occurred at the same rate in the two treatment groups (odds ratio, 0.8; 95% confidence interval, 0.4–1.7). However, patients in the intervention group developed vascular disease at a lower rate (odds ratio, 0.5; 95% confidence interval, 0.25–0.85). Conclusions: Patients aged ≥60 years with cryptogenic stroke may undergo transcatheter closure of an atrial shunt after thorough screening for other potential causes of stroke. © 2023 The Authors

Knowledge about risks for overuse of psychoactive analgesics in patients having primary surgery for carpal tunnel syndrome (CTS) or ulnar nerve entrapment (UNE), or both, is limited. We investigated if patients with those nerve entrapment disorders have a higher risk of overuse of psychoactive analgesics (i.e., opioids and gabapentinoid drugs) before, after, and both before and after surgery than observed in the general population after accounting for demographical and socioeconomic factors. Using a large record linkage database, we analysed 5,966,444 individuals (25-80 years), residing in Sweden December 31st, 2010-2014, of which 31,380 underwent surgery 2011-2013 for CTS, UNE, or both, applying logistic regression to estimate relative risk (RR) and 95% confidence interval (CI). Overall, overuse of the psychoactive analgesics was low in the general population. Compared to those individuals, unadjusted RR (95% CI) of overuse ranged in patients between 2.77 (2.57-3.00) with CTS after surgery and 6.21 (4.27-9.02) with both UNE and CTS after surgery. These risks were only slightly reduced after adjustment for demographical and socioeconomic factors. Patients undergoing surgery for CTS, UNE, or both, have a high risk of overuse of psychoactive analgesics before, after, and both before and after surgery., Funding Agencies|Swedish Research Council [2017-01321, 2022-01942]; Swedish Diabetes Foundation [DIA2020-492]; Region Skane; Lund University [2018-Projekt 0104]; Skane University Hospital [2019-659]; Elly Olssons Foundation; Stig and Ragna Gorthon Foundation; Almroth Foundation; Kockska foundation; Magnus Bergvall Foundation [2020-03612]

Aims Patients with bicuspid aortic valve (BAV) and aortic regurgitation have higher rate of aortic complications compared with patients with BAV and stenosis, as well as BAV without valvular disease. Aortic regurgitation alters blood haemodynamics not only in systole but also during diastole. We therefore sought to investigate wall shear stress (WSS) during the whole cardiac cycle in BAV with aortic regurgitation.Methods and results Fifty-seven subjects that underwent 4D flow cardiovascular magnetic resonance imaging were included: 13 patients with BAVs without valve disease, 14 BAVs with aortic regurgitation, 15 BAVs with aortic stenosis, and 22 normal controls with tricuspid aortic valve. Peak and time averaged WSS in systole and diastole and the oscillatory shear index (OSI) in the ascending aorta were computed. Students t-tests were used to compare values between the four groups where the data were normally distributed, and the non-parametric Wilcoxon rank sum tests were used otherwise. BAVs with regurgitation had similar peak and time averaged WSS compared with the patients with BAV without valve disease and with stenosis, and no regions of elevated WSS were found. BAV with aortic regurgitation had twice as high OSI as the other groups (P <= 0.001), and mainly in the outer mid-to-distal ascending aorta.Conclusion OSI uniquely characterizes altered WSS patterns in BAVs with aortic regurgitation, and thus could be a haemodynamic marker specific for this specific group that is at higher risk of aortic complications. Future longitudinal studies are needed to verify this hypothesis. Graphical Abstract Patients with bicuspid aortic valve and aortic regurgitation present with regions of elevated oscillatory shear index in the ascending aorta, namely in the outer mid-to-distal segments. The 2D map represents segments with higher oscillatory shear index for a group of patients with bicuspid aortic valve and aortic regurgitation compared with patients with bicuspi, Funding Agencies|Swedish Research Council [2021-03716]; Medical Faculty at Linkoeping University; ALF; Region Ostergoetland; University of Calgary [1054341]; Libin Cardiovascular Institute; Siemens Healthineers; Natural Science and Engineering Research Council of Canada [DGECR-2020-00204, RGPIN- 2020-04549]

Aims: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce mortality/morbidity in heart failure (HF). We explored the implementation of SGLT2i over time, and patient characteristics associated with their use, in a large, nationwide population with HF with reduced ejection fraction (HFrEF).Methods and results: Patients with HFrEF (ejection fraction <40%), no type 1 diabetes, estimated glomerular filtration rate (eGFR) <20 ml/min/1.73 m(2) and/or on dialysis, registered in the Swedish HF Registry between 1 November 2020 and 5 August 2022 were included. Independent predictors of use were investigated by multivariable logistic regressions. Of 8192 patients, 37% received SGLT2i. Use increased overall from 20.5% to 59.0% over time, from 46.2% and 12.5% to 69.8% and 55.4% in patients with and without type 2 diabetes, from 14.7% and 22.3% to 58.0% and 59.8% in eGFR <60 versus =60 ml/min/1.73 m(2), from 21.0% and 18.9% to 61.6% and 52.0% in males versus females, from 24.2% and 18.0% to 60.8% and 57.7% in patients with versus without recent HF hospitalization, from 26.1% and 19.8% to 54.7% and 59.6% in inpatients versus outpatients, and from 20.2% and 21.2% to 59.2% and 58.7% in those with HF duration <6 versus =6 months, respectively. Important characteristics associated with SGLT2i use were male sex, recent HF hospitalization, specialized HF follow-up, lower ejection fraction, type 2 diabetes, higher education level, use of other HF/cardiovascular interventions. Older age, higher blood pressure, atrial fibrillation and anaemia were associated with less use. Discontinuation rate at 6 and 12 months was 13.1% and 20.0%, respectively.Conclusions: Use of SGLT2i increased three-fold over 2 years. Although this indicates a more rapid translation of trial results and guidelines into clinical practice compared to previous HF drugs, further efforts are advocated to complete the implementation process while avoiding inequities across different patient, Funding Agencies|Swedish Heart and Lung Foundation; [20220680]

Background Guideline recommendations for the treatment of heart failure with mildly reduced ejection fraction (HFmrEF) derive from small subgroups in post-hoc analyses of randomized trials. Objectives We investigated predictors of renin-angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI) and beta-blockers use, and the associations between these medications and mortality/morbidity in a large real-world cohort with HFmrEF. Methods and results Patients with HFmrEF (EF 40-49%) from the Swedish HF Registry were included. The associations between medications and cardiovascular (CV) mortality/HF hospitalization (HFH), and all-cause mortality were assessed through Cox regressions in a 1:1 propensity score-matched cohort. A positive control analysis was performed in patients with EF < 40%, while a negative control outcome analysis had cancer-related hospitalization as endpoint. Of 12 421 patients with HFmrEF, 84% received RASI/ARNI and 88% beta-blockers. Shared-independent predictors of RASI/ARNI and beta-blockers use were younger age, being an outpatient, follow-up in specialty care, and hypertension. In the matched cohorts, use of both RASI/ARNI and beta-blocker use was separately associated with lower risk of CV mortality/HFH [hazard ratio (HR) = 0.90, 95% confidence interval (CI): 0.83-0.98 and HR = 0.82, 95% CI: 0.74-0.90, respectively] and of all-cause mortality (HR = 0.75, 95% CI: 0.69-0.81 and HR = 0.79, 95% CI: 0.72-0.87, respectively). Results were consistent at the positive control analysis, and there were no associations between treatment use and the negative control outcome. Conclusions RASI/ARNI and beta-blockers were extensively used in this large real-world cohort with HFmrEF. Their use was safe since associated with lower mortality and morbidity. Our findings confirm the real-world evidence from previous post-hoc analyses of trials, and represent a further call for implementing guideline recommendations.

Aims Compelling evidence from randomized trials has shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) are effective in heart failure (HF) across the spectrum of left ventricular ejection fractions. However, there are very few studies with real-world data.Methods and results A retrospective cohort analysis was performed based on patient-level data from the Swedish Heart Failure Registry (SwedeHF) linked with three other national registers. Patients included had an index registration between 3 September 2013 and 31 December 2020 in SwedeHF and were on treatment with guideline-recommended therapy without or with SGLT2i 3 months before or 6 months after their index registration. Endpoints were mortality or readmissions. Association between the use of SGLT2i and endpoints was studied using adjusted Cox models. In the overall cohort, 796/22 405 patients were included with/without SGLT2i. In patients with SGLT2i, 93.5% had diabetes mellitus. In the overall cohort, SGLT2i was statistically significantly associated with all-cause mortality {hazard ratio [HR]: 0.61 [95% confidence interval (CI) 0.48-0.79], P < 0.0001}, cardiovascular mortality [HR: 0.29 (95% CI 0.17-0.50), P < 0.0001], cardiovascular mortality or HF readmission [HR: 0.89 (95% CI 0.80-1.00), P = 0.046], and all-cause readmissions [HR: 0.90 (95% CI 0.81-0.99), P = 0.038]. Similar results were obtained for the diabetes cohort. However, no association with cause-specific readmissions was observed.Conclusions This nationwide real-world study indicates that patients with HF, in which majority coexisted with diabetes mellitus, who received SGLT2i were statistically significantly associated with lower risk for all-cause mortality, cardiovascular mortality, cardiovascular mortality or HF readmissions, and all-cause readmissions, in line with the randomized trials assessing SGLT2i.

Background: The prevalence of aortic valve stenosis (AS) is increasing due to an ageing population. Despite that right ventricular function has prognostic value for postoperative outcome, the right ventricle (RV) is not extensively studied and often not routinely assessed in AS. Our aim was to explore the relation between severe AS and RV function in a surgical aortic valve replacement (SAVR) cohort, comparing two imaging modalities for RV evaluation.Methods: Patients with severe AS, underwent cardiovascular magnetic resonance imaging (CMR) and transthoracic echocardiography (TTE) before SAVR. RV dysfunction was defined as one or more of the following: tricuspid annular plane systolic excursion (TAPSE) < 17 mm, RV free wall strain (RVFWS) > -20% by TTE and RV ejection fraction (RVEF) <50% by CMR.Results: Sixteen (33%) patients were found to have RV dysfunction. Patients with RV dysfunction showed significantly lower indexed aortic valve area, left ventricular (LV) ejection fraction as well as RV and LV stroke volumes compared to patients with maintained RV function. All patients with reduced RVEF also had changes in TAPSE or RVFWS and a larger number of patients had a reduced longitudinal RV function despite a normal RVEF.Conclusion: In a SAVR cohort one-third of the patients had RV dysfunction, defined by RVEF, TAPSE or RVFW strain. Echocardiography detected subtle changes in RV function before RVEF was reduced. It is likely that the more pronounced the AS, the more frequent the occurrence of RV dysfunction., Funding Agencies|ALF grant; Region Ostergotland and Linkoping University [RO-935260]; From student to docent, Region Ostergotland [RO-965090]

Aims The Heart Failure Association of the European Society of Cardiology has recently proposed to optimize guideline-directed medical treatments according to patient s profiles. The aim of this analysis was to investigate prevalence/characteristics/treatments/outcomes for individual profiles Methods and results Patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in the Swedish Heart Failure Registry (SwedeHF) between 2013 and 2021 were considered. Among 108 profiles generated by combining different strata of renal function (by estimated glomerular filtration rate [eGFR]), systolic blood pressure (sBP), heart rate, atrial fibrillation (AF) status and presence of hyperkalaemia, 93 were identified in our cohort. Event rates for a composite of cardiovascular (CV) mortality or first HF hospitalization were calculated for each profile. The nine most frequent profiles accounting for 70.5% of the population had eGFR 30- 60 or =60 ml/min/1.73m(2), sBP 90-140mmHg and no hyperkalaemia. Heart rate and AF were evenly distributed. The highest risk of CV mortality/first HF hospitalization was observed in those with concomitant eGFR 30- 60ml/min/1.73m(2) and AF. We also identified nine profiles with the highest event rates, representing only 5% of the study population, characterized by no hyperkalaemia, even distribution among the sBP strata, predominance of eGFR < 30 ml/min/1.73m(2) and AF. The three profiles with eGFR 30- 60ml/min/1.73m(2) also showed sBP < 90 mmHg Conclusions In a real-world cohort, most patients fit in a few easily identifiable profiles; the nine profiles at highest risk of mortality/morbidity accounted for only 5% of the population. Our data might contribute to identifying profile-tailored approaches to guide drug implementation and follow-up., Funding Agencies|Swedish Heart and Lung Foundation; [20220680]

Despite abundant knowledge about the relationship between inflammation and coronary atherosclerosis, it is still unknown whether systemic inflammation measured as high-sensitivity C-reactive protein (hsCRP) is associated with coronary atherosclerosis in a general population. This study aimed to examine the association between hsCRP and coronary computed tomography angiography (CCTA)-detected coronary atherosclerosis in a population-based cohort. Out of 30,154 randomly invited men and women aged 50 to 64 years in the Swedish Cardiopulmonary Bioimage Study (SCAPIS), 25,408 had a technically acceptable CCTA and analysed hsCRP. Coronary atherosclerosis was defined as presence of plaque of any degree in any of 18 coronary segments. HsCRP values were categorised in four groups. Compared with hsCRP below the detection limit, elevated hsCRP (& GE; 2.3 mg/L) was weakly associated with any coronary atherosclerosis (OR 1.15, 95% CI 1.07-1.24), coronary diameter stenosis & GE; 50% (OR 1.27, 95% CI 1.09-1.47), & GE; 4 segments involved (OR 1.13, 95% CI 1.01-1.26 ) and severe atherosclerosis (OR 1.33, 95% CI 1.05-1.69) after adjustment for age, sex and traditional risk factors. The associations were attenuated after further adjustment for body mass index (BMI), although elevated hsCRP still associated with noncalcified plaques (OR 1.16, 95% CI 1.02-1.32), proposed to be more vulnerable. In conclusion, the additional value of hsCRP to traditional risk factors in detection of coronary atherosclerosis is low. The association to high-risk noncalcified plaques, although unlikely through a causal pathway, could explain the relationship between hsCRP and clinical coronary events in numerous studies., Funding Agencies|Karolinska Institute

Blood pressure variability (BPV) represents a cardiovascular risk factor, regardless of mean level of blood pressure (BP). In this post-hoc analysis from the PERson-centredness in Hypertension management using Information Technology (PERHIT) study, we aimed to explore BPV in daily home measurements in hypertensive patients from primary care, to identify factors associated with high BPV and to investigate whether estimated glomerular filtration rate (eGFR) and pulse pressure, as markers of target organ damage (TOD), are associated with BPV. For eight consecutive weeks, 454 participants reported their daily BP and heart rate in their mobile phone, along with reports of lifestyle and hypertension-related factors. Systolic BP (SBP) values were used to calculate BPV with coefficient of variation (CV) as primary estimate. Background characteristics and self-reports were tested between fifths of CV in a linear regression model, adjusted for age and sex. Associations between BPV and eGFR and pulse pressure were tested with linear and logistic regression models. Higher home BPV was associated with higher age, BP, heart rate, and smoking. BPV was lower for participants with low alcohol consumption and treatment with calcium channel blockers. There was a significant association between BPV and pulse pressure (P = 0.015), and between BPV and eGFR (P = 0.049). Participants with high BPV reported more dizziness and palpitations. In conclusion, pulse pressure and eGFR were significantly associated with home BPV. Older age, high BP, heart rate, and smoking were associated with high BPV, but treatment with calcium channel blockers and low alcohol consumption was associated with low BPV. Trial registration: The study was registered with ClinicalTrials.gov [NCT03554382]., Funding Agencies|Kamprad Foundation [20170102]; Lung Foundation [20170251, 20200507]; Swedish Research Council [2018-02648]; University of Gothenburg Centre for Person-centred Care (GPCC), Sweden; Swedish Governments grant for Strategic Research Areas (Care Sciences); University of Gothenburg, Sweden; Lund University

ObjectiveTo investigate the association between health-related quality of life (HRQoL) and major adverse cardiovascular and cerebrovascular events (MACCE) in individuals with ischaemic heart disease (IHD).MethodsMedline(R), Embase, APA PsycINFO and CINAHL (EBSCO) from inception to 3 April 2023 were searched. Studies reporting association of HRQoL, using a generic or cardiac-specific tool, with MACCE or components of MACCE for individuals with IHD were eligible for inclusion. Risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale to assess the quality of the studies. Descriptive synthesis, evidence mapping and random-effects meta-analysis were performed stratified by HRQoL measures and effect estimates. Between-study heterogeneity was assessed using the Higgins I2 statistic.ResultsFifty-one articles were included with a total of 134 740 participants from 53 countries. Meta-analysis of 23 studies found that the risk of MACCE increased with lower baseline HeartQoL score (HR 1.49, 95% CI 1.16 to 1.93) and Short Form Survey (SF-12) physical component score (PCS) (HR 1.39, 95% CI 1.28 to 1.51). Risk of all-cause mortality increased with a lower HeartQoL (HR 1.64, 95% CI 1.34 to 2.01), EuroQol 5-dimension (HR 1.17, 95% CI 1.12 to 1.22), SF-36 PCS (HR 1.29, 95% CI 1.19 to 1.41), SF-36 mental component score (HR 1.18, 95% CI 1.08 to 1.30).ConclusionsThis study found an inverse association between baseline values or change in HRQoL and MACCE or components of MACCE in individuals with IHD, albeit with between-study heterogeneity. Standardisation and routine assessment of HRQoL in clinical practice may help risk stratify individuals with IHD for tailored interventions.PROSPERO registration numberCRD42021234638., Funding Agencies|We thank Deirdre Andre for assistance with electronic search strategy.

IntroductionAdverse left ventricular remodelling (AR) develops over time in approximately 30% of patients with a history of coronary artery disease. AR manifests as a structural change in the left ventricle (LV) in terms of increased volumes and reduced left ventricular ejection fraction (LVEF). Manganese dipyridoxyl diphosphate (mangafodipir) has demonstrated interesting cardioprotective features in acute myocardial ischaemia. Pharmacological postconditioning (PP) with mangafodipir as an adjunct to primary percutaneous coronary intervention may possibly reduce the development of AR over time in ST-elevation myocardial infarction (STEMI). The aim of this 4-7-year follow-up study is to investigate the potential benefits of PP with mangafodipir in STEMI patients. MethodThirteen out of the initial 20 patients that were included in the primary study of Karlsson et al. were followed up between April and June 2017. The study group underwent review of the hospital records, a clinical examination with ECG and blood sample analysis before cardiac magnetic resonance examination of the patient. LVEF, left ventricular diastolic volume, left ventricular end systolic volume, LV mass and myocardial strain in all directions were computed. ResultsThe PP group showed a decrease in LV volume, mass and higher LVEF at follow-up (p < 0.05) while the individual response of the placebo group showed features that are seen in AR. Although there was no difference in myocardial strain, measurement for the PP-group was higher in absolute terms. ConclusionPharmacological postconditioning with mangafodipir in STEMI demonstrated cardioprotective features compared to the placebo group at follow-up. This article is protected by copyright. All rights reserved., Funding Agencies|Futurum-Academy for Health and Care, Region Jonkoeping County [414891, 598791, 635951, 851331]

Aims Hospital admission during nighttime and off hours may affect the outcome of patients with various cardiovascular conditions due to suboptimal resources and personnel availability, but data for acute heart failure remain controversial. Therefore, we studied outcomes of acute heart failure patients according to their time of admission from the global International Registry to assess medical practice with lOngitudinal obseRvation for Treatment of Heart Failure.Methods and results Overall, 18 553 acute heart failure patients were divided according to time of admission into morning (7:00-14:59), evening (15:00-22:59), and night (23:00-06:59) shift groups. Patients were also dichotomized to admission during working hours (9:00-16:59 during standard working days) and non-working hours (any other time). Clinical characteristics, treatments, and outcomes were compared across groups. The hospital length of stay was longer for morning (odds ratio: 1.08; 95% confidence interval: 1.06-1.10, P < 0.001) and evening shift (odds ratio: 1.10; 95% confidence interval: 1.07-1.12, P < 0.001) as compared with night shift. The length of stay was also longer for working vs. non-working hours (odds ratio: 1.03; 95% confidence interval: 1.02-1.05, P < 0.001). There were no significant differences in in-hospital mortality among the groups. Admission during working hours, compared with non-working hours, was associated with significantly lower mortality at 1 year (hazard ratio: 0.88; 95% confidence interval: 0.80-0.96, P = 0.003).Conclusions Acute heart failure patients admitted during the night shift and non-working hours had shorter length of stay but similar in-hospital mortality. However, patients admitted during non-working hours were at a higher risk for 1 year mortality. These findings may have implications for the health policies and heart failure trials., Funding Agencies|Novartis

Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice. In cardiac surgery, the negative influence of AF on short- and long-term outcomes has made concomitant ablation procedures more common. The indications, clinical aspects, results, risks, and benefits of the additional surgical ablation are still valuable topics for discussion. This compilation thesis consists of four papers aiming to investigate some of the clinical, biochemical, and echocardiographic aspects of surgical ablation for AF (Cox-Maze IV) when performed concomitant to mitral valve surgery (MVS). Through a retrospective, case-control, single-center study, we described the impact of the Cox-Maze IV procedure added to MVS with focus on postoperative heart failure (paper I). Cryoenergy (cryo) and radiofrequency (RF) are the two different energy sources mainly used in Cox-Maze IV for AF ablation. To achieve linear scars in the atrial wall, the RF procedure uses heat damage, whereas the cryo method freezes down to -150°C. Through a prospective, randomized, longitudinal, controlled study, we compared the biochemical responses of the two ablative methods in concomitant MVS and the release of enzymes expressing myocardial injury, as well as inflammatory, cell stress, and apoptosis-specific proteins. We could show that cryo results in a larger release of markers for myocardial damage but has no impact on the early inflammatory response (paper II). Extended scar lesions resulting after maze may influence atrial function. As the left atrium plays a key role in the altered cardiac hemodynamics in AF, an echocardiographic analysis of the effects of the Cox-Maze IV procedure concomitant to MVS on the left atrium was carried out. The impacts of the two energy sources (cryo and RF) on left atrial remodeling and function had not been compared previously. Their direct effect on left atrial remodeling and mechanical function were assessed 1 year after surgery in patients with restored sinus rh, Förmaksflimmer (FF) är den vanligaste arytmin som ses i klinisk praxis. Inom hjärtkirurgi har den negativa inverkan på kort- och långtidsutfall för patienter med FF gjort samtidiga ablationsprocedurer vanligare. Indikationerna, de kliniska aspekterna, resultaten, riskerna och fördelarna med den extra kirurgiska ablationen är fortfarande under diskussion. Den aktuella avhandligen består av fyra artiklar som syftar till att undersöka några av de kliniska, biokemiska och ekokardiografiska aspekterna av kirurgisk ablation vid förmaksflimmer (Cox-Maze IV) när det utförs samtidigt med mitralisklaffkirurgi. I en retrospektiv fallkontrollstudie beskrev vi effekten av Cox-Maze IVproceduren som tillägg till mitralisklaffkirurgin med fokus på postoperativ hjärtsvikt (första artikeln). Kryo och Radiofrekvens är de två olika energikällorna som huvudsakligen används vid Cox-Maze IV för FF-ablation. För att uppnå ärrlinjer i förmaksväggen använder Radiofrekvens-proceduren värmeskada, medan Kryo-metoden fryser ner vävnader till minus 150º C grader Celsius. En jämförelse av de biokemiska svaren presenteras mellan de två ablativa metoderna vid samtidig mitralisklaffkirurgi. Frisättningen av biokemiska markörer som uttrycker myokardskada samt inflammatoriska, cellstress- och apoptosspecifika (celldödsspecifika) proteiner rapporteras. Genom en prospektiv randomiserad longitudinell kontrollerad studie kunde vi visa att Kryo hade en större frisättning av hjärtskademarkörer, men ingen inverkan på tidig inflammatorisk respons (andra artikeln). Ärrskador som uppstår efter Cox-Maze IV kan påverka förmaksfunktionen. Eftersom det vänstra förmaket spelar en nyckelroll vid förmaksflimmer förändrade hemodynamiken, genomfördes en ekokardiografisk analys av effekterna av Cox-Maze IV-proceduren samtidigt med mitralisklaffkirurgi på vänster förmak. Effekten av de två energikällorna (Kryo och Radiofrekvens) på vänster förmaks remodeling och funktion har inte jämförts tidigare på ett prospektivt sätt.

BackgroundAtrial linear scars in Cox-Maze IV procedures are achieved using Cryothermy (Cryo) or radiofrequency (RF) techniques. The subsequent postoperative left atrial (LA) reverse remodelling is unclear. We used 2- and 3-dimensional echocardiography (2-3DE) to compare the impact of Cryo and RF procedures on LA size and function 1 year after Cox-maze IV ablation concomitant with Mitral valve (MV) surgery. MethodsSeventy-two patients with MV disease and AF were randomized to Cryo (n = 35) or RF (n = 37) ablation. Another 33 patients were enroled without ablation (NoMaze). All patients underwent an echocardiogram the day before and 1 year after surgery. The LA function was assessed on 2D strain by speckle tracking and 3DE. ResultsForty-two ablated patients recovered sinus rhythm (SR) 1 year after surgery. They had comparable left and right systolic ventricular function, LA volume index (LAVI), and 2D reservoir strain before surgery. At follow-up, the 3DE extracted reservoir and booster function were higher after RF (37 & PLUSMN; 10% vs. 26 & PLUSMN; 6%; p < 0.001) than Cryo ablation (18 & PLUSMN; 9 vs. 7 & PLUSMN; 4%; p < 0.001), while passive conduit function was comparable between groups (24 & PLUSMN; 11 vs. 20 & PLUSMN; 8%; p = 0.17). The extent of LAVI reduction depended on the duration of AF preoperatively. ConclusionsSR restoration after MV surgery and maze results in LA size reduction irrespective of the energy source used. Compared to RF, the extension of ablation area produced by Cryo implies a structural LA remodelling affecting LA systolic function., Funding Agencies|ALF Grant Region Ostergotland

Assessment of left atrial (LA) fibrosis from late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) adds to the management of patients with atrial fibrillation (AF). However, accurate assessment of fibrosis in the LA wall remains challenging. Excluding anatomical structures in the LA proximity using clipping techniques can reduce misclassification of LA fibrosis. A novel FK-means approach for combined automatic clipping and automatic fibrosis segmentation was developed. This approach combines a feature-based Voronoi diagram with a hierarchical 3D K-means fractal-based method. The proposed automatic Voronoi clipping method was applied on LGE MRI data and achieved a Dice score of 0.75, similar as the score obtained by a deep learning method (3D UNet) for clipping (0.74). The automatic fibrosis segmentation method, which utilizes the Voronoi clipping method, achieved a Dice score of 0.76. This outperformed a 3D U-Net method for clipping and fibrosis classification, which had a Dice score of 0.69. Moreover, the proposed automatic fibrosis segmentation method achieved a Dice score of 0.90, using manual clipping of anatomical structures. The findings suggest that the automatic FK-means analysis approach enables reliable LA fibrosis segmentation and that clipping of anatomical structures in the atrial proximity can add to the assessment of atrial fibrosis., For access to data and code please contact datamanagement@liu.se for further information.

Aims Heart failure (HF) medication may reduce blood pressure (BP). Low BP is associated with worse outcomes but how this association is modified by HF medication has not been studied. We evaluated the association between BP and outcomes according to HF medication dose in HF with reduced ejection fraction (HFrEF). Methods and results We studied HFrEF patients from the Swedish HF registry (2000-2018). Associations between systolic BP (SBP) and cardiovascular death (CVD) and/or HF hospitalization (HFH) were analysed according to doses of renin-angiotensin system (RAS) inhibitors, beta-blockers and mineralocorticoid receptor antagonists (MRA). Among 42 040 patients (median age 74.0), lower baseline SBP was associated with higher risk of CVD/HFH (adjusted hazard ratio [HR] per 10 mmHg higher SBP: 0.92, 95% confidence interval [CI] 0.92-0.93), which was less high risk under optimized RAS inhibitor and beta-blocker doses (10% decrease in event rates per 10 mmHg SBP increase in untreated patients vs. 7% decrease in patients at maximum dose, both adjusted p < 0.02). Among the 13 761 patients with repeated measurements, 9.9% reported a SBP decrease >10 mmHg when HF medication doses were increased, whereas 24.6% reported a SBP decrease >10 mmHg with stable/decreasing doses. Decreasing SBP was associated with higher risk of CVD/HFH in patients with stable (HR 1.10, 95% CI 1.04-1.17) or decreasing (HR 1.29, 95% CI 1.18-1.42) HF medication dose but not in patients with an increase in doses (HR 0.94, 95% CI 0.86-1.02). Conclusions The association of lower SBP with higher risk of CVD/HFH is attenuated in patients with optimized HF medication. These results suggest that low or declining SBP should not limit HF medication optimization., Funding Agencies|French National Research Agency Fighting Heart Failure [ANR-15-RHU-0004]; French PIA project Lorraine Universite dExcellence GEENAGE [ANR-15-IDEX-04-LUE]; Contrat de Plan Etat Region Lorraine; FEDER

Background and Aims The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linkoping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9(-/-) mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. Results In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9(-/-) mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9(-/-) mice, confirming target specificity. Conclusion Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological, Funding Agencies|Lund University; Marianne and Marcus Wallenberg Foundation; Swedish Heart and Lung Foundation; Swedish Research Council; Bundy Academy foundation at Lund University; Skane Region Research Funds; Malmoe University Hospital Funds; Crafoord Foundation; Royal Physiographic Society in Lund; Ostergotland Region Research Funds; Ministry of Research and Education of Romania [PNRR-C9/I8-CF148]

Aims How different degrees of adherence to guideline-directed medical therapy (GDMT) affect mortality risk in patients with heart failure (HF) in a real-world clinical setting is poorly understood. This study sought to investigate how different levels of adherence to GDMT were associated with the risk of all-cause mortality in patients with HF across a spectrum of left ventricular ejection fractions (LVEFs) in a real-world clinical setting.Methods and results A total of 64 610 HF patients with no missing value of LVEF from the Swedish Heart Failure Registry were included in the study. Patients were divided according to different LVEFs (<30%, 30-39%, 40-49%, and >= 50%) and stratified by an adherence score (good, moderate, or poor) according to the triple, double, and single one usage of GDMT: angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists. The outcome is time to all-cause mortality. The mean age of the whole cohort was 73.9 +/- 12.1 years, and the proportion of patients in LVEF < 30%, 30-39%, 40-49%, and >= 50% groups was 27.6%, 26.9%, 22.1%, and 23.3%, respectively. Patients with LVEF < 30% had the highest mortality rate, almost 20% higher than those with LVEF >= 50% {hazard ratio [HR] [95% confidence interval (CI)]: 0.80 [0.71-0.90], P < 0.001}. After treatment of GDMT with good adherence, patients with LVEF < 30% had similar mortality to those with LVEF >= 50% [HR (95% CI): 0.97 (0.86-1.10), P = 0.664]. However, the percentage of moderate or poor GDMT was alarmingly high, with good adherence only in 20% of the patients.Conclusions Good adherence to GDMT works best in patients with LVEF < 50%, whereas moderate adherence to GDMT varies in efficacy depending on the components of the drug combinations., Funding Agencies|Swedish Heart Lung Foundation (Hjart-Lungfonden) [20210247]; Swedish Federal Government through the Swedish Association of Local Authorities and Regions

Introduction: Life after stroke is a comprehensive area that involves engagement in meaningful everyday activities, including work, and can be adversely affected by post-stroke fatigue. This study investigates post-stroke fatigue, its development over time, and its impact on return to work and other everyday life activities. In addition, we investigated whether post-stroke fatigue could predict functioning in everyday life activities one year after stroke.Material and methods: This prospective registry-based study includes 2850 working age (18 - 63 years) patients registered in the Swedish Stroke Register (Riksstroke) during year 2017 and 2018. Post-stroke fatigue and everyday activities were analyzed 3- and 12-months post-stroke.Results: The mean age of the included participants was 54 years and the majority, 65%, were men. Three months post-stroke, 43% self-reported fatigue, at 12-months the proportion increased to 48%. About 90% of the patients were independent in basic ADL at 3-month. Dependence in complex activities one year post-stroke was significantly associated with fatigue. Not experiencing fatigue one year after stroke could predict positive functioning in everyday activities, increasing the chance of returning to work (OR = 3.7) and pre-stroke life and everyday activities (OR = 5.7).Conclusion: Post-stroke fatigue is a common persistent disability that negatively impacts complex activities; therefore, fatigue needs to be acknowledged and addressed long term after discharge., Funding Agencies|We would like to thank Riksstroke for their collaboration, providing a unique database, and supplying us with the dataset.