Colchicine's Role in Cardiovascular Disease Management.

Colchicine-an anti-inflammatory alkaloid-has assumed an important role in the management of cardiovascular inflammation ≈3500 years after its first medicinal use in ancient Egypt. Primarily used in high doses for the treatment of acute gout flares during the 20th century, research in the early 21st century demonstrated that low-dose colchicine effectively treats acute gout attacks, lowers the risk of recurrent pericarditis, and can add to secondary prevention of major adverse cardiovascular events. As the first Food and Drug Administration-approved targeted anti-inflammatory cardiovascular therapy, colchicine currently has a unique role in the management of atherosclerotic cardiovascular disease. The safe use of colchicine requires careful monitoring for drug-drug interactions, changes in kidney and liver function, and counseling regarding gastrointestinal upset. Future research should elucidate the mechanisms of anti-inflammatory effects of colchicine relevant to atherosclerosis, the potential role of colchicine in primary prevention, in other cardiometabolic conditions, colchicine's safety in cardiovascular patients, and opportunities for individualizing colchicine therapy using clinical and molecular diagnostics.

Management of direct oral anticoagulant drug interactions in hospitalized patients.

Moderate-strong CYP3A4 or Pgp inhibitors and inducers alter direct oral anticoagulant (DOAC) pharmacokinetics. Whether the presence of a DOAC drug-drug interaction (DDI) prompts in- hospital changes in management remains unknown. We identified all hospitalized patients at our institution who were admitted with a clinically relevant DOAC DDI from 01/2021 to 06/2021. Clinically relevant DOAC DDIs were defined as those listed in the prescribing information or FDA CYP3A4/Pgp inhibitors clinical indexes. We assessed the prevalence of DOAC DDIs and categorized their management as: drug stopped, drug held, or drug continued. For drugs that were continued we assessed whether the dose of the DOAC or interacting drug was increased, decreased or unchanged during the admission. We ascertained the number of DOAC DDIs that prompted an automated prescribing alert in our electronic health record (EHR). Finally, we conducted a logistic regression model to compare users of DOACs with DDI who had their regimen adjusted versus those without adjustments, focusing on outcomes of rehospitalization and death, adjusting for age and gender. Among 3,725 hospitalizations with a DOAC admission order, 197 (5%) had a clinically relevant DOAC DDI. The DOAC and the interacting drug were continued at discharge for 124 (63%) hospitalizations. The most frequent adjustments were stopping the interacting drug (73%) and stopping the DOAC (15%). Only 7 (4%) of DOAC DDIs prompted an EHR alert. The adjusted odds ratios for rehospitalizations and death, respectively, among patients whose regimens were adjusted compared to those whose were not, were 1.29 (95% CI, 0.67 to 2.48; P = 0.44) and 1.88 (95% CI, 0.91 to 3.89; P = 0.09). Clinically relevant DDIs with DOACs occur infrequently among hospitalized patients and usually are managed without stopping the DOAC. The clinical impact of such DDIs and subsequent adjustments on thrombotic and hemorrhagic outcomes requires further investigation.

Anemia, Iron Deficiency, and Cause-Specific Mortality: The Atherosclerosis Risk in Communities (ARIC) Study.

INTRODUCTION: Anemia is a risk factor for all-cause mortality in older adults. Iron deficiency may also be associated with adverse outcomes, independent of its role in causing anemia. This study tested the hypotheses that anemia, and low ferritin among non-anemic participants, were associated with all-cause and cause-specific mortality in a community-based cohort of older adults. METHODS: Fasting blood was obtained from 5,070 ARIC participants (median age: 75) in 2011-2013. Anemia was defined by hemoglobin concentrations <12 g/dL in women and <13 g/dL in men. We classified 4,020 non-anemic participants by quartiles of plasma ferritin, measured by the SomaScan proteomics platform. Cox proportional hazards regression was used. RESULTS: Over a median of 7.5 years, there were 1147 deaths, including 357 due to cardiovascular disease (CVD), 302 to cancer and 132 to respiratory disease. Compared to those with normal hemoglobin, participants with anemia had a higher risk of all-cause mortality [hazard ratio 1.81 (95% CI: 1.60-2.06)], and mortality due to CVD [1.77 (1.41-2.22)], cancer [1.81 (1.41-2.33)], and respiratory disease [1.72 (1.18-2.52)] in demographics-adjusted models. In fully adjusted models, associations with all-cause mortality [1.37 (1.19-1.58)] and cause-specific mortality were attenuated. In non-anemic participants, lower ferritin levels were not associated with all-cause or cause-specific mortality, though associations were observed among participants with lesser evidence of inflammation and for cancer mortality in men only. CONCLUSION: Anemia is an important risk factor in older adults and may contribute to mortality due to CVD, cancer, and respiratory disease. Our results do not provide evidence that iron deficiency, independent of anemia, is a risk factor for mortality in this population.

Targeting pharmacotherapies for inflammatory and cardiorenal endpoints in kidney disease.

ABSTRACT: Inflammation is an important contributor to excess cardiovascular risk and progressive renal injury in people with CKD. Dysregulation of the innate and adaptive immune system is accelerated by CKD and results in increased systemic inflammation, a heightened local vascular inflammatory response leading to accelerated atherosclerosis, and dysfunction of the cardiac and renal endothelium and microcirculation. Understanding and addressing the dysregulated immune system is a promising approach to modifying cardiorenal outcomes in people with CKD. However, targeted pharmacotherapies adopted from trials of non-CKD and cardio-rheumatology populations are only beginning to be developed and tested in human clinical trials. Pharmacotherapies that inhibit activation of the NLRP3 inflammasome and the downstream cytokines IL-1 and IL-6 are the most well-studied. However, most of the available evidence for efficacy is from small clinical trials with inflammatory and cardiorenal biomarker endpoints, rather than cardiovascular event endpoints, or from small CKD subgroups in larger clinical trials. Other pharmacotherapies that have proven beneficial for cardiorenal endpoints in people with CKD have been found to have pleiotropic anti-inflammatory benefits including statins, mineralocorticoid receptor antagonists, SGLT-2 inhibitors, and GLP-1 agonists. Finally, emerging therapies in CKD such as IL-6 inhibition, small-interfering RNA against lipoproteins, AhR inhibitors, and therapies adopted from the renal transplant population including mTOR inhibitors and T regulatory cell promoters may have benefits for cardiorenal and inflammatory endpoints but require further investigation in clinical trials.

Mid- to Late-Life Inflammation and Risk of Cardiac Dysfunction, HFpEF and HFrEF in Late Life.

BACKGROUND: Epidemiologic data supporting the association of accumulated inflammation from mid- to late life with late-life risk of cardiac dysfunction and heart failure (HF) is limited. METHODS AND RESULTS: Among 4011 participants in the Atherosclerosis Risk in Communities study who were free of prevalent cardiovascular disease at study Visit 5, accumulated inflammation was defined as time-averaged high-sensitivity c-reactive protein (hsCRP) over 3 visits spanning 1990 to 2013. Associations with left ventricular (LV) function at Visit 5 and with incident adjudicated HF post Visit 5 were assessed using linear and Cox regression, adjusting for demographics and comorbidities. Higher accumulated hsCRP was associated with greater LV mass index, lower e', higher E/e', and higher adjusting for demographics (all P ≤0.01), but only with higher pulmonary artery systolic pressure after adjustment for comorbidities (P = 0.024). At 5.3 ± 1.2 year follow-up, higher accumulated hsCRP was associated with greater risk of incident HF (HR 1.31 [95% CI 1.18-1.47], P < 0.001), HFrEF (1.26 [1.05-1.52], P = 0.01), and HFpEF (1.30 [1.11-1.53], P = 0.001) in demographic-adjusted models, but not after adjustment for comorbidities (all P > 0.10). Only Visit 5 hsCRP remained associated with incident HF (1.12 [1.02-1.24], P = 0.02) after full adjustment. CONCLUSIONS: Greater accumulated inflammation is associated with worse LV function and heightened HF risk in late-life. These relationships are attenuated after adjusting for HF risk factors.

Cardiac Myosin Activation for the Treatment of Systolic Heart Failure.

ABSTRACT: Left ventricular systolic dysfunction is the hallmark pathology in heart failure with reduced ejection fraction. Increasing left ventricular contractility with beta-adrenergic receptor agonists, phosphodiesterase-3 inhibitors, or levosimendan has failed to improve clinical outcomes and, in some situations, increased the risk of sudden cardiac death. Beta-adrenergic receptor agonists and phosphodiesterase-3 inhibitors retain an important role in advanced heart failure. Thus, there remains an unmet need for safe and effective therapies to improve left ventricular systolic function. Two novel cardiac myotropes, omecamtiv mecarbil and danicamtiv, target cardiac myosin to increase left ventricular systolic performance. Neither omecamtiv mecarbil nor danicamtiv affects cardiomyocyte calcium handling, the proposed mechanism underlying the life-threatening arrhythmias associated with cardiac calcitropes and calcium sensitizers. Phase 2 clinical trials have demonstrated that these cardiac myosin activators prolong left ventricular systolic ejection time and promote left ventricular and atrial reverse remodeling. At higher plasma concentrations, these agents may be associated with myocardial ischemia and impaired diastolic function. An ongoing phase 3 clinical trial will estimate the clinical efficacy and safety of omecamtiv mecarbil. An additional study of these agents, which have minimal hemodynamic and renal effects, is warranted in patients with advanced heart failure refractory to guideline-directed neurohormonal blockers.

Cardiovascular Pharmacology in the Time of COVID-19: A Focus on Angiotensin-Converting Enzyme 2.

Coronavirus disease-2019 (COVID-19) has emerged as a pandemic affecting millions of adults. Severe acute respiratory syndrome coronavirus-2019 (SARS-CoV-2), the causative virus of COVID-19, infects host cells through angiotensin-converting enzyme 2 (ACE2). Preclinical models suggest that ACE2 upregulation confers protective effects in acute lung injury. In addition, renin-angiotensin aldosterone system inhibitors reduce adverse atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease outcomes, but may increase ACE2 levels. We review current knowledge of the role of ACE2 in cardiovascular physiology and SARS-CoV-2 virology, as well as clinical data to inform the management of patients with or at risk for COVID-19 who require renin-angiotensin-aldosterone system inhibitor therapy.

Acute Effects of Interleukin-1 Blockade Using Anakinra in Patients With Acute Pericarditis.

Interleukin-1 (IL-1) receptor antagonist (anakinra) has been shown to be effective in steroid-dependent recurrent pericarditis resistant to nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine. We sought to evaluate the acute efficacy of anakinra given early in patients with acute pericarditis. We enrolled patients within 24 hours of presentation of a first or recurrent episode of acute pericarditis who were experiencing severe pain (≥6 in 11-point Likert scale), despite treatment with at least one dose of NSAIDs and of colchicine. The primary outcome was pain relief at 24 hours. Subcutaneous anakinra 100 mg was administered in all patients, whereas NSAIDs and colchicine were suspended for 24 hours. Serum levels of interleukin-6 (IL-6) were measured at baseline and 24 hours. Data are reported as median (interquartile range). We treated 5 patients (4 male and 1 female; 38 [31-54] years old). Anakinra significantly reduced pain from 6.0 (6.0-7.5) to 4.0 (2.5-4.0) at 6 hours (P = 0.012 vs. baseline) and to 2.0 (1.5-2.5) at 24 hours (P = 0.0025 vs. baseline). No patients required rescue pain medication. IL-6 levels were also significantly reduced from 95.3 (24.2-155.1) to 23.9 (4.5-71.9) pg/mL at 24 hours (P = 0.037). The reduction in pain intensity paralleled the reduction in IL-6 serum levels (R = +0.966, P = 0.007). No adverse events related to treatment occurred. The administration of anakinra given early in acute pericarditis treatment course rapidly and significantly improved chest pain from acute pericarditis. The improvement is correlated with a reduction in IL-6 levels.

Inhibiting NLRP3 Inflammasome Activity in Acute Myocardial Infarction: A Review of Pharmacologic Agents and Clinical Outcomes.

The NLRP3 inflammasome is an intracellular, multimeric protein complex that initiates a potent inflammatory response to danger signals. After acute myocardial infarction, NLRP3 inflammasome-dependent inflammation promotes adverse left ventricular remodeling and recurrent atherosclerotic events. Selective and nonselective inhibitors of the NLRP3 inflammasome or its downstream effectors (interleukin-1ß and interleukin-18) may prevent adverse left ventricular remodeling and recurrent atherosclerotic events. In this review, we highlight strategies to inhibit NLRP3 inflammasome activity and their potential roles in the management of acute myocardial infarction.

Noninvasive Hemodynamic Monitoring of Cocaine-Induced Changes in Cardiac Output and Systemic Vascular Resistance in Subjects With Chronic Cocaine Use Disorder.

BACKGROUND: Cocaine use disorder (CUD) is a common problem in the United States and worldwide. The mechanisms by which cocaine induces acute cardiovascular toxicity are various. When systemically absorbed through inhaled or intravenous routes, cocaine induces an acute rise in the heart rate (HR) and blood pressure (BP) leading to a significant increase in the cardiac output (CO) and myocardial oxygen demand. Subjects with chronic CUD represent a special population that has experienced long-term cocaine exposure, often without showing signs of cardiovascular disease. We herein present prospectively collected data on the acute hemodynamic effects of intravenous cocaine in a cohort of nontreatment-seeking individuals with CUD without cardiovascular disease. METHODS AND RESULTS: Baseline physiologic data were collected while participants underwent infusion of escalating doses of cocaine (10, 20, and 40 mg administered over 2 minutes) at baseline and after receiving single-blind placebo treatment. Continuous noninvasive hemodynamic monitoring was performed throughout the infusion sessions using the ccNexfin finger cuffs (Edwards Lifesciences Corp, Irvine, CA). The recorded arterial BP tracings allowed for the measurement of beat-to-beat changes in HR, BP, stroke volume, CO, and systemic vascular resistance (SVR). None of the subjects experienced a treatment-related serious adverse event. Cocaine produced significant dose-dependent increases in median HR, BP, CO, and +dP/dt (a measure of cardiac contractility) and a significant dose-dependent reduction in median SVR. CONCLUSIONS: Intravenous cocaine in a cohort of otherwise healthy subjects with CUD produced dose-dependent increases in CO, largely explained by an increase in HR, accompanied by a dose-dependent decrease in SVR.

Alirocumab in Acute Myocardial Infarction: Results From the Virginia Commonwealth University Alirocumab Response Trial (VCU-AlirocRT).

Alirocumab improves outcomes in patients with a history of recent acute coronary syndrome, but treatment acutely at the time of myocardial infarction is untested. We present the results of a randomized, placebo-controlled, double-blinded pilot study of alirocumab treatment at the time of non-ST elevation MI (NSTEMI). Twenty patients with type 1 NSTEMI and low-density lipoprotein cholesterol (LDL-C) >70 mg/dL despite high intensity statin therapy were randomized 1:1 to one dose of alirocumab 150 mg subcutaneously or placebo within 24 hours of presentation. LDL-C and inflammatory biomarkers-including C-reactive protein-were obtained at baseline, 72 hours, and 14 days. Median (interquartile range) and number (%) were: age 59 (49, 65) years, 7 (35%) men, 16 (80%) black; baseline characteristics were similar between groups. Alirocumab significantly reduced LDL-C from baseline to 14 days by 64 mg/dL (-96, -47) compared with placebo [+1 mg/dL (-25, +16)] (primary endpoint). There were no significant between-group differences in C-reactive protein changes at any time point (all P > 0.2) or serious adverse events attributable to the study treatment. In conclusion, alirocumab administration at the time of NSTEMI significantly reduced LDL-C levels at 14 days, was safe, and had neutral effects on inflammatory biomarkers. Further studies are warranted to explore the effects on clinical outcomes.

Interleukin-1 blockade in cardiovascular diseases: a clinical update.

Interleukin-1 (IL-1) is the prototypical pro-inflammatory cytokine. IL-1 was implicated as a cardiodepressant factor in septic shock, and subsequent pre-clinical and clinical research has defined important roles for IL-1 in atherosclerosis, acute myocardial infarction (AMI), and heart failure (HF). IL-1 promotes the formation of the atherosclerotic plaque and facilitates its progression and complication. In a large phase III clinical trial of stable patients with prior AMI, blocking IL-1 activity using a monoclonal antibody prevented recurrent atherothrombotic cardiovascular events. IL-1 also contributes to adverse remodelling and left ventricular dysfunction after AMI, and in phase II studies, IL-1 blockade quenched the inflammatory response associated with ST-segment elevation AMI and prevented HF. In patients with established HF, IL-1 is thought to impair beta-adrenergic receptor signalling and intracellular calcium handling. Phase II studies in patients with HF show improved exercise capacity with IL-1 blockade. Thus, IL-1 blockade is poised to enter the clinical arena as an additional strategy to reduce the residual cardiovascular risk and/or address inflammatory cardiovascular conditions refractory to standard treatments. There are several IL-1 blockers available for clinical use, which differ in mechanism of action, and potentially also efficacy and safety. While IL-1 blockade is not immunosuppressive and not associated with opportunistic infections or an increased risk of cancer, fatal infections may occur more frequently while on treatment with IL-1 blockers likely due to a blunting of the inflammatory signs of infection leading to delayed presentation and diagnosis. We discuss the practical use of IL-1 blockade, including considerations for patient selection and safety monitoring.

Effect of intensive blood pressure control in patients with type 2 diabetes mellitus over 9 years of follow-up: A subgroup analysis of high-risk ACCORDION trial participants.

Although guidelines recommend strict blood pressure (BP) control in patients with type 2 diabetes mellitus (T2DM) and elevated cardiovascular risk, the long-term effects of this approach are unknown. We investigated the effect of intensive BP control on clinical outcomes in patients with T2DM over 9 years of follow-up. We included Action to Control Cardiovascular Risk in Diabetes - Blood Pressure participants in the standard glucose control arm who had established cardiovascular disease, chronic kidney disease, were ≥75 years of age or who had a 10-year coronary heart risk ≥15%. Participants were randomized to either intensive (systolic BP < 120 mm Hg) or standard (systolic BP < 140 mm Hg) BP control for an average of 5 years. Observational follow-up occurred for an average of 4 years thereafter. After an average total follow-up of 9 years, intensive BP control reduced the composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke by 25% (hazard ratio, 0.75; 95% confidence interval, 0.60-0.95; P = .02). The overall benefit was driven by a reduction in nonfatal myocardial infarction (P = .01). In this post-hoc analysis, the benefits of a fixed-duration intensive BP control intervention in patients with T2DM persisted throughout 9 years of follow-up.

Effects of empagliflozin on cardiorespiratory fitness and significant interaction of loop diuretics.

The effects of empagliflozin on cardiorespiratory fitness in patients with type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF) are unknown. In this pilot study we determined the effects of empagliflozin 10 mg/d for 4 weeks on peak oxygen consumption (VO2 ) in 15 patients with T2DM and HFrEF. As an exploratory analysis, we assessed whether there was an interaction of the effects of empagliflozin on peak VO2 of loop diuretics. Empagliflozin reduced body weight (-1.7 kg; P = .031), but did not change peak VO2 (from 14.5 mL kg-1 min-1 [12.6-17.8] to 15.8 [12.5-17.4] mL kg-1 min-1 ; P = .95). However, patients using loop diuretics (N = 9) demonstrated an improvement, whereas those without loop diuretics (N = 6) experienced a decrease in peak VO2 (+0.9 [0.1-1.4] vs -0.9 [-2.1 to -0.3] mL kg-1 min-1 ; P = .001), and peak VO2 changes correlated with the baseline daily dose of diuretics (R = +0.83; P < .001). Empagliflozin did not improve peak VO2 in patients with T2DM and HFrEF. However, as a result of exploratory analysis, patients concomitantly treated with loop diuretics experienced a significant improvement in peak VO2 .

Inhibiting the Inflammatory Injury After Myocardial Ischemia Reperfusion With Plasma-Derived Alpha-1 Antitrypsin: A Post Hoc Analysis of the VCU-α1RT Study.

BACKGROUND: Despite the benefits of reperfusion in limiting myocardial injury, the infarct size continues to expand after reperfusion because of secondary inflammatory injury. Plasma-derived alpha-1 antitrypsin (AAT) inhibits the inflammatory injury in myocardial ischemia and reperfusion. To explore the effects of plasma-derived AAT on the inflammatory response to ischemia-reperfusion injury, we analyzed time-to-reperfusion and enzymatic infarct size estimates in a post hoc analysis of the VCU-α1RT clinical trial (clinicaltrials.gov NCT01936896). METHODS: Ten patients with ST-segment elevation acute myocardial infarction (STEMI) were enrolled in an open-label, single-arm treatment study of Prolastin C, plasma-derived AAT, at 60 mg/kg infused intravenously within 12 hours of reperfusion. Biomarkers were measured serially over the first 72 hours, and patients were followed clinically for the occurrence of new-onset heart failure, recurrent MI, or death. Twenty patients with STEMI who had been enrolled in previous randomized trials with identical inclusion/exclusion criteria and had been assigned to placebo served as historical controls. RESULTS: Time to percutaneous coronary intervention and time to drug did not significantly differ between groups. AAT-treated patients had a significantly shorter time-to-peak creatine kinase myocardial band (CK-MB) values (525 [480-735] vs. 789 [664-959] minute, P = 0.005) and CK-MB area under the curve (from 1204 [758-2728] vs. 2418 [1551-4289] U·day, P = 0.035), despite no differences in peak CK-MB (123 [30-196] vs. 123 [71-213] U/mL, P = 0.71). CONCLUSIONS: A single administration of Prolastin C given hours after reperfusion in patients with STEMI led to a significant shorter time to peak and area under the curve for CK-MB, despite similar peak CK-MB values. These preliminary data support the hypothesis that Prolastin C shortens the duration of the ischemia-reperfusion injury in patients with STEMI.

Effect of Interleukin-1 Blockade on Left Ventricular Systolic Performance and Work: A Post Hoc Pooled Analysis of 2 Clinical Trials.

BACKGROUND: Interleukin-1 (IL-1) blockade seems to improve anaerobic exercise in patients with systolic heart failure through improved left ventricular (LV) systolic performance. However, it is unclear whether IL-1 blockade affects LV systolic performance. METHODS: We pooled data from 2 clinical trials of patients with systolic heart failure who were randomized to IL-1 blockade or placebo. We estimated changes in LV systolic performance (LV ejection fraction [LVEF] and end-systolic elastance [LVEes]) and pressure-volume area (PVA), a surrogate of oxygen consumption, after 14 days of treatment. RESULTS: LVEF increased from 30% (24%-38%) to 36% (29%-43%) between baseline and day 14 only in anakinra-treated patients (P = 0.03 for within-group change and P = 0.02 for between-group change compared with placebo). LVEes increased from 1.0 mm Hg/mL (0.7-1.5) to 1.3 mm Hg/mL (0.8-1.6) in anakinra-treated patients between baseline and day 14 but not in placebo-treated patients (P = 0.03 for within-group change and P = 0.08 for between-group change). A change in PVA between baseline and 14 days was not detected in either anakinra or placebo patients. CONCLUSIONS: In this post hoc analysis, LVEes and LVEF increased significantly in patients treated with an IL-1 blocker but not in placebo-treated patients. An effect of IL-1 blockade on calculated PVA was not detected.

A Systematic Review of Beliefs About Hypertension and its Treatment Among African Americans.

PURPOSE OF REVIEW: The prevalence of hypertension and uncontrolled hypertension is higher among African Americans than any other ethnicity in the USA. Certain patient medical beliefs may lead to adverse health behaviors. The aim of this study was to systematically review and narratively synthesize beliefs about hypertension among African Americans. RECENT FINDINGS: In a narrative review of 22 studies, many participants attributed hypertension to stress and fatty foods. Hypertension was perceived to be an episodic, symptomatic disease. Many patients exhibited a strong faith in the efficacy of medications, but used them as needed to treat perceived intermittent hypertensive episodes or infrequently to avoid addiction and dependence. Home remedies were often reported to be used concurrently to treat the folk disease "high blood" or in place of medications associated with unwanted effects. Nevertheless, participants were invested in treatment of hypertension to prevent long-term complications. Trends over time suggest that beliefs about hypertension among African Americans have change significantly and now reflect the currently accepted biomedical model. African American beliefs about hypertension may frequently differ from those of healthcare professionals. These results suggest that reconciliation of differences between patient and provider expectations for disease management may improve adherence to and acceptance of medical treatments among African Americans with hypertension. Nevertheless, discordant health beliefs are common among all patients and additional work to elucidate beliefs of other patient subgroups such as age and gender is warranted.