Pro-oxidative priming but maintained cardiac function in a broad spectrum of murine models of chronic kidney disease.

AIMS: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular events and exhibit myocardial changes including left ventricular (LV) hypertrophy and fibrosis, overall referred to as 'uremic cardiomyopathy'. Although different CKD animal models have been studied for cardiac effects, lack of consistent reporting on cardiac function and pathology complicates clear comparison of these models. Therefore, this study aimed at a systematic and comprehensive comparison of cardiac function and cardiac pathophysiological characteristics in eight different CKD models and mouse strains, with a main focus on adenine-induced CKD. METHODS AND RESULTS: CKD of different severity and duration was induced by subtotal nephrectomy or adenine-rich diet in various strains (C57BL/6J, C57BL/6 N, hyperlipidemic C57BL/6J ApoE-/-, 129/Sv), followed by the analysis of kidney function and morphology, blood pressure, cardiac function, cardiac hypertrophy, fibrosis, myocardial calcification and inflammation using functional, histological and molecular techniques, including cardiac gene expression profiling supplemented by oxidative stress analysis. Intriguingly, despite uremia of variable degree, neither cardiac dysfunction, hypertrophy nor interstitial fibrosis were observed. However, already moderate CKD altered cardiac oxidative stress responses and enhanced oxidative stress markers in each mouse strain, with cardiac RNA sequencing revealing activation of oxidative stress signaling as well as anti-inflammatory feedback responses. CONCLUSION: This study considerably expands the knowledge on strain- and protocol-specific differences in the field of cardiorenal research and reveals that several weeks of at least moderate experimental CKD increase oxidative stress responses in the heart in a broad spectrum of mouse models. However, this was insufficient to induce relevant systolic or diastolic dysfunction, suggesting that additional "hits" are required to induce uremic cardiomyopathy. TRANSLATIONAL PERSPECTIVE: Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular adverse events and exhibit myocardial changes, overall referred to as 'uremic cardiomyopathy'. We revealed that CKD increases cardiac oxidative stress responses in the heart. Nonetheless, several weeks of at least moderate experimental CKD do not necessarily trigger cardiac dysfunction and remodeling, suggesting that additional "hits" are required to induce uremic cardiomyopathy in the clinical setting. Whether the altered cardiac oxidative stress balance in CKD may increase the risk and extent of cardiovascular damage upon additional cardiovascular risk factors and/or events will be addressed in future studies.

Impact of light therapy on rotating night shift workers: the EuRhythDia study.

AIMS: Disturbances in circadian rhythms may promote cardiometabolic disorders in rotating night shift workers (r-NSWs). We hypothesized that timed light therapy might reverse disrupted circadian rhythms and glucose intolerance observed among r-NSWs). METHODS: R-NSWs were randomly assigned to a protocol that included 12 weeks on followed by 12 weeks off light therapy (n = 13; 6 men; mean age, 39.5 ± 7.3 years) or a no-treatment control group (n = 9; 3 men; mean age 41.7 ± 6.3 years). Experimental and control participants underwent identical metabolic evaluations that included anthropometric, metabolic (including oral glucose tolerance tests), lipid, and inflammation-associated parameters together with an assessment of sleep quality and expression of circadian transcription factors REV-ERBα and BMAL1 in peripheral blood mononuclear cells (PBMCs) at baseline, 12 weeks, and 24 weeks of the protocol. RESULTS: Twelve weeks of warm white-light exposure (10,000 lx at 35 cm for 30 min per day) had no impact on sleep, metabolic, or inflammation-associated parameters among r-NSWs in the experimental group. However, our findings revealed significant decreases in REV-ERBα gene expression (p = 0.048) and increases in the REV-ERBα/BMAL1 ratio (p = 0.040) compared to baseline in PBMCs isolated from this cohort. Diminished expression of REV-ERBα persisted, although the REV-ERBα/BMAL1 ratio returned to baseline levels after the subsequent 12-day wash-out period. CONCLUSIONS: Our results revealed that intermittent light therapy had no impact on inflammatory parameters or glucose tolerance in a defined cohort of r-NSWs. However, significant changes in the expression of circadian clock genes were detected in PBMCs of these subjects undergoing light therapy.

Efficacy and Safety of ELOM-080 as Add-On Therapy in COVID-19 Patients with Acute Respiratory Insufficiency: Exploratory Data from the Prospective Placebo-Controlled COVARI Trial.

INTRODUCTION: Enhancement of mucociliary clearance (MCC) might be a potential target in treating COVID-19. The phytomedicine ELOM-080 is an MCC enhancer that is used to treat inflammatory respiratory diseases. PATIENTS/METHODS: This randomised, double-blind exploratory study (EudraCT number 2020-003779-17) evaluated 14 days' add-on therapy with ELOM-080 versus placebo in patients with COVID-19 hospitalised with acute respiratory insufficiency. RESULTS: The trial was terminated early after enrolment of 47 patients as a result of poor recruitment. Twelve patients discontinued prematurely, leaving 35 in the per-protocol set (PPS). Treatment with ELOM-080 had no significant effect on overall clinical status versus placebo (p = 0.49). However, compared with the placebo group, patients treated with ELOM-080 had less dyspnoea in the second week of hospitalisation (p = 0.0035), required less supplemental oxygen (p = 0.0229), and were more often without dyspnoea when climbing stairs at home (p < 0.0001). CONCLUSION: These exploratory data suggest the potential for ELOM-080 to improve respiratory status during and after hospitalisation in patients with COVID-19.

Influence of rivaroxaban compared to vitamin K antagonist treatment upon development of cardiovascular calcification in patients with atrial fibrillation and/or pulmonary embolism.

BACKGROUND: Vitamin K antagonists (VKA) such as warfarin or phenprocoumon have been the mainstay of therapy for long-term oral anticoagulant therapy (OAT) in patients with atrial fibrillation or with pulmonary embolism. Due to interferences with matrix Gla-protein, an important vitamin K-dependent local calcification inhibitor in cardiovascular structures, VKA antagonists stimulate cardiovascular calcification (CVC). In contrast, rivaroxaban, a nonvitamin K-dependent oral anticoagulant (NOAC), should be neutral in terms of CVC. We seek to investigate these potential differences in CVC development between VKA versus NOACs in a randomized controlled trial (RCT). METHODS: The influence of rivaroxaban compared to vitamin K antagonist treatment upon development of cardiovascular calcification in patients with atrial fibrillation and/or pulmonary embolism trial (NCT02066662) is a multicenter, prospective RCT with a two-arm, open-label study design. The primary endpoint is the progression of coronary and aortic valve calcification (quantified as calcification volume score) as assessed by cardiac computed tomography (CT) at 24 months in patients either treated by rivaroxaban or VKA. A total of 192 patients were randomized in a 1:1 fashion. The main inclusion criteria were the presence of atrial fibrillation and/or pulmonary embolism with the indication for OAT and pre-existent coronary calcification. The development of CVC will be assessed by follow-up CT at 12 and 24 months. RESULTS: In total 192 patients (median age 70, 72% male) were enrolled over a period of 5 years and followed up for 2 years.

Light therapy improves diurnal blood pressure control in night shift workers via reduction of catecholamines: the EuRhythDia study.

OBJECTIVES: Night shift work is associated with high rates of hypertension and cardiometabolic disease, which are linked to disrupted circadian rhythms. We hypothesized that timed light therapy might improve disrupted circadian rhythms and stabilize diurnal control of blood pressure and glucose in night shift workers. METHODS: We randomized 24 rotating night shift workers (mean age, 36 ±â€Š13 years, 7 men) who had spent a median of 6 years on rotating night shifts (median, six night shifts per month) to 12 weeks of light therapy or no intervention and compared them with 12 daytime workers (37 ±â€Š11 years, 6 men). We measured oral glucose tolerance (OGTT), 24-h blood pressure and arterial stiffness, and the circadian profiles of melatonin, cortisol, metanephrine and nor-metanephrine at baseline, after 12 weeks of intervention, and 12 weeks after the end of intervention. RESULTS: At baseline, fewer night shift workers showed dipper status as compared with daytime workers (29 vs. 58%; P < 0.001). After 12 weeks of light therapy, there was a highly significant increase in the proportion of dippers (to 58%; P < 0.0001). We also observed a significant decrease in serum glucose during OGTT in the light therapy group (-22%; P < 0.05) with no change in serum insulin. Whilst circadian profiles of melatonin and cortisol were unchanged, plasma metanephrine and nor-metanephrine levels were significantly reduced in the light therapy group (P < 0.01). CONCLUSION: Timed light therapy improves diurnal blood pressure control and glucose tolerance in rotating night shift workers. This effect is unrelated to melatonin and cortisol but is paralleled by reduced catecholamine levels.

[Magnesium: a kardio-renal viewpoint]. / Magnesiumstoffwechsel.

Disturbances in magnesium homeostasis are frequent clinical conditions, particularly the prevalence of hypomagnesaemia is high. However, it remains an open question which laboratory method is optimal to assess the magnesium level in the body. Most frequently physicians measure total magnesium in serum. Many associative data from observational studies point towards an association between low magnesium levels and increased cardiovascular risk as well as increased mortality. Vice versa, normal-to-high magnesium levels in patients with advanced renal failure translate to a better outcome. The present review summarizes our knowledge on protective effects of magnesium. Additionally, we address the limited evidence supporting targeted magnesium supplementation.

Electromagnetic interference with implantable cardioverter-defibrillators at power frequency: an in vivo study.

BACKGROUND: The number of implantable cardioverter-defibrillators (ICDs) for the prevention of sudden cardiac death is continuing to increase. Given the technological complexity of ICDs, it is of critical importance to identify and control possible harmful electromagnetic interferences between various sources of electromagnetic fields and ICDs in daily life and occupational environments. METHODS AND RESULTS: Interference thresholds of 110 ICD patients (1-, 2-, and 3-chamber ICDs) were evaluated in a specifically developed test site. Patients were exposed to single and combined electric and magnetic 50-Hz fields with strengths of up to 30 kV·m⁻¹ and 2.55 mT. Tests were conducted considering worst-case conditions, including maximum sensitivity of the device or full inspiration. With devices being programmed to nominal sensitivity, ICDs remained unaffected in 91 patients (83%). Five of 110 devices (5%) showed transient loss of accurate right ventricular sensing, whereas 14 of 31 (45%) of the 2- and 3-chamber devices displayed impaired right atrial sensing. No interference was detected in 71 patients (65%) within the tested limits with programming to maximum sensitivity, whereas 20 of 110 subjects (18%) exhibited right ventricular disturbances and 19 of 31 (61%) subjects exhibited right atrial disturbances. CONCLUSIONS: Extremely low-frequency daily-life electromagnetic fields do not disturb sensing capabilities of ICDs. However, strong 50-Hz electromagnetic fields, present in certain occupational environments, may cause inappropriate sensing, potentially leading to false detection of atrial/ventricular arrhythmic events. When the right atrial/right ventricular interferences are compared, the atrial lead is more susceptible to electromagnetic fields. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov/ct2/show/NCT01626261. Unique identifier: NCT01626261.

Medical options to fight mortality in end-stage renal disease: a review of the literature.

Many therapeutic strategies for end-stage renal disease (ESRD) patients have failed to exhibit survival improvement in large-scale randomized controlled trials (RCTs). The current review gives an overview on the medical strategies for treatment of ESRD patients that have previously been tested in RCTs with mortality reduction as pre-specified study endpoint. We identified 19 RCTs with the following therapeutic strategies: haematocrit increase by erythropoietin (n = 1), growth hormone application (n = 1), lipid-lowering by statins (n = 3), renin-angiotensin system blockage (n = 4), ß-receptor blockage (n = 1), homocysteine lowering (n = 5), application of anti-oxidative substances (n = 2), omega-3-fatty-acid supplementation (n = 1) and calcium-free phosphate binders (n = 1). While several of these studies were able to demonstrate reductions in hard cardiovascular endpoints such as myocardial infarction, survival improvement in ESRD patients was demonstrated in only three studies. The substances tested in these three trials were telmisartan, candesartan and carvedilol. In summary, most pharmaceutical mono-interventions failed to reduce mortality in ESRD patients, i.e. a multi-morbid population. Apart from the issues relating to future trial design, this raises the question of whether we need multi-faceted interventions to improve this dismal situation. Until then, nephrologists are left with little evidence and lots of opinions.

The role of vitamin D in cardiovascular disease: from present evidence to future perspectives.

Vitamin D and its metabolites have wide-spread physiological roles far beyond the well described effects in skeletal biology. Many physiological processes are directly or indirectly regulated by vitamin D and in consequence, vitamin D deficiency is implicated in numerous disease conditions. Summarizing previous assumptions on the optimal vitamin D levels in humans these data point towards calcidiol levels of approximately 30 ng/ml as being sufficient. The role of vitamin D deficiency in cardiovascular disease is a relatively novel field of interest. Well substantiated experimental data describe convincingly regulatory effects of vitamin D regarding various cardiovascular risk factors such as hypertension and diabetes mellitus. Activation of the vitamin D receptor suppresses e.g. the renin-angiotensin system. These experimental data are strongly supported by epidemiological and observational human data that link vitamin D deficiency to the incidence, degree and prevalence of cardiovascular risk factors and disease conditions. In contrast to the in vivo data and to the homogenous non-interventional observations, we know much less about controlled prospectively evaluated supplementation of vitamin D as a potentially therapeutic agent on cardiovascular events. High quality, large, and randomized controlled trials aiming primarily on cardiovascular end-points are absent. Speculations about the vitamin D usage in prevention or therapy of cardiovascular disease need to take potential drawbacks of vitamin D overdosing into account: Vitamin D overdosing might induce hypercalcemia, hyperphosphatemia, and increases in fibroblast growth-factor 23. The limited evidence regarding vitamin D therapy currently prevents general recommendations for vitamin D application in cardiology.

The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia.

Despite achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure, and glycemia in accordance with current standards of care, patients with dyslipidemia remain at high residual risk of vascular events. Atherogenic dyslipidemia, characterized by elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease (CVD), type 2 diabetes mellitus, or metabolic syndrome and contributes to both macrovascular and microvascular residual risk. However, atherogenic dyslipidemia is largely underdiagnosed and undertreated in clinical practice. The Residual Risk Reduction Initiative (R3i) was established to address this highly relevant clinical issue. The aims of this position paper are (1) to highlight evidence that atherogenic dyslipidemia is associated with residual macrovascular and microvascular risk in patients at high risk for CVD, despite current standards of care for dyslipidemia and diabetes; and (2) to recommend therapeutic intervention for reducing this residual vascular risk supported by evidence and expert consensus. Lifestyle modification with nutrition and exercise is an important, effective, and underutilized first step in reducing residual vascular risk. Therapeutic intervention aimed at achievement of all lipid targets is also often required. Combination lipid-modifying therapy, with the addition of niacin, a fibrate, or omega-3 fatty acids to statin therapy, increases the probability of achieving all lipid goals. Outcomes studies are in progress to evaluate whether these combination treatment strategies translate to a clinical benefit greater than that achieved with statins alone. The R3i highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual risk of CVD events and microvascular complications among patients with dyslipidemia receiving therapy for high levels of LDL cholesterol and for diabetes in accordance with current standards of care.

The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient.

Despite current standards of care aimed at achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure and glycaemia, dyslipidaemic patients remain at high residual risk of vascular events. Atherogenic dyslipidaemia, specifically elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease, type 2 diabetes, obesity or metabolic syndrome and is associated with macrovascular and microvascular residual risk. The Residual Risk Reduction Initiative (R3I) was established to address this important issue. This position paper aims to highlight evidence that atherogenic dyslipidaemia contributes to residual macrovascular risk and microvascular complications despite current standards of care for dyslipidaemia and diabetes, and to recommend therapeutic intervention for reducing this, supported by evidence and expert consensus. Lifestyle modification is an important first step. Additionally, pharmacotherapy is often required. Adding niacin, a fibrate or omega-3 fatty acids to statin therapy improves achievement of all lipid risk factors. Outcomes studies are evaluating whether these strategies translate to greater clinical benefit than statin therapy alone. In conclusion, the R3I highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual vascular risk among dyslipidaemic patients who are treated in accordance with current standards of care.

Anti-atherosclerotic properties of telmisartan in advanced atherosclerotic lesions in apolipoprotein E deficient mice.

Clinical studies have demonstrated that the inhibition of the renin-angiotensin system (RAS) by either an angiotensin-converting enzyme (ACE)-inhibitor or an angiotensin II receptor type 1 (AT(1))-antagonist reduces cardiovascular disease. The objective of this study was to evaluate underlying mechanisms of the AT(1)-antagonist telmisartan in comparison to the ACE-inhibitor ramipril on advanced atherosclerotic lesions. Thirty-two-week-old apolipoprotein E deficient mice (n=60) exhibiting advanced atherosclerotic lesions were fed a chow diet supplemented with ramipril or telmisartan for 16 weeks. Twenty mice received a standard diet. Mice receiving telmisartan had a 38% and mice receiving ramipril had a 18% reduction in progression of atherosclerotic lesion size within the innominate artery. Signs of plaque instability such as frequency of intra-plaque hemorrhage and size of the necrotic cores were reduced in mice receiving telmisartan. Furthermore, telmisartan-treated mice had fewer macrophages and reduced expression of early growth response gene-1 (Egr-1) within the lesions. Electrophoretic mobility shift assays revealed reduced DNA-binding activity of nuclear factor kappaB (NFkappaB) in the aorta of telmisartan-treated mice. In vitro studies in mouse macrophages demonstrated enhanced promoter activation of the nuclear transcription factor peroxisome proliferators-activated receptor gamma (PPARgamma). Target genes of PPARgamma, such as inducible nitric oxide synthase, NFkappaB and Egr-1, showed reduced activity after telmisartan pretreatment. These data suggest that chronic inhibition of the RAS by telmisartan prevails in reducing advanced atherosclerosis and promoting plaque stability over ramipril, possibly through the reduced activity of the pro-inflammatory transcription factors NFkappaB and Egr-1 and through the activation of PPARgamma.

Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells.

A large body of data gathered over the past couple of years has identified the peroxisome proliferator-activated receptors (PPAR) alpha, gamma, and beta/delta as transcription factors exerting modulatory actions in vascular cells. PPARs, which belong to the nuclear receptor family of ligand-activated transcription factors, were originally described as gene regulators of various metabolic pathways. Although the PPARalpha, gamma, and beta/delta subtypes are approximately 60% to 80% homologous in their ligand- and DNA-binding domains, significant differences in ligand and target gene specificities are observed. PPARalpha is activated by polyunsaturated fatty acids and oxidized derivatives and by lipid-modifying drugs of the fibrate family, including fenofibrate or gemfibrozil. PPARalpha controls expression of genes implicated in lipid metabolism. PPARgamma, in contrast, is a key regulator of glucose homeostasis and adipogenesis. Ligands of PPARgamma include naturally occurring FA derivatives, such as hydroxyoctadecadienoic acids (HODEs), prostaglandin derivatives such as 15-deoxyDelta12,14-prostaglandin J2, and glitazones, insulin-sensitizing drugs presently used to treat patients with type 2 diabetes. Ligands for PPARbeta/delta are polyunsaturated fatty acids, prostaglandins, and synthetic compounds, some of which are presently in clinical development. PPARbeta/delta stimulates fatty acid oxidation predominantly acting in muscle. All PPARs are expressed in vascular cells, where they exhibit antiinflammatory and antiatherogenic properties. In addition, studies in various animal models as well as clinical data suggest that PPARalpha and PPARgamma activators can modulate atherogenesis in vivo. At present, no data are available relating to possible effects of PPARbeta/delta agonists on atherogenesis. Given the widespread use of PPARalpha and PPARgamma agonists in patients at high risk for cardiovascular disease, the understanding of their function in the vasculature is not only of basic interest but also has important clinical implications. This review will focus on the role of PPARs in the vasculature and summarize the present understanding of their effects on atherogenesis and its cardiovascular complications.