Baylor Jack and Jane Hamilton Heart and Vascular Hospital

BACKGROUND: Endothelial dysfunction (ED) has emerged as a critical process in cardiorenal syndrome (CRS). The concept that ED is closely linked with cardiac and renal dysfunction has become an important target for CRS-related research and clinical practice. SUMMARY: The sequence of events leading to ED is initiated by type I endothelial activation (almost immediately) and type II endothelial activation (over hours, days, and even months), followed by endothelial apoptosis and endothelial necrosis. The fact that ED is a continual cellular event divides this process into reversible ED (endothelial activation) and irreversible ED (endothelial apoptosis and necrosis). This basic research-defined concept may have clinical implications. Although most antihypertensive drugs (ACE inhibitors, statins, etc.) are effective in patients with hypertension and diabetes, some of them have proved to be ineffective, which may partly be attributed to irreversible ED. Even though the etiology of ED consists mainly of asymmetric dimethylarginine, nitric oxide, oxidative stress, and anti-endothelial cell antibodies, many other inducers of ED have been identified. In addition, a distinct role of ED has been reported for each type of CRS in humans. KEY MESSAGES: Further study is warranted to prove whether ED holds promise as a pharmacological target in CRS patients.

AIMS: Gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) is emerging as a new potentially important cause of increased cardiovascular risk. The purpose of this meta-analysis was to systematically estimate and quantify the association between TMAO plasma levels, mortality, and major adverse cardio and cerebrovascular events (MACCE). METHODS AND RESULTS: MEDLINE, ISI Web of Science, and SCOPUS databases were searched for ad hoc studies published up to April 2017. Associations between TMAO plasma levels, all-cause mortality (primary outcome) and MACCE (secondary outcome) were systematically addressed. A total of 17 clinical studies were included in the analytic synthesis, enrolling 26 167 subjects. The mean follow-up in our study population was 4.3 ± 1.5 years. High TMAO plasma levels were associated with increased incidence of all-cause mortality [14 studies for 16 cohorts enrolling 15 662 subjects, hazard ratio (HR): 1.91; 95% confidence interval (CI): 1.40-2.61, P < 0.0001, I2 = 94%] and MACCE (5 studies for 6 cohorts enrolling 13 944 subjects, HR: 1.67, 95% CI: 1.33-2.11, P < 0.00001, I2 = 46%,). Dose-response meta-analysis revealed that the relative risk (RR) for all-cause mortality increased by 7.6% per each 10 μmol/L increment of TMAO [summary RR: 1.07, 95% CI (1.04-1.11), P < 0.0001; based on seven studies]. Association of TMAO and mortality persisted in all examined subgroups and across all subject populations. CONCLUSIONS: This is the first systematic review and meta-analysis demonstrating the positive dose-dependent association between TMAO plasma levels and increased cardiovascular risk and mortality.

BACKGROUND: The effects of cardiac resynchronization therapy (CRT) in patients with mildly symptomatic heart failure have not been fully elucidated. METHODS AND RESULTS: The Multicenter InSync ICD Randomized Clinical Evaluation II (MIRACLE ICD II) was a randomized, double-blind, parallel-controlled clinical trial of CRT in NYHA class II heart failure patients on optimal medical therapy with a left ventricular (LV) ejection fraction < or =35%, a QRS > or =130 ms, and a class I indication for an ICD. One hundred eighty-six patients were randomized: 101 to the control group (ICD activated, CRT off) and 85 to the CRT group (ICD activated, CRT on). End points included peak VO2, VE/CO2, NYHA class, quality of life, 6-minute walk distance, LV volumes and ejection fraction, and composite clinical response. Compared with the control group at 6 months, no significant improvement was noted in peak VO2, yet there were significant improvements in ventricular remodeling indexes, specifically LV diastolic and systolic volumes (P=0.04 and P=0.01, respectively), and LV ejection fraction (P=0.02). CRT patients showed statistically significant improvement in VE/CO2 (P=0.01), NYHA class (P=0.05), and clinical composite response (P=0.01). No significant differences were noted in 6-minute walk distance or quality of life scores. CONCLUSIONS: In patients with mild heart failure symptoms on optimal medical therapy with a wide QRS complex and an ICD indication, CRT did not alter exercise capacity but did result in significant improvement in cardiac structure and function and composite clinical response over 6 months.

SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression of cardiomyopathy and nephropathy, which is characterized by a reduction in oxidative and endoplasmic reticulum stress, restoration of mitochondrial health and enhanced mitochondrial biogenesis, a decrease in proinflammatory and profibrotic pathways, and preservation of cellular and organ integrity and viability. A substantial body of evidence indicates that this characteristic pattern of responses can be explained by the action of SGLT2 inhibitors to promote cellular housekeeping by enhancing autophagic flux, an effect that may be related to the action of these drugs to produce simultaneous upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling, as manifested by an increase in the expression and activity of AMPK (adenosine monophosphate-activated protein kinase), SIRT1 (sirtuin 1), SIRT3 (sirtuin 3), SIRT6 (sirtuin 6), and PGC1-α (peroxisome proliferator-activated receptor γ coactivator 1-α) and decreased activation of mTOR (mammalian target of rapamycin). The distinctive pattern of cardioprotective and renoprotective effects of SGLT2 inhibitors is abolished by specific inhibition or knockdown of autophagy, AMPK, and sirtuins. In the clinical setting, the pattern of differentially increased proteins identified in proteomics analyses of blood collected in randomized trials is consistent with these findings. Clinical studies have also shown that SGLT2 inhibitors promote gluconeogenesis, ketogenesis, and erythrocytosis and reduce uricemia, the hallmarks of nutrient deprivation signaling and the principal statistical mediators of the ability of SGLT2 inhibitors to reduce the risk of heart failure and serious renal events. The action of SGLT2 inhibitors to augment autophagic flux is seen in isolated cells and tissues that do not express SGLT2 and are not exposed to changes in environmental glucose or ketones and may be related to an ability of these drugs to bind directly to sirtuins or mTOR. Changes in renal or cardiovascular physiology or metabolism cannot explain the benefits of SGLT2 inhibitors either experimentally or clinically. The direct molecular effects of SGLT2 inhibitors in isolated cells are consistent with the concept that SGLT2 acts as a nutrient surplus sensor, and thus, its inhibition causes enhanced nutrient deprivation signaling and its attendant cytoprotective effects, which can be abolished by specific inhibition or knockdown of AMPK, sirtuins, and autophagic flux.

OBJECTIVE: To evaluate the efficacy and safety of topiramate (TPM) for weight loss in healthy obese subjects. RESEARCH METHODS AND PROCEDURES: A randomized, double-blind, placebo-controlled, dose-ranging trial was conducted. Three hundred eighty-five subjects, 18 and 75 years of age, were randomized to receive either placebo or TPM at 64, 96, 192, or 384 mg daily. Dosing began at 16 mg once daily. In week 2, the dose was increased to 16 mg twice daily. Thereafter, the dose was raised every week by 32 mg/d (16 mg twice daily) until subjects reached their target dose. Twenty-four weeks after beginning treatment, all subjects were tapered off treatment by a dose reduction of 50% per week. All participants received the same lifestyle program. RESULTS: Mean percent weight loss from baseline to week 24 was -2.6% in placebo-treated patients vs. -5.0%, -4.8%, -6.3%, and -6.3% in the 64, 96, 192, and 384 mg/d TPM groups, respectively. Greater percentages of TPM-treated patients lost at least 5% or 10% of body weight compared with placebo. The most frequent adverse events were related to the central or peripheral nervous system, including paresthesia, somnolence, and difficulty with memory, concentration, and attention. Most events were dose-related, occurred early in treatment, and usually resolved spontaneously; only 21% receiving TPM withdrew due to adverse events compared with 11% on placebo. DISCUSSION: TPM produced significantly greater weight loss than placebo at all doses.

The prolonged QT interval is both widely seen and associated with the potentially deadly rhythm, Torsades de Pointes (TdP). While it can occur spontaneously in the congenital form, there is a wide array of drugs that have been implicated in the prolongation of the QT interval. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. The list of drugs that cause QT prolongation continues to grow, and an updated list of specific drugs that prolong the QT interval can be found at www.qtdrugs.org. This review focuses on the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention and monitoring of prolonged drug-induced QT prolongation and treatment strategies.

BACKGROUND: Transcatheter aortic-valve replacement (TAVR) for the treatment of aortic stenosis can lead to embolization of debris. Capture of debris by devices that provide cerebral embolic protection (CEP) may reduce the risk of stroke. METHODS: We randomly assigned patients with aortic stenosis in a 1:1 ratio to undergo transfemoral TAVR with CEP (CEP group) or without CEP (control group). The primary end point was stroke within 72 hours after TAVR or before discharge (whichever came first) in the intention-to-treat population. Disabling stroke, death, transient ischemic attack, delirium, major or minor vascular complications at the CEP access site, and acute kidney injury were also assessed. A neurology professional examined all the patients at baseline and after TAVR. RESULTS: A total of 3000 patients across North America, Europe, and Australia underwent randomization; 1501 were assigned to the CEP group and 1499 to the control group. A CEP device was successfully deployed in 1406 of the 1489 patients (94.4%) in whom an attempt was made. The incidence of stroke within 72 hours after TAVR or before discharge did not differ significantly between the CEP group and the control group (2.3% vs. 2.9%; difference, -0.6 percentage points; 95% confidence interval, -1.7 to 0.5; P = 0.30). Disabling stroke occurred in 0.5% of the patients in the CEP group and in 1.3% of those in the control group. There were no substantial differences between the CEP group and the control group in the percentage of patients who died (0.5% vs. 0.3%); had a stroke, a transient ischemic attack, or delirium (3.1% vs. 3.7%); or had acute kidney injury (0.5% vs. 0.5%). One patient (0.1%) had a vascular complication at the CEP access site. CONCLUSIONS: Among patients with aortic stenosis undergoing transfemoral TAVR, the use of CEP did not have a significant effect on the incidence of periprocedural stroke, but on the basis of the 95% confidence interval around this outcome, the results may not rule out a benefit of CEP during TAVR. (Funded by Boston Scientific; PROTECTED TAVR ClinicalTrials.gov number, NCT04149535.).

BACKGROUND: Experimental and clinical observations suggest that lowering serum lipid levels may reduce the risk of restenosis after coronary angioplasty. We report the results of a prospective, randomized, double-blind trial evaluating whether lowering lipid levels with lovastatin can prevent or delay restenosis after angioplasty. METHODS: Seven to 10 days before angioplasty, we randomly assigned eligible patients to receive lovastatin (40 mg orally twice daily) or placebo. Patients who underwent successful, complication-free, first-time angioplasty of a native vessel (the index lesion) continued to receive therapy for six months, when a second coronary angiogram was obtained. The primary end point was the extent of restenosis of the index lesion, as assessed by quantitative coronary arteriography. Of 404 patients randomly assigned to study groups, 384 underwent angioplasty; 354 of the procedures were successful, and 321 patients underwent angiographic restudy at six months. RESULTS: At base line, the patients in the lovastatin group (n = 203) and the placebo group (n = 201) were similar with respect to demographic clinical, angiographic, and laboratory characteristics. At base line the mean (+/- SD) degree of stenosis, expressed as a percentage of the diameter of the vessel, was 64 +/- 11 percent in the lovastatin group, as compared with 63 +/- 11 percent in the placebo group (P = 0.22). Despite a 42 percent reduction in the serum level of low-density lipoprotein cholesterol in the lovastatin group, after six months of treatment the amount of stenosis seen in the second angiogram was 46 +/- 20 percent in the placebo group, as compared with 44 +/- 21 percent in the lovastatin group (P = 0.50). Similarly, there were no significant differences in minimal luminal diameter or other measures of restenosis. A trend was noted toward more myocardial infarctions in the lovastatin group, as a result of acute vessel closure or restenosis at the site of angioplasty, but there were no other important differences between the two groups in the frequency of fatal or nonfatal events at six months. CONCLUSIONS: Treatment with high-dose lovastatin initiated before coronary angioplasty does not prevent or delay the process of restenosis in the first six months after the procedure.

BACKGROUND: Acute kidney injury (AKI) remains a deadly condition. Tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein (IGFBP)7 are two recently discovered urinary biomarkers for AKI. We now report on the development, and diagnostic accuracy of two clinical cutoffs for a test using these markers. METHODS: We derived cutoffs based on sensitivity and specificity for prediction of Kidney Disease: Improving Global Outcomes Stages 2-3 AKI within 12 h using data from a previously published multicenter cohort (Sapphire). Next, we verified these cutoffs in a new study (Opal) enrolling 154 critically ill adults from six sites in the USA. RESULTS: One hundred subjects (14%) in Sapphire and 27 (18%) in Opal met the primary end point. The results of the Opal study replicated those of Sapphire. Relative risk (95% CI) in both studies for subjects testing at ≤0.3 versus >0.3-2 were 4.7 (1.5-16) and 4.4 (2.5-8.7), or 12 (4.2-40) and 18 (10-37) for ≤0.3 versus >2. For the 0.3 cutoff, sensitivity was 89% in both studies, and specificity 50 and 53%. For 2.0, sensitivity was 42 and 44%, and specificity 95 and 90%. CONCLUSIONS: Urinary [TIMP-2]•[IGFBP7] values of 0.3 or greater identify patients at high risk and those >2 at highest risk for AKI and provide new information to support clinical decision-making. CLINICAL TRIALS REGISTRATION: Clintrials.gov # NCT01209169 (Sapphire) and NCT01846884 (Opal).

Cardiac arrhythmias comprise a heterogenous group of disorders ranging from benign premature heart beats to malignant sustained ventricular tachyarrhythmias. Catheter and device-based therapies coupled with landmark clinical trials have enhanced our understanding and treatment of these disorders. Studies evaluating pathophysiology, disease course, and therapeutic options for cardiac arrhythmias have been performed in predominantly male patients. Sex differences have the potential to impact diagnostic and therapeutic interventions in a wide variety of medical conditions and cardiac arrhythmias are no exception. This chapter will review sex differences in different cardiac arrhythmias with an emphasis on clinical evaluation, treatment, and outcomes.

AIMS: No therapy has shown to reduce the risk of hospitalization for heart failure across the entire range of ejection fractions seen in clinical practice. We assessed the influence of ejection fraction on the effect of the sodium-glucose cotransporter 2 inhibitor empagliflozin on heart failure outcomes. METHODS AND RESULTS: A pooled analysis was performed on both the EMPEROR-Reduced and EMPEROR-Preserved trials (9718 patients; 4860 empagliflozin and 4858 placebo), and patients were grouped based on ejection fraction: <25% (n = 999), 25-34% (n = 2230), 35-44% (n = 1272), 45-54% (n = 2260), 55-64% (n = 2092), and ≥65% (n = 865). Outcomes assessed included (i) time to first hospitalization for heart failure or cardiovascular mortality, (ii) time to first heart failure hospitalization, (iii) total (first and recurrent) hospitalizations for heart failure, and (iv) health status assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The risk of cardiovascular death and hospitalization for heart failure declined progressively as ejection fraction increased from <25% to ≥65%. Empagliflozin reduced the risk of cardiovascular death or heart failure hospitalization, mainly by reducing heart failure hospitalizations. Empagliflozin reduced the risk of heart failure hospitalization by ≈30% in all ejection fraction subgroups, with an attenuated effect in patients with an ejection fraction ≥65%. Hazard ratios and 95% confidence intervals were: ejection fraction <25%: 0.73 (0.55-0.96); ejection fraction 25-34%: 0.63 (0.50-0.78); ejection fraction 35-44%: 0.72 (0.52-0.98); ejection fraction 45-54%: 0.66 (0.50-0.86); ejection fraction 55-64%: 0.70 (0.53-0.92); and ejection fraction ≥65%: 1.05 (0.70-1.58). Other heart failure outcomes and measures, including KCCQ, showed a similar response pattern. Sex did not influence the responses to empagliflozin. CONCLUSION: The magnitude of the effect of empagliflozin on heart failure outcomes was clinically meaningful and similar in patients with ejection fractions <25% to <65%, but was attenuated in patients with an ejection fraction ≥65%. KEY QUESTION: How does ejection fraction influence the effects of empagliflozin in patients with heart failure and either a reduced or a preserved ejection fraction? KEY FINDING: The magnitude of the effect of empagliflozin on heart failure outcomes and health status was similar in patients with ejection fractions <25% to <65%, but it was attenuated in patients with an ejection fraction ≥65%. TAKE HOME MESSAGE: The consistency of the response in patients with ejection fractions of <25% to <65% distinguishes the effects of empagliflozin from other drugs that have been evaluated across the full spectrum of ejection fractions in patients with heart failure.

BACKGROUND: The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium-glucose co-transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large-scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. STUDY DESIGN: The EMPEROR-Preserved Trial is enrolling ≈5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co-morbidities. STUDY AIMS: The primary endpoint is the time-to-first-event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR-Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.

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BACKGROUND: Percutaneous coronary intervention (PCI) is associated with periprocedural myocardial infarction (MI) in 3% to 15% of cases (depending on the definition used). In many cases, these MIs result from distal embolization of lipid-core plaque (LCP) constituents. Prospective identification of LCP with catheter-based near-infrared spectroscopy (NIRS) may predict an increased risk of periprocedural MI and facilitate development of preventive measures. METHODS AND RESULTS: The present study analyzed the relationship between the presence of a large LCP (detected by NIRS) and periprocedural MI. Patients with stable preprocedural cardiac biomarkers undergoing stenting were identified from the COLOR Registry, an ongoing prospective observational study of patients undergoing NIRS before PCI. The extent of LCP in the treatment zone was calculated as the maximal lipid-core burden index (LCBI) measured by NIRS for each of the 4-mm longitudinal segments in the treatment zone. A periprocedural MI was defined as new cardiac biomarker elevation above 3× upper limit of normal. A total of 62 patients undergoing stenting met eligibility criteria. A large LCP (defined as a maxLCBI(4 mm) ≥500) was present in 14 of 62 lesions (22.6%), and periprocedural MI was documented in 9 of 62 (14.5%) of cases. Periprocedural MI occurred in 7 of 14 patients (50%) with a maxLCBI(4 mm) ≥500, compared with 2 of 48 patients (4.2%) patients with a lower maxLCBI(4 mm) (P=0.0002). CONCLUSIONS: NIRS provides rapid, automated detection of extensive LCPs that are associated with a high risk of periprocedural MI, presumably due to embolization of plaque contents during coronary intervention.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).

BackgroundSince the release of the second-generation cryoballoon (CB2; Arctic Front AdvanceTM, Medtronic Inc) and its design modifications with improved cooling characteristics, the technique, dosing, and complication profile is significantly different from that of the first-generation cryoballoon. A comprehensive report of CB2 procedural recommendations has not been reported.ObjectiveThe purpose of this study was to review the current best practices from a group of experienced centers to create a user’s consensus guide for CB2 ablation.Methods/ResultsHigh-volume operators with a combined experience of more than 3000 CB2 cases were interviewed, and consensus for technical and procedural best practice was established.ConclusionComprehensive review of the CB2 ablation best practice guide will provide a detailed technique for achieving safer and more effective outcomes for CB2 atrial fibrillation ablation. Since the release of the second-generation cryoballoon (CB2; Arctic Front AdvanceTM, Medtronic Inc) and its design modifications with improved cooling characteristics, the technique, dosing, and complication profile is significantly different from that of the first-generation cryoballoon. A comprehensive report of CB2 procedural recommendations has not been reported. The purpose of this study was to review the current best practices from a group of experienced centers to create a user’s consensus guide for CB2 ablation. High-volume operators with a combined experience of more than 3000 CB2 cases were interviewed, and consensus for technical and procedural best practice was established. Comprehensive review of the CB2 ablation best practice guide will provide a detailed technique for achieving safer and more effective outcomes for CB2 atrial fibrillation ablation.

CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins ( i.e. , uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.

Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). There is growing evidence to suggest that the angiotensin converting enzyme 2 receptor (ACE2 receptor) is expressed on endothelial cells (ECs) in the lung, heart, kidney, and intestine, particularly in systemic vessels (small and large arteries, veins, venules, and capillaries). Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL-6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with SARS-CoV-2 infection. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Here we present an update on ED-relevant vasculopathy in COVID-19. Further research for ED in COVID-19 patients is warranted to understand therapeutic opportunities.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

AIMS: Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE--a Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies. METHODS AND RESULTS: Heart failure patients with evidence of hyperkalaemia (serum potassium ≥5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population. CONCLUSION: Compared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population.