Background: High-intensity interval training (HIIT) is increasingly used in exercise-based cardiac rehabilitation (ebCR) after myocardial infarction (MI), yet the temporal sequence of physiological, cardiac, biochemical, and functional adaptations remains incompletely characterized. Methods: Stable post-STEMI (ST-segment elevation myocardial infarction, MI-group) and previously inactive participants without known cardiovascular, metabolic or systemic disease (CTRL group) completed 12-week supervised outpatient HIIT (4 × 4 min intervals at 85-90% HRpeak (peak heart rate), ~80-90% of VO2peak, 3 sessions/week). Assessments were performed at baseline (T1), 4 (T2), 8 (T3), and 12 weeks (T4), including cardiopulmonary exercise testing (CPET), echocardiography, blood biomarkers, body composition, six-minute walk test (6MWT), and RAND-36. Longitudinal changes were analyzed using Friedman tests with Dunn post hoc comparisons; between-group differences used Mann-Whitney U tests with Holm correction. Results: VO2peak increased significantly in both groups (p < 0.001), increasing by ~22% from T1 to T4 in MI (median 20.1 to 24.5 mL·kg-1·min-1) and ~23% from T1 to T4 in CTRL (median 22.3 to 27.6 mL·kg-1·min-1). LVEF (left ventricular ejection fraction) improved early in MI, increasing from 52.5% (50.0-55.0) at T1 to 57.5% (55.2-58.7) at T2 and up to 60% (55.8-60.0) at T4 (all p < 0.001), while LV dimensions remained stable. NT-proBNP (N-terminal pro-B-type natriuretic peptide) showed no significant longitudinal change (p = 0.510), and CRP (C-reactive protein) decreased from 2.1 to 0.7 mg·L-1 (p = 0.008) in MI. Both groups improved body fat % and 6MWT distance (p < 0.001). Conclusions: In low-risk stable post-STEMI patients, longitudinal changes during supervised HIIT-based ebCR were consistent with improved VO2peak and LVEF, without clinically relevant increases in cardiac stress biomarkers. However, due to the observational design and absence of clinical comparator groups, these findings should be interpreted as descriptive and support further evaluation in larger randomized studies.

Background/Objectives: Vitamin D insufficiency is common in patients with spondyloarthritis (SpA). We analyzed the relationship between vitamin D, disease activity, and left ventricular (LV) function in patients with SpA. Methods: A total of 298 patients with SpA and 57 healthy controls were enrolled. Serum vitamin D and laboratory cardiovascular risk factors were analyzed, and LV function was assessed by echocardiography. Vitamin D, the Ankylosing Spondylitis Disease Activity Score (ASDAS), and the Disease Activity Index for Psoriatic Arthritis (DAPSA) were examined for mutual correlations using univariate and multivariate linear regression models and were compared between groups. Results: Vitamin D levels did not differ between the SpA group and controls, although vitamin D supplementation was more frequent among SpA patients. Vitamin D was not associated with SpA activity. ASDAS and DAPSA were positively correlated with isovolumic relaxation time, and DAPSA was inversely correlated with peak early diastolic mitral annular velocity (e'), after adjustment for age, sex, metabolic factors, and/or therapy. Patients with insufficient serum vitamin D levels (<75 nmol/L) showed greater impairment of systolic and diastolic LV function and a diabetic-like lipid profile compared with those with sufficient vitamin D levels. The e' wave was positively correlated with vitamin D after controlling for confounding factors. These findings in patients with SpA are consistent with those previously reported in patients with psoriatic arthritis (PsA). Conclusions: Patients with SpA were characterized by vitamin D supplementation, increased disease activity parameters, and impaired LV function. SpA activity, independent of vitamin D, was associated with LV functional impairment, and vitamin D was associated with an increase in the e' wave after adjustment for confounding factors. However, causal inferences cannot be drawn from correlational analyses.

Objective: The oral cavity is the beginning of the digestive tract and the composition of saliva could indicate immune events in the gut and joints. The objective of this research was to evaluate the diagnostic accuracy of salivary interleukin (IL)-17A for temporomandibular joint (TMJ) internal derangements (IDs) in patients with spondyloarthritis (SpA). Methods: SpA disease activity was assessed using the Bath Ankylosing Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS) and Disease Activity Index for Psoriatic Arthritis (DAPSA). Salivary cytokines were analyzed using enzyme-linked immunosorbent assay. TMJ conditions were evaluated using The Diagnostic Criteria for Temporomandibular Disorder (DC/TMD) protocol. A symptomatic TMJ-ID group with intracapsular arthralgia (n = 64) and asymptomatic TMJ-ID group without intracapsular arthralgia (n = 50), regardless of joint sounds, were compared with controls (healthy TMJs, n = 86). Results: Women were more prevalent and salivary IL-17A concentration was higher in both ID groups than in controls. Salivary IL-17A levels positively correlated with erythrocyte sedimentation rate, anti-streptolysin-O titer, salivary IL-12/23 p40 and matrix metalloproteinase-3 levels, sore and swollen joint counts, BASDAI, chronic TMJ pain and anxiety. IL-17A demonstrated diagnostic accuracy for currently symptomatic (cutoff, 11 pg/mL) and asymptomatic (cutoff, 11.6 pg/mL) TMJ-ID vs. controls. Patients with IL-17A levels above these cutoffs more frequently exhibited disc displacement with reduction and degenerative TMJ disease, higher self-reported spinal pain and higher SpA activity, as assessed by ASDAS, than patients with IL-17A levels ≤ cutoffs. TMJ-related headache and somatization contributed to greater TMJ pain in those with IL-17A > cutoffs, when compared with dichotomous controls. Conclusions: Salivary IL-17A concentration provides an accurate laboratory marker of SpA activity and enables the diagnosis of both currently symptomatic and asymptomatic TMJ-IDs in patients with SpA.

Purpose: The widely spread membrane and soluble Klotho protein plays a pivotal role in vascular calcification by orchestrating calcium/phosphate/magnesium homeostasis mediated by the Klotho/fibroblast growth factor 23 receptor complex. Our aim was to review new scientific data and discuss the role(s) of Klotho in vascular calcification. The basic procedures were to review the literature concerning Klotho and its mechanisms of action during physiological and pathological aging. Main findings: A lack of Klotho shortens the lifespan, increases vascular calcification and the frequency of cardiovascular diseases with multiple organ degeneration and weakness in experimental animal models. In humans, the most prominent decrease of Klotho protein and mRNA is found in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD), which shows accelerated aging due to increased vascular calcification. Additionally, Klotho acts in an endocrine manner participating in different signaling pathways as an anti-inflammatory, antioxidant, anti-fibrotic and anti-aging mediator, preserving vascular structure and function. Principal conclusions: Klotho is a possible early marker for the detection and monitoring of subclinical arterial calcification in patients with CKD-MBD and in the general population.

Objectives: The group of spondyloarthritis (SpA) disorders shares common clinical manifestations, including internal derangement (ID) of temporomandibular joint (TMJ). This study aimed to investigate SpA activity in patients with ID of TMJ. Materials and Methods: We assessed 200 patients with neck pain using the Assessment of Spondyloarthritis International Society (ASAS) criteria. TMJ was examined using Diagnostic Criteria for Temporomandibular Disorders (DC/TMD protocol). Patients with SpA were divided into three groups: symptomatic ID of TMJ, asymptomatic ID of TMJ, or healthy TMJ (controls). Activity of SpA was evaluated using the Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Disease Activity Index in Psoriatic Arthritis (DAPSA), patients’ self-estimated SpA activity, difficulties in performing daily activities, pain intensity (visual analogue scale) and laboratory parameters. Results: Patients with symptomatic and asymptomatic ID showed statistically significantly increased ASDAS, anti-streptolysin titer, patients’ self-estimated axial pain and activity of SpA, and decreased hematocrit than the control. Patients with symptomatic ID also had statistically significant earlier onset of SpA, along with increased BASDAI and DAPSA, total body pain, difficulties in performing daily activities, platelet count, and serum alpha-amylase but lower hemoglobin concentration than controls. Patients with asymptomatic ID had higher frequencies of exacerbated axial SpA and sacroiliac joint ankylosis compared to the control. Conclusion: All patients with SpA and ID showed increased axial disease activity.

Kardiovaskularne bolesti (KVB) su vodeći uzrok pobola i smrtnosti diljem svijeta pa tako i u Hrvatskoj. Budući da je u većine bolesnika prisutno više poremećaja i bolesti kojima su u podlozi u najvećem dijelu isti čimbenici rizika, te kako je nužno svakom bolesniku pristupati kao osobi sa svim poremećajima, danas se govori o novoj paradigmi – kardio-reno-metaboličkom (KRM) sindromu i kardio-reno-metaboličkom zdravlju, u što je neizostavno uključeno i zdravlje mozga. Povišen sistolički arterijski tlak, LDL-kolesterol, pušenje, debljina, šećerna bolest, oštećena bubrežna funkcija, tj. kronična bubrežna bolest, u podlozi kojih je nedovoljno tjelesne aktivnosti, nezdrava prehrana s prekomjernim unosom kuhinjske soli zajedno s onečišćenjem zraka vodeći su uzroci ukupnoga pobola i smrtnosti od KRM bolesti, a napose smrtnosti od KVB. Stručnjaci iz raznih područja ključnih za KRM zdravlje napisali su ovaj dokument s ciljem da bude sastavni dio nacionalnog plana za prevenciju kroničnih nezaraznih bolesti s fokusom na KVB koji treba postati obvezujući, a utemeljen na postojećim smjernicama stručnih društava. Naglašena je važnost pravovremenog probira i postavljanja dijagnoze, no težište je stavljeno i na nužnost organiziranja i provođenja mjera primordijalne i primarne prevencije. Istaknuta je važnost multidisciplinarnoga pristupa i trajnog obrazovanja opće populacije i bolesnika kako bi se promijenile loše životne navike i povećala ustrajnost uzimanja lijekova, ali isto tako podizanje zdravstvene pismenosti zdravstvenih radnika, napose liječnika kako bi se smanjila klinička inercija.

BACKGROUND:Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is a prospective registry of outcomes from patients with newly diagnosed AF at risk of stroke. In the propensity score (PS)-matched global population of phase 3 GLORIA-AF, at 3 years, dabigatran-treated patients experienced reduced risk for major bleeding, and similar risk for stroke and myocardial infarction, compared with vitamin K antagonist (VKA)-treated patients.STUDY QUESTION:Do patients in Eastern Europe benefit from treatment with dabigatran versus VKA?STUDY DESIGN:Descriptive analysis, without PS matching. To contextualize the Eastern Europe results of GLORIA-AF phase 3, we also descriptively analyzed the global population without PS matching. Consecutive patients with newly diagnosed AF and CHA2DS2-VASc-score ≥1 were enrolled until December 2016 in 38 countries (9 in Eastern Europe).MEASURES AND OUTCOMES:Three-year outcomes with dabigatran and VKA.RESULTS:In Eastern Europe, 1341 patients were eligible (6% of patients globally), and incidence rates (per 100 patient-years) for the following outcomes were numerically lower with dabigatran (N = 498) versus VKA (N = 466): major bleeding (0.26 vs. 0.90), all-cause death (2.04 vs. 3.50), and a composite of stroke, systemic embolism, myocardial infarction, life-threatening bleeding, and vascular death (1.37 vs. 1.92); stroke was comparable (0.51 vs. 0.50). All incidence rates were numerically lower in Eastern Europe versus the global population for both treatments. Chronic concomitant use of high bleeding risk medications (eg, nonsteroidal anti-inflammatories) was lower in Eastern Europe (dabigatran 3.8%, VKA 9.3%) than globally (dabigatran 14.8%, VKA 20.6%) and persistence with dabigatran was higher in Eastern Europe (76%) than globally (64%).CONCLUSIONS:Dabigatran was associated with numerically reduced major bleeding, all-cause death, and cardiovascular (CV) composite, with comparable risk of stroke versus VKA, in Eastern Europe. Limitations of this descriptive analysis include few CV events (n = 11 for stroke, in the dabigatran and VKA groups combined) and a lack of statistical analysis and PS matching, which precludes definitive conclusions; however, the CV outcomes in Eastern Europe were consistent with the beneficial impact of dabigatran versus VKA in the statistically analyzed global population with PS matching.

Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality worldwide, including in Croatia. Since most patients have multiple disorders and diseases caused largely by the same risk factors, and as it is essential to approach each patient as a person with all disorders, today, we are talking about a new paradigm—cardio-renal-metabolic (CKM) syndrome and cardio-renal-metabolic health, which necessarily includes brain health. Elevated systolic blood pressure, LDL cholesterol, smoking, obesity, diabetes, impaired renal function or chronic kidney disease, which all stem from insufficient physical activity, an unhealthy diet with excessive intake of table salt, and air pollution, are the leading causes of overall morbidity and mortality from CKM diseases, especially mortality from CVD. Experts from various fields key to CKM health have written this document with the aim of integrating it as part of the national plan for the prevention of chronic non-communicable diseases with a focus on CVD, which should become mandatory and be based on the existing guidelines of professional societies.

IntroductionAmiodarone is a potent antiarrhythmic medication used to treat life-threatening ventricular arrhythmias; however, its well-established adverse effect is a thyroid disorder. Amiodarone-induced thyroiditis (AIT), a clinical entity involving two types with different etiopathology and treatment approaches, may occur at the beginning or even several years after amiodarone treatment discontinuation. The toxicity profile of amiodarone becomes especially important in young patients with lifelong cardiac disorders, which are often refractory to other antiarrhythmic drugs. Herein, we report the first case of non-sustained ventricular tachycardia (NSVT), an unusual presentation of type II AIT, in a young male patient who was previously diagnosed with left ventricular cardiomyopathy with excessive trabeculation.Case reportA 36-year-old male non-athlete presented with tiredness during regular follow-up. Continuous electrocardiographic monitoring (cECG) revealed NSVT, whereas echocardiography and cardiac magnetic resonance imaging detected discrete structural and functional changes that could not fully explain the observed cECG report. Conversely, an unmeasurably low thyrotropin level on admission and previous exposure to amiodarone pointed the diagnostic pathway in the direction of the thyroid gland. Elevated free thyroxine and undetectable autoantibody titers with unremarkable sonographic findings raised clinical suspicion of type II AIT. Scintigraphic imaging with 99mTc-2-methoxyisobutylisonitrile (sestamibi) revealed decreased thyroid uptake; hence, prednisone was introduced for treatment. Clear improvements in both biochemical and electrocardiographic parameters were observed after immunomodulatory treatment of type II AIT in this young patient with cardiomyopathy and excessive trabeculation.ConclusionTreatment of reversible causes of cardiac rhythm abnormalities such as type II AIT should be considered before choosing other treatment modalities, particularly in patients with structural cardiac disorders. The importance of a multidisciplinary approach in complex cases such as the one reported, thus, cannot be emphasized enough.

Psoriatic arthritis (PsA) is influenced by a complex genetic predisposition. In patients with PsA, interleukin (IL) -17A plays a key role in triggering a complex autoimmune/autoinflammatory immune response in conjunction with other pro-inflammatory cytokines (such as tumor necrosis factor-alpha, IL-23, monocyte chemotactic protein-1, and IL-6). PsA manifests with various clinical symptoms, including musculoskeletal diseases and extra-articular manifestations. In particular, mediated by the soluble IL-17A presents a higher cardiovascular risk, suggesting connection between inflammation and cardiovascular diseases beyond the traditional risk factors. Moreover, studies have shown that patients with psoriasis are ten times at higher risk of developing dilated cardiomyopathy than those without psoriasis. Therefore, owing to the prominent role of IL-17A and psoriasis in the pathogenesis of PsA and endothelial dysfunction, we hypothesized that IL-17A is crucial in the early development of diastolic dysfunction (DD) and could serve as a tool to identify patients with asymptomatic DD and PsA. Although transthoracic echocardiography is the primary evaluation method for DD, it requires skilled personnel, routine parameters assessment, such as mitral inflow, and tissue Doppler imaging. As a result, assessing parameters such as left atrial deformity using novel techniques could be valuable for a more specific evaluation and diagnosis of DD. Clinical characteristics and laboratory parameters of PsA activity, cardiac ultrasound parameters, or cardiac functional markers like N-terminal pro-brain natriuretic peptide (NT-pro-BNP) can be correlated with the concentration of serum IL-17A. Moreover, determining the diagnostic accuracy of circulating IL-17A for early DD can also serve as a laboratory biomarker for diagnosing DD in asymptomatic patients. Thus, if the diagnostic accuracy of IL-17A for DD can be proven, the identification of biological drugs that inhibit IL-17A could be advantageous in treating patients with PsA and echocardiography-verified asymptomatic DD.

To showcase results of arterial blood gases’ analysis in elite breath-hold divers sampled at depths where their total lung capacities are below their residual lung volume on surface. Three male elite breath-hold divers performed body plethysmographies to determine their lung volumes. Two dives were performed, one on normal inhalation to 60 m of depth and the second on complete exhalation to 10 m of depth. Blood samples were taken on five occasions; before the first dive, at 60 and 10 m of depth and immediately after resurfacing after both dives. Arterial blood gases’ analysis at 60 m of depth showed an increase in partial pressures of oxygen and carbon dioxide, a consequent decrease in pH and an increase in concentration of HCO3−. After resurfacing, in two divers, values mostly returned to normal; hypoxemia was observed in one diver. At 10 m of depth, all values showed similar variation, and hypoxemia was observed in the same diver but at depth. Upon resurfacing, all values returned to normal. This is the first study performed at depths where the total lung capacities of participants are below their residual lung volumes at the surface. Partial pressure of carbon dioxide increases at depth to higher than normal values causing pH to decrease thus exceeding the buffering potential of the blood. In addition, previous assumptions that maximum depth in breath-hold divers is where total lung capacity is reduced to their residual volume proved wrong as our group of divers had no symptoms after resurfacing.

Arterio-venous fistula (AVF) closure is sometimes performed in patients with well-functioning kidney graft, either as a policy, on patient's request or due to complications (high-flow, aneurysms, etc.). Possible long-term complications on the arm with closed AVF are rarely discussed in the literature. In this study we report long-term complications after AVF closure in a cohort of transplant patients.

Background Oxidized low-density lipoprotein (oxLDL) particles support low-grade inflammation and have been found in synovial fluid from osteoarthritis (OA) joints [1]. Their component is 7-ketocholesterol (7-KC), which arises as the result of the oxidation of cholesterol [1]. 7-KC acts proinflammatory and it binds to Toll-like receptor (TLR) 4 expressed on macrophages [1]. Activation of TLR4 stimulates the classical macrophage maturation program, resulting in a specific phenotype of inducible nitric oxide synthase positive (iNOS+) and macrophage (M) 1 function, which produce and secrete proinflammatory chemokines and cytokines [2]. M2 macrophages are associated with wound healing by the production of arginase-1 [2,3]. Synovial macrophages are of critical importance in the symptomatology and structural progression of OA since M1 polarized macrophages accumulate in human OA synovial tissue during exacerbation [3]. However, it is not known whether 7-KC can re-program synovial tissue macrophages and support M1 polarization. Objectives We analyzed the influence of 7-KC on the polarization of CD68+ macrophages in the suspension of synovial mononuclear cells (SMCs) in respect to lipopolysaccharide (LPS), as M1 inducer. Methods Mature synovial tissue samples were obtained during alloarthroplasty of the knee (N = 56). Paraffin embedded tissue sections were labelled by double immunofluorescence using a combination of antibodies directed toward CD68 and iNOS, arginase-1, CCL2 or CCL22. Suspension of SMCs was prepared by enzymatic digestion of tissue samples using collagenase IV and gradient density centrifugation. We analyzed intracellular (iNOS, arginase-1, CCL2, and CCL22) and surface (CD91, mannose receptor, HLA-DR, CD80, CD86 and decoy D6) antigens expression in CD68+ cells in the suspension of freshly isolated or 18 hour-cultured SMCs with 7-KC (25 μM), LPS (10 ng/ml), their combination or in the medium only. Results iNOS and CCL2 were more frequently labelled in lymphocyte clusters, while arginase-1 and CCL22 were labelled in synovial lining CD68+ cells. Phenotype of CD68+ cells did not change significantly after the 18 hour- culture in the medium only, except the decrease of mannose receptor and CD91, when compared with freshly isolated cells. 7-KC increased the percentage of CD86 expressing CD68+ cells, whereas decreased surface expression of CD91 and chemokine decoy D6, like in the culture with LPS, when compared with cells cultured in the medium only. 7-KC decreased the frequency of arginase-1+/CD68+ cells in the suspension and did not change iNOS+ in CD68+ cells, thus increasing the ratio of iNOS+/arginase-1+ in CD68+ subset. 7-KC was unable to increase CCL2 like LPS in comparison with cells cultured in the medium only. Neither 7-KC nor LPS affected CCL22 expression in the CD68+ subset. Conclusion These data provide a new perspective in understanding the polarization of macrophages toward the M1 phenotype mediated with oxysterol 7-KC in vitro . References [1]Niki E. Biomarkers of lipid peroxidation in clinical material. Biochim Biophys Acta. 2014;1840(2):809-17. [2]Fernandes TL, Gomoll AH, Lattermann C, Hernandez AJ, Bueno DF, Amano MT. Macrophage: A Potential Target on Cartilage Regeneration. Front Immunol. 2020;11:111. [3]Zhang H, Cai D, Bai X. Macrophages regulate the progression of osteoarthritis. Osteoarthritis Cartilage. 2020;28(5):555-561. Acknowledgements The University of Rijeka supported the research by the grants No. Uni-ri-biomed-18-110 and No. Uni-ri-biomed-18-160. Disclosure of Interests None declared.

Background:The vitamin D receptor (VDR) is a nuclear receptor responsible for the transcription of many vitamin D-dependent genes.Recently vitamin D low serum level have been recognized as a risk factor for cardiovascular disease.Since vitamin D achieves its biological function through the vitamin D receptor, it can be assumed that polymorphisms of the VDR gene that affect its functionality may be associated with an increased risk for cardiovascular diseases. 1The aim of this research is to investigate the possible association of three known VDR polymorphisms -FokI (rs2228570), BsmI (rs1544410) and Taq1 (rs731236) with acute myocardial infarction.Also, to determine the vitamin D serum level and its association with acute myocardial infarction in the population of the northern Adriatic.Methods: This cross-sectional study included 155 subjects with acute myocardial infarction and 105 healthy subjects in the control group.Serum vitamin D level was determined using liquid chromatography tandem mass spectrometry (LC-MS/MS).Allele frequencies at polymorphic sites rs2228570, rs1544410 and rs731236 of the VDR gene were determined using real time polymerase chain reaction (RT-PCR).Results: No significant difference was found in the serum level of vitamin D between the studied groups.There was no association between the Fok1 (rs2228570) VDR polymorphism and acute myocardial infarction.A significant association between the T/T genotype of the BsmI (rs1544410) and the G/G genotype of the Taq1 (rs731236) VDR polymorphism and acute myocardial infarction was found. Conclusion:The results of this study suggest a potential association of BsmI (rs1544410) and Taq1 (rs731236) VDR polymorphisms with acute myocardial infarction. 2 Since no difference was found in the vitamin D serum level between the studied groups, it could be concluded that the investigated VDR polymorphisms are associated with acute myocardial infarction independently of the vitamin D serum level.