Ivermectin: a multifaceted drug of Nobel prize-honoured distinction with indicated efficacy against a new global scourge, COVID-19.

In 2015, the Nobel Committee for Physiology or Medicine, in its only award for treatments of infectious diseases since six decades prior, honoured the discovery of ivermectin (IVM), a multifaceted drug deployed against some of the world's most devastating tropical diseases. Since March 2020, when IVM was first used against a new global scourge, COVID-19, more than 20 randomized clinical trials (RCTs) have tracked such inpatient and outpatient treatments. Six of seven meta-analyses of IVM treatment RCTs reporting in 2021 found notable reductions in COVID-19 fatalities, with a mean 31% relative risk of mortality vs. controls. During mass IVM treatments in Peru, excess deaths fell by a mean of 74% over 30 days in its ten states with the most extensive treatments. Reductions in deaths correlated with the extent of IVM distributions in all 25 states with p < 0.002. Sharp reductions in morbidity using IVM were also observed in two animal models, of SARS-CoV-2 and a related betacoronavirus. The indicated biological mechanism of IVM, competitive binding with SARS-CoV-2 spike protein, is likely non-epitope specific, possibly yielding full efficacy against emerging viral mutant strains.

Increased central adiposity in morbidly obese patients with obstructive sleep apnoea.

BACKGROUND: With the growing epidemic of obesity, few data are available regarding adipose distribution and the severity of sleep apnoea. Our aim was to measure precisely adipose distribution with dual-energy X-ray absorptiometry (DXA) in a morbidly obese population with and without obstructive sleep apnoea (OSA). METHODS: Morbidly obese female subjects without a history of OSA underwent overnight polysomnography and DXA analysis. Subject demographics, DXA variables, serum laboratory markers and physical exam characteristics were compared between individuals with and without OSA. RESULTS: For the study population (n= 26), mean body mass index (BMI) was 45.9 ± 7.8 kg/m(2); mean age was 47.5 ± 10.2 years and all were female. The central adiposity ratio (CAR) was higher in individuals with OSA (apnoea-hypopnoea index > 5) than those without OSA (1.1 ± 0.05 vs 1.0 ± 0.04; P = 0.004). No difference was observed in Epworth Sleepiness Scale scores, body mass index (BMI) or neck circumference between groups. CONCLUSIONS: OSA is associated with increased central adipose deposition in patients with a BMI of >40 kg/m(2). These data may be helpful in designing future studies regarding the pathophysiology of OSA, and potential treatment options.

Cardiovascular risk modification in participants with coronary disease screened by the Kidney Early Evaluation Program.

BACKGROUND: Coronary artery disease (CAD) identifies the need for intensive treatment of risk factors among individuals with chronic kidney disease (CKD), a high-risk, complex cardiovascular risk state. METHODS: An estimated glomerular filtration rate<60 mL/min/1.73 m2 or a urine albumin:creatinine ratio (ACR)≥30 mg/g (3.4 mg/mmol) defined CKD. RESULTS: Of 70,454 volunteers screened the mean age was 53.5±15.7 years and 68.3% were female. A total of 5410 (7.7%) had a self-reported history of CAD; 1295 (1.8%) had a history of prior percutaneous coronary intervention (PCI); and 1124 (1.6%) had a prior history of coronary artery bypass surgery (CABG). Multivariate analysis for the outcome of suboptimal CAD risk management (composite of systolic blood pressure≥130 mmHg, glucose≥125 mg/dL (6.9 mmol/L) for diabetics, total cholesterol≥200 mg/dL (5.2 mmol/L), or current smoking; n=38,746/53,403, 72.5%) revealed older age (per year) (odds ratio (OR)=1.04, 95% confidence interval (CI) 1.03-1.04, P<0.0001), male gender (OR=1.40, 95% CI 1.34-1.47, P<0.0001), ACR≥30 mg/g (3.4 mg/mmol) (OR=1.66, 95% CI 1.55-1.79, P<0.0001), body mass index (per kg/m2) (OR=1.06, 95% CI 1.06-1.06, P<0.0001), CAD without a history of revascularization (OR=1.14, 95% CI 1.02-1.28, P=0.02) and care received by a nephrologist (OR=1.49, 95% CI 1.22-1.83, P<0.0001) were associated with worse risk factor control. Prior coronary revascularization and being under the care of a cardiologist were not associated with either improved or suboptimal risk factor control. CONCLUSIONS: Chronic kidney disease is associated with overall poor rates of CAD risk factor control.

Kidney's role in hypertension.

Hypertension is both the cause and effect of kidney disease. Together these two diseases have become epidemics in our society and are associated with an increased risk of cardiovascular events. Over the last several decades multiple clinical and transplant studies have shown the kidney to be an important determinant of essential hypertension. However, little is known about the direct mechanisms in which the kidney induces hypertension or why the blood pressure tends to rise in the failing kidney. This document provides a systematic analysis of peer-reviewed, published literature pertaining to the central role of the kidney in the development of essential hypertension in adults. We will describe the pathophysiology of essential hypertension and its relationship to chronic kidney disease and cardiovascular disease. Particular focus will be drawn to effects of sodium handling, the renin angiotensin aldosterone system, the sympathetic system and mediators of vascular tone in the development of kidney induced hypertension. In addition, the mediators which initiate and maintain the progression of chronic kidney disease, and how these factors are related in the development of hypertension will also be discussed. Finally, therapeutic strategies to treat individuals with chronic kidney disease in order to prevent the development of essential hypertension and lower their cardiovascular risk will be presented.

Contrast-induced acute kidney injury in renal transplant recipients after cardiac catheterization.

Renal transplant (RTX) recipients remain at high-risk for acute kidney injury (AKI) despite having improved renal function and quality of life after transplantation. We sought to identify the incidence and risk factors for contrast-induced AKI in RTX recipients after cardiac catheterization at our institute as identified by electronic records. After excluding patients on dialysis at time of procedure due to failed transplant and who did not have post-exposure creatinine values within 3 days, we reviewed 77 procedures on 57 patients. We studied one case per patient (the most recent procedure). Among the 57 patients, 42 were male, 42 were Caucasian and mean age was 58.2 +/- 10.1 years. Mean serum creatinine 24 h pre-procedure was 1.7 +/- 0.8 mg/dl. Contrast-induced AKI, defined as rise in serum creatinine of 25% or 0.5 mg/dl within 3 days post-catheterization, occurred in 9 procedures (15.8%). One procedure was complicated by AKI requiring dialysis. AKI occurred more frequently with use of low-osmolar contrast (ioxaglate or iohexol) in comparison with iso-osmolar contrast (iodixanol) (9/36 vs. 0/21, p = 0.019). Patients who received prophylactic N-acetylcysteine had lower incidence of AKI than those who did not (4/41 vs. 5/16, p = 0.046). Exact logistic regression analysis revealed odds ratio of developing AKI with use of low-osmolar vs. iso-osmolar contrast to be 7.747 (1.101 - yen); p = 0.0381). Contrast-induced AKI was common in RTX recipients after cardiac catheterization. Iso-osmolar contrast was associated with a lower risk of contrast-induced AKI in comparison with low-osmolar contrast.

The effect of weight loss after bariatric surgery on albuminuria.

BACKGROUND: Bariatric surgery achieves long-term weight loss in obese adults with improvement of diabetes and hypertension. Little is known about the effect of this weight loss on renal parameters. METHODS: We performed a retrospective study of 94 obese adults who had Roux-en-Y gastric bypass surgery with a mean 12-month follow-up. Baseline (preoperative) mean age was 49 years, 76% were female, 37 had blood pressure (BP) >or= 140/90 mmHg and 32 had Type 2 diabetes. 73 patients had normoalbuminuria (urine albumin creatinine ratio (ACR) <30 mg/g) while 21 had microalbuminuria (ACR 30<300 mg/g). RESULTS: At follow-up (postoperative), we observed a decrease in mean body weight (133.6 to 97.9 kg, p<0.0001), mean hemoglobin A1c (6.3 to 5.6%, p<0.0001) and mean systolic blood pressure (132.7 to 114.0 mmHg, p<0.0001). There was a significant reduction in ACR (median with interquartile range) from 9.5 (5-28) to 5.5 (3-10) mg/g, p < 0.0001. Fewer patients had microalbuminuria (22.2 to 6.2%, p=0.004) after surgery. Subgroup analysis revealed that significant decrease in ACR was present in the 32 patients with diabetes (16.5 (5-67) to 6.0 (4-11) mg/g, p=0.001) and in the 37 patients with metabolic syndrome (8.0 (5-16) to 6.0 (3-13) mg/g, p=0.012), while 25 patients with obesity alone had a lower ACR (6.5 (4-13) to 4.5 (3-8) mg/g, p=0.270). Multiple linear regression analysis showed change in hemoglobin A1c (p=0.011) and baseline level of ACR (p<0.0001) to be significantly associated with change in ACR. CONCLUSION: We conclude that obese adults have a reduction in albuminuria after surgical weight loss, most importantly in patients with diabetes or metabolic syndrome.

Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study.

Clinical practice guidelines recommend blockers of the renin-angiotensin system alone or in combination with other agents to reduce blood pressure and albuminuria in patients with type 2 diabetes. Dihydropyridine calcium channel blockers, however, may lower blood pressure but not albuminuria in these patients. Here we tested the hypothesis that combining an ACE inhibitor with either a thiazide diuretic or a calcium channel blocker will cause similar reductions in blood pressure and albuminuria in hypertensive type 2 diabetics. We conducted a double blind randomized controlled trial on 332 hypertensive, albuminuric type 2 diabetic patients treated with benazepril with either amlodipine or hydrochlorothiazide for 1 year. The trial employed a non-inferiority design. Both combinations significantly reduced the urinary albumin to creatinine ratio and sitting blood pressure of the entire cohort. The percentage of patients progressing to overt proteinuria was similar for both groups. When we examined patients who had only microalbuminuria and hypertension we found that a larger percentage of the diuretic and ACE inhibitor normalized their albuminuria. We conclude that initial treatment using benzaepril with a diuretic resulted in a greater reduction in albuminuria compared to the group of ACE inhibitor and calcium channel blocker. In contrast, blood pressure reduction, particularly the diastolic component, favored the combination with amilodipine. The dissociation between reductions in blood pressure and albuminuria may be related to factors other than blood pressure.

The pathophysiology of cardiac surgery-associated acute kidney injury (CSA-AKI).

Cardiac surgery associated acute kidney injury (CSA-AKI) is a significant clinical problem. Its pathogenesis is complex and multifactorial. It likely involved at least six major injury pathways: exogenous and endogenous toxins, metabolic factors, ischemia and reperfusion, neurohormonal activation, inflammation and oxidative stress. These mechanisms of injury are likely to be active at different times with different intensity and probably act synergistically. Because of such complexity and the small number of randomised controlled investigations in this field only limited recommendations can be made. Nonetheless, it appears important to avoid nephrotoxic drugs and desirable to avoid hyperglycemia in the peri-operative period. The duration of cardiopulmonary bypass should be limited whenever possible. Off-pump surgery, when indicated, may decrease the risk of AKI. Invasive hemodynamic monitoring focussed on attention to maintaining euvolemia, an adequate cardiac output and an adequate arterial blood pressure is desirable. Echocardiography may be useful in minimizing atheroembolic complications. The administration of N-acetylcysteine to protect the kidney from oxidative stress is not recommended. There is marked lack of randomised controlled trials in this field.

Low birth weight is associated with chronic kidney disease only in men.

The association of low birth weight and chronic kidney disease was examined in a screened volunteer population by the National Kidney Foundation's Kidney Early Evaluation Program. This is a free, community-based health program enrolling individuals aged 18 years or older with diabetes, hypertension, or a family history of kidney disease, diabetes, or hypertension. Self-reported birth weight was categorized and chronic kidney disease defined as an estimated glomerular filtration rate less than 60 ml per min per 1.73 m(2) or a urine albumin/creatinine ratio >or=30 mg/g. Among 12 364 participants, 15% reported a birth weight less than 2500 g. In men, significant corresponding odds ratios were found after adjustment for demographic characteristics and health conditions to this low birth weight and chronic kidney disease, but there was no association among women. There was no significant interaction between birth weight and race for either gender. Efforts to clinically understand the etiology of this association and potential means of prevention are essential to improving public health.

Effect of enhanced external counterpulsation on medically refractory angina patients with erectile dysfunction.

Patients with refractory angina often suffer from erectile dysfunction. Enhanced external counterpulsation (EECP) decreases symptoms of angina, and increases nitric oxide release. This study evaluated the effect of EECP on sexual function in men with severe angina. The International Index of Erectile Function (IIEF) was used to assess erectile function of severe angina patients enroled in the International EECP Patient Registry. Their symptom status, medication use, adverse clinical events and quality of life were also recorded before and after completing a course of EECP. A cohort of 120 men (mean age 65.0+/-9.7) was enroled. The men had severe coronary disease with 69% having a prior myocardial infarction, 90% prior coronary artery bypass graft or percutaneous coronary intervention, 49% with three vessel coronary artery disease, 86% were not candidates for further revascularisation, 71% hypertensive, 83% dyslipidaemia, 42% diabetes mellitus, 75% smoking and 68% using nitrates. Functional status was low with a mean Duke Activity Status Inventory score of 16.6+/-14.8. After 35 h of EECP anginal status improved in 89%, and functional status in 63%. A comparison of the IIEF scores pre- and post-EECP therapy demonstrated a significant improvement in erectile function from 10.0+/-1.0 to 11.8+/-1.0 (p=0.003), intercourse satisfaction (4.2+/-0.5 to 5.0+/-0.5, p=0.009) and overall satisfaction (4.7+/-0.3 to 5.3+/-0.3, p=0.001). However, there were no significant changes in orgasmic function (4.2+/-0.4 to 4.6+/-0.4, p=0.19) or sexual desire (5.3+/-0.2 to 5.5+/-0.2). The findings suggest that EECP therapy is associated with improvement in erectile function in men with refractory angina.

Rationale and design of a study comparing two fixed-dose combination regimens to reduce albuminuria in patients with type II diabetes and hypertension.

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). The early stage of nephropathy is manifested by the presence of low levels of urinary albumin (microalbuminuria or urinary albumin excretion >or=30 and <299 mg/day). Albuminuria is a marker for development of nephropathy in type II diabetes and for increased cardiovascular morbidity and mortality. Recent studies have demonstrated the importance of antihypertensive agents that inhibit the renin-angiotensin-aldosterone (RAA) system to reduce the risk and slow down the progression of renal disease. A new clinical trial, GUARD (Gauging Albuminuria Reduction With Lotrel in Diabetic Patients With Hypertension), is designed to compare the change in urinary albumin to creatinine ratio after 1 year of initial treatment with either amlodipine besylate/benazepril HCl or benazepril HCl/hydrochlorothiazide. Other objectives include a comparison of the proportion of patients who progress to overt diabetic nephropathy and the safety of these two combination therapies in these high-risk patients.

Clinical applications of B-type natriuretic peptide levels in the care of cardiovascular patients.

B-type natriuretic peptide (BNP), is a cardiac neurohormone, and is released as prepro BNP and then enzymatically cleaved to the N-terminal-proBNP and BNP upon ventricular myocyte stretch. Blood measurements of BNP have been used to identify patients with heart failure (HF). The BNP assay is currently used in diagnosis, prognosis, screening, and response to treatment for patients with HF. In general, a BNP level below 100 pg/mL excludes acutely decompensated HF and levels > 500 pg/ml indicate decompensation. There are supportive data for using BNP to guide both inpatient and outpatient HF diagnosis and treatment. When BNP is elevated in acute coronary syndromes, pulmonary embolism, and sepsis, it implies that subclinical left ventricular dysfunction is present and a higher mortality rate can be expected. Elevated BNP levels before cardiac surgery are associated with higher rates of atrial fibrillation and death. After bypass surgery, as left ventricular function improves, the BNP level can be expected to fall. Lastly, in patients with aortic stenosis, aortic regurgitation, and mitral regurgitation, BNP elevates and is associated or may precede the development of symptoms and possibly can serve as a trigger for additional evaluation or intervention.

B-type natriuretic peptides. A diagnostic breakthrough in heart failure.

B-type natriuretic peptide (BNP) is a neurohormone synthesized in the cardiac ventricles, which is released as N-terminal pro-brain natriuretic peptide (NT-proBNP) and then enzymatically cleaved in to the NT fragment and the immunoreactive BNP. Both tests have been used to identify patients with congestive heart failure (CHF). Important considerations for these tests include their half-lives in plasma, dependence on renal function for clearance, and the interpretation of their units of measure. In general, a BNP level below 100 pg/mL has strong negative predictive value in the assessment of patients with dyspnea caused by a disorder other than CHF. In addition, BNP levels can be used to gauge the effect of short-term treatment of acutely decompensated heart failure, and the peptide has been shown to be a reliable independent predictor of sudden cardiac death. In the absence of renal dysfunction NT-proBNP has also been shown to be an independent predictor of sudden death in CHF patients. Because both a large area of myonecrosis or concomitant left ventricular failure are related to prognosis in acute coronary syndromes, B-type natriuretic peptides have also been linked to outcomes in this condition. This article describes the physiology and timing of release of B-type natriuretic peptides and the rationale for their use in the following settings: 1) evaluation of decompensated CHF, 2) screening for chronic CHF, 3) prognosis of CHF and sudden death, and 4) prognosis in acute coronary syndromes with inferred left ventricular dysfunction.

Ninety-minute exclusion of acute myocardial infarction by use of quantitative point-of-care testing of myoglobin and troponin I.

BACKGROUND: Diagnostic strategies with ECG and serum cardiac markers have been used to rule out acute myocardial infarction in 6 to 12 hours. The present study evaluated whether a multimarker strategy that used point-of-care measurement of myoglobin, creatine kinase (CK)-MB, and troponin I could exclude acute myocardial infarction in

Underuse of invasive procedures among Medicaid patients with acute myocardial infarction.

OBJECTIVES: The purpose of this study was to determine whether underuse of cardiac procedures among Medicaid patients with acute myocardial infarction is explained by or is independent of fundamental differences in age, race, or sex distribution; income, coexistent illness; or location of care. METHODS: Administrative data from 226 hospitals in New York were examined for 11,579 individuals hospitalized with a primary diagnosis of acute myocardial infarction. Use of various cardiac procedures was compared among Medicaid patients and patients with other forms of insurance. RESULTS: Medicaid patients were older, were more frequently African American and female, and had lower median household incomes. They also had a higher prevalence of hypertension, diabetes, lung disease, renal disease, and peripheral vascular disease. After adjustment for these and other factors, Medicaid patients were less likely to undergo cardiac catheterization, percutaneous transluminal coronary angioplasty, and any revascularization procedure. CONCLUSIONS: Factors other than age, race, sex, income, coexistent illness, and location of care account for lower use of invasive procedures among Medicaid patients. The influence of Medicaid insurance on medical practice and process of care deserves investigation.

Coronary calcification and cardiac events after percutaneous intervention in dialysis patients.

BACKGROUND: Previous studies have described increased vascular calcification in renal dialysis patients. The clinical significance of this finding with respect to outcomes after percutaneous coronary intervention in this population is unknown. METHODS: We analysed a prospective interventional database at a single tertiary center and identified 41 dialysis patients who underwent coronary angioplasty. All studies were reviewed for the presence of coronary calcium in the target and reference vessels and compared with respect to baseline clinical factors and cardiovascular outcomes. RESULTS: The mean ages for those with and without coronary calcification were 63.6 +/- 11.0 and 67.3 +/- 11.0, respectively, P = 0.30. The groups were similar in years on dialysis, diabetes, hypertension, smoking, and measures of calcium and phosphate balance. The total cholesterol, LDL-C, HDL-C, and triglycerides were 162.5 +/- 42.3 and 202.0 +/- 54.5, P = 0.02; 94.9 +/- 39.6 and 121.2 +/- 48.1, P = 0.18; 39.3 +/- 12.4 and 47.3 +/- 12.2, P = 0.15; 157.4 +/- 100.4 and 181.3 +/- 187.4, P = 0.15, for those with and without calcification, respectively. The composite of target vessel revascularization, myocardial infarction, or death was 47.4% and 77.3% for those with and without calcification, respectively, P = 0.06. The Cox proportional hazards model, controlling for years on dialysis, showed a significant, event-free survival in those with coronary calcium seen fluoroscopically, P = 0.05. CONCLUSIONS: In dialysis patients, coronary calcification identified in the target or reference vessels is associated with lower total cholesterol and favourable interventional outcomes.

Determinants of mortality after myocardial infarction in patients with advanced renal dysfunction.

Previous studies using administrative data have shown high mortality in patients with renal failure requiring dialysis after acute myocardial infarction (AMI). There has been little investigation into the mortality after AMI in those with advanced renal disease who are not on dialysis therapy. We analyzed a prospective coronary care unit registry of 1,724 patients with ST segment elevation myocardial infarction admitted over an 8-year period at a single tertiary-care center. Those not on chronic dialysis therapy were stratified into groups based on corrected creatinine clearance, with cutoff values of 46.2, 63.1, and 81.5 mL/min/72 kg. Dialysis patients (n = 47) were considered as a fifth comparison group. Older age, black race, diabetes, hypertension, previous coronary disease, and heart failure were incrementally more common across increasing renal dysfunction strata. There were also graded increases in the relative risk for atrial and ventricular arrhythmias, heart block, asystole, development of pulmonary congestion, acute mitral regurgitation, and cardiogenic shock. Primary angioplasty, thrombolysis, and beta-blockers were used less often across the risk strata (P < 0.0001 for all trends). There was an early mortality hazard (age-adjusted relative risk, 8.76; P < 0.0001) for those with renal dysfunction but not on dialysis therapy for the first 60 months, followed by graded decrements in survival across increasing renal dysfunction strata. The excess mortality in this population appears to be mediated through arrhythmias, adverse hemodynamic events, and the lower use of mortality-reducing therapy.