Chronic kidney disease and arrhythmias: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Patients with chronic kidney disease (CKD) are predisposed to heart rhythm disorders, including atrial fibrillation (AF)/atrial flutter, supraventricular tachycardias, ventricular arrhythmias, and sudden cardiac death (SCD). While treatment options, including drug, device, and procedural therapies, are available, their use in the setting of CKD is complex and limited. Patients with CKD and end-stage kidney disease (ESKD) have historically been under-represented or excluded from randomized trials of arrhythmia treatment strategies,1 although this situation is changing.2 Cardiovascular society consensus documents have recently identified evidence gaps for treating patients with CKD and heart rhythm disorders [...

Upgrade of right ventricular pacing to cardiac resynchronisation therapy in heart failure : a randomised trial

De novo implanted cardiac resynchronisation therapy with defibrillator (CRT-D) reduces the risk of morbidity and mortality in patients with left bundle branch block, heart failure and reduced ejection fraction (HFrEF). However, among HFrEF patients with right ventricular pacing (RVP), the efficacy of CRT-D upgrade is uncertain.In this multicentre, randomised, controlled trial, 360 symptomatic (New York Heart Association class II-IVa) HFrEF patients with a pacemaker or implantable cardioverter defibrillator (ICD), high RVP burden ≥20%, and a wide, paced QRS complex duration ≥150 ms were randomly assigned to receive CRT-D upgrade (n = 215) or ICD (n = 145) in a 3:2 ratio. The primary outcome was the composite of all-cause mortality, heart failure hospitalisation or <15% reduction of left ventricular end-systolic volume assessed at 12 months. Secondary outcomes included all-cause mortality or heart failure hospitalisation.Over a median follow-up of 12.4 months, the primary outcome occurred in 58/179 (32.4%) in the CRT-D arm vs. 101/128 (78.9%) in the ICD arm [odds ratio 0.11; 95% confidence interval (CI) 0.06-0.19; p < 0.001]. All-cause mortality or heart failure hospitalization occurred in 22/215 (10%) in the CRT-D arm vs. 46/145 (32%) in the ICD arm (hazard ratio 0.27; 95% CI 0.16-0.47; p < 0.001). The incidence of procedure- or device-related complications was similar between the two arms [CRT-D group 25/211 (12.3%) vs. ICD group 11/142 (7.8%)].In pacemaker or ICD patients with significant RVP burden and reduced ejection fraction, upgrade to CRT-D compared to ICD therapy reduced the combined risk of all-cause mortality, heart failure hospitalisation or absence of reverse remodelling

International longitudinal registry of patients with atrial fibrillation and treated with rivaroxaban: RIVaroxaban Evaluation in Real life setting (RIVER)

Background Real-world data on non-vitamin K oral anticoagulants (NOACs) are essential in determining whether evidence from randomised controlled clinical trials translate into meaningful clinical benefits for patients in everyday practice. RIVER (RIVaroxaban Evaluation in Real life setting) is an ongoing international, prospective registry of patients with newly diagnosed non-valvular atrial fibrillation (NVAF) and at least one investigator-determined risk factor for stroke who received rivaroxaban as an initial treatment for the prevention of thromboembolic stroke. The aim of this paper is to describe the design of the RIVER registry and baseline characteristics of patients with newly diagnosed NVAF who received rivaroxaban as an initial treatment. Methods and results Between January 2014 and June 2017, RIVER investigators recruited 5072 patients at 309 centres in 17 countries. The aim was to enroll consecutive patients at sites where rivaroxaban was already routinely prescribed for stroke prevention. Each patient is being followed up prospectively for a minimum of 2-years. The registry will capture data on the rate and nature of all thromboembolic events (stroke / systemic embolism), bleeding complications, all-cause mortality and other major cardiovascular events as they occur. Data quality is assured through a combination of remote electronic monitoring and onsite monitoring (including source data verification in 10% of cases). Patients were mostly enrolled by cardiologists (n = 3776, 74.6%), by internal medicine specialists 14.2% (n = 718) and by primary care/general practice physicians 8.2% (n = 417). The mean (SD) age of the population was 69.5 (11.0) years, 44.3% were women. Mean (SD) CHADS2 score was 1.9 (1.2) and CHA2DS2-VASc scores was 3.2 (1.6). Almost all patients (98.5%) were prescribed with once daily dose of rivaroxaban, most commonly 20 mg (76.5%) and 15 mg (20.0%) as their initial treatment; 17.9% of patients received concomitant antiplatelet therapy. Most patients enrolled in RIVER met the recommended threshold for AC therapy (86.6% for 2012 ESC Guidelines, and 79.8% of patients according to 2016 ESC Guidelines). Conclusions The RIVER prospective registry will expand our knowledge of how rivaroxaban is prescribed in everyday practice and whether evidence from clinical trials can be translated to the broader cross-section of patients in the real world

Transcriptional Profiling of Human Liver Identifies Sex-Biased Genes Associated with Polygenic Dyslipidemia and Coronary Artery Disease

Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Top biological functions and diseases significantly enriched in sex-biased genes include transcription, chromatin organization and modification, sexual reproduction, lipid metabolism and cardiovascular disease. Notably, sex-biased genes are enriched at loci associated with polygenic dyslipidemia and coronary artery disease in genome-wide association studies. Moreover, of the 8 sex-biased genes at these loci, 4 have been directly linked to monogenic disorders of lipid metabolism and show an expression profile in females (elevated expression of ABCA1, APOA5 and LDLR; reduced expression of LIPC) that is consistent with the lower female risk of coronary artery disease. Female-biased expression was also observed for CYP7A1, which is activated by drugs used to treat hypercholesterolemia. Several sex-biased drug-metabolizing enzyme genes were identified, including members of the CYP, UGT, GPX and ALDH families. Half of 879 mouse orthologs, including many genes of lipid metabolism and homeostasis, show growth hormone-regulated sex-biased expression in mouse liver, suggesting growth hormone might play a similar regulatory role in human liver. Finally, the evolutionary rate of protein coding regions for human-mouse orthologs, revealed by dN/dS ratio, is significantly higher for genes showing the same sex-bias in both species than for non-sex-biased genes. These findings establish that human hepatic sex differences are widespread and affect diverse cell metabolic processes, and may help explain sex differences in lipid profiles associated with sex differential risk of coronary artery disease

Health outcomes of vitamin D. Part I. Characteristics and classic role

Vitamin D is a compound responsible for maintaining mineral homeostasis. It protects against calcium and phosphate deficiency through the effects on the intestine, kidney, parathyroid gland and bone. All mechanisms that help maintain mineral homeostasis of the body are regulated by the vitamin D hormonal form - calcitriol. Synthesis of vitamin D starts in the skin as a non-enzymatic process, which begins during exposure to sunlight, when the absorption of ultraviolet B (UVB) radiation results in convertion of 7-dehydrocholesterol, a metabolite of cholesterol that is stored in the skin, to precholecalciferol (previtamin-D3) that is immediately converted into cholecalciferol (vitamin D3). After the skin synthesis cholecalciferol is transported to the liver where it undergoes hydroxylation, what results in formation of calcidiol (25(OH) D3). The second metabolic process takes place in the kidney, where calcidiol undergoes hydroxylation at the C-1 position to the hormonal, the most active metabolite - 1,25-dihydroxyvitamin D (calcitriol). Vitamin D deficiency may result in bone diseases, such as rickets in children and osteomalacia and osteoporosis in adults. Symptoms of osteomalacia affect mainly the skeletal system and are similar to that observed in rickets. It concerns thoracic kyphosis, pelvis deformities and also the varus knee. Osteoporosis is another condition that is related to abnormalities of mineral homeostasis. It is characterized by the progressive loss of bone mass, impaired bone microarchitecture, and consequently increased fragility and susceptibility to fracture. For the last several years other, non-classic actions of vitamin D3 have been discussed. It was engendered by the discovery of vitamin D3 receptor (VDR) in the most of body tissues and cells. Hence, there are many hypotheses which suggest the inverse relationship between vitamin D status and various diseases, such as cancer, autoimmune diseases, diabetes mellitus and others.Witamina D jest związkiem chemicznym odpowiedzialnym za utrzymanie homeostazy mineralnej organizmu. Poprzez wpływ na jelita, nerki, przytarczyce i kości zapobiega niedoborowi wapnia i fosforanów. Aktywną formą witaminy D3 o właściwościach hormonalnych jest kalcytriol, który odpowiada za utrzymanie homeostazy mineralnej organizmu. Pierwszy etap syntezy witaminy D zachodzi w skórze, pod wpływem ekspozycji na światło słoneczne (UVB). Polega on na nieenzymatycznej przemianie 7-dehydrocholesterolu do prowitaminy D (pre-D3), która natychmiast ulega przekształceniu do cholekalcyferolu (witaminy D3). Wyprodukowana w skórze witamina D3 jest następnie transportowana do wątroby, gdzie ulega hydroksylacji, w wyniku której powstaje kalcydiol (25(OH)D3). Drugi proces metaboliczny zachodzi w nerkach, gdzie kalcydiol ulega hydroksylacji w pozycji C-1 do hormonalnie najbardziej aktywnego metabolitu witaminy D - 1,25-dihydroksywitaminy D (kalcytriol). Niedobór witaminy D może prowadzić do chorób kości, takich jak krzywica u dzieci oraz osteomalacja i osteoporoza u osób dorosłych. Objawy osteomalacji dotyczą głównie układu kostnego i są zbliżone do tych obserwowanych w krzywicy. Są to m.in.: kifoza piersiowa, deformacje miednicy i szpotawość kolan. Osteoporoza to choroba, która także związane jest z zaburzeniem homeostazy mineralnej. Charakteryzuje się postępującą utratą masy kostnej, uszkodzeniami mikroarchitektury kości, i w konsekwencji zwiększoną ich kruchością i podatnością na złamania. Na przestrzeni ostatnich lat pojawiły się doniesienia dotyczące innych, nieklasycznych działań witaminy D3. Stwierdzono obecność receptora witaminy D (VDR) w wielu tkankach organizmu, które nie biorą udziału w utrzymaniu homeostazy wapniowo-fosforanowej. Świadczy to o wielokierunkowym działaniu tego związku. Pojawiło się wiele hipotez sugerujących związek między niedoborem witaminy D a występowaniem wielu różnych chorób, takich jak: nowotwory, choroby autoimmunologiczne, cukrzyca i inne

Health outcomes of vitamin D. Part II. Role in prevention of diseases

Apart from the classic role of vitamin D, its hormonal active form, calcitriol is also characterized by pleiotropic effects on various organs and tissues. For the last several years, many researchers have shown an association between deficiency of vitamin D and the risk of type 2 diabetes mellitus (T2DM). Recent investigations suggested the need of vitamin D supplementation in T2DM prevention. It was shown that vitamin D deficiency decreases insulin secretion. It was also observed that proper vitamin D supplementation may improve the ability of the cells of the islets of Langerhans to synthesize many proteins de novo and to convert proinsulin to insulin. Apart from regulating bone metabolism and also calcium and phosphate homeostasis, 1,25(OH)2D3 exerts antiproliferative and pro-differentiating effects on a wide variety of cell types. It also induces apoptosis of cancer cells and slows their proliferation. In a number of major studies the relationship between low vitamin D levels and increased risk of various cancers was observed. It concerns colorectal, lung, prostate, breast and ovarian cancer. It was observed that in patients with low serum vitamin D concentrations such disorders as ischemic heart disease, heart attack, stroke, cardiac arrhythmia, and hypertension were more frequent and mortality was significantly higher. These results led the researchers to consider vitamin D deficiency as a potential risk factor for cardiovascular diseases. The possible mechanism in the pathogenesis of cardiovascular diseases that may be related to low levels of vitamin D, is its adverse effect on the renin-angiotensin-aldosterone system (RAAS). Calcitriol is also an important determinant of muscle cell proliferation and differentiation, as well as inhibition of apoptosis. Vitamin D is synthesized in the skin. However, there are only a few food products that are rich in vitamin D3, e.g.: fish oils, fish and fortified-products, such as dairy products and margarines. Individuals who are vulnerable to vitamin D deficiency should be supplemented.Poza klasyczną rolą witaminy D, jej hormonalna postać – kalcytriol wykazuje plejotropowe działanie na różne tkanki i narządy w organizmie. W ciągu ostatnich lat, wielu badaczy wykazało związek pomiędzy niedoborem witaminy D a ryzykiem wystąpienia cukrzycy typu 2 (T2DM). Wyniki badań sugerują potrzebę jej suplementacji w profilaktyce T2DM. Udowodniono związek między niedoborem witaminy D a upośledzonym wydzielaniem insuliny. Zaobserwowano również, że prawidłowa jej suplementacja poprawia zdolność komórek wysp Langerhansa do syntezy de novo wielu białek oraz przekształcania proinsuliny w insulinę. Poza regulowaniem metabolizmu kości i utrzymaniem homeostazy wapniowo-fosforowej, 1,25(OH)2D3 reguluje procesy proliferacji i różnicowania różnych komórek. Ponadto indukuje apoptozę komórek nowotworowych i zwalnia tempo ich proliferacji. W wielu badaniach zaobserwowano związek pomiędzy niskim poziomem witaminy D a zwiększonym ryzykiem wystąpienia różnych nowotworów. Dotyczyło to raka jelita grubego, płuc, prostaty, piersi i jajników. U pacjentów z niskimi stężeniami witaminy D w surowicy zaobserwowano częstsze występowanie schorzeń takich jak choroba niedokrwienna serca, zawał serca, udar mózgu, zaburzenia rytmu serca, nadciśnienie tętnicze oraz wyższą umieralność. Wyniki tych badań skłoniły do uznania niedoboru witaminy D za potencjalny czynnik ryzyka rozwoju chorób sercowo-naczyniowych. Możliwym mechanizmem w ich patogenezie, mogącym tłumaczyć omawiane zjawisko, jest wpływ witaminy D na układ renina-angiotensyna-aldosteron (RAAS). Kalcytriol jest także ważnym czynnikiem, który determinuje proliferację i różnicowanie komórek mięśniowych, jak również hamowanie ich apoptozy. Witamina D jest syntetyzowana w skórze. Niewiele jest jednak produktów spożywczych, które są dobrymi jej źródłami. Są to głównie: oleje rybne, ryby oraz produkty wzbogacane w witaminę D, takie jak produkty mleczne i margaryny. Osoby, które są szczególnie narażone na niedobór tej witaminy powinny stosować jej suplementację

Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial

OBJECTIVES The purpose of this study was to compare the effectiveness of bucindolol with that of metoprolot sucdnate for the maintenance of sinus rhythm in a genetically defined heart failure (HF) population with atrial fibrillation (AF). BACKGROUND Bucindolol is a beta-blocker whose unique pharmacologic properties provide greater benefit in HF patients with reduced ejection fraction (HFrEF) who have the beta(1)-adrenergic receptor (ADRB1) Arg389Arg genotype. METHODS A total of 267 HFrEF patients with a left ventricular ejection fraction (LVEF) RESULTS The hazard ratio (HR) for the primary endpoint was 1.01 (95% confidence interval [CI]: 0.71 to 1.42), but trends for bucindolol benefit were observed in several subgroups. Precision therapeutic phenotyping revealed that a differential response to bucindolol was associated with the interval of time from the initial diagnoses of AF and HF to randomization and with the onset of AF relative to that of the initial HF diagnosis. In a cohort whose first AF and HF diagnoses were CONCLUSIONS Pharmacogeneticalty guided bucindolol therapy did not reduce the recurrence of AF/AFL or ACM compared to that of metoprolol therapy in HFrEF patients, but populations were identified who merited further investigation in future phase 3 trials. (C) 2019 Published by Elsevier on behalf of the American College of Cardiology Foundation