Blood pressure response to extended-release naltrexone in heroin and prescription opioid users and its implications for cardiovascular morbidity.

BACKGROUND: Consuming opioid agonists is a risk factor for cardiovascular disease particularly in intravenous heroin users. The monthly injectable extended-release opioid antagonist, naltrexone (XR-NTX) is an effective treatment for opioid use disorder. The impact of opioid receptor blockade through XR-NTX on blood pressure, a critical risk factor for cardiovascular morbidity, has not yet been characterized. METHODS: The study evaluated the change in blood pressure during XR-NTX treatment among 14 patients who predominately used intravenous heroin and 24 patients who used prescription oral opioids, all with opioid use disorder. Blood pressure was measured in each patient immediately before the first XR-NTX injection and ∼two weeks after the first injection. The change in diastolic and systolic pressure was compared between the heroin users and the prescription opioids users using analysis of variance. RESULTS: XR-NTX treatment was associated with significant decreases in diastolic blood pressure in the heroin group, but not in the prescription opioids group. Systolic blood pressure values in the heroin users showed a decline at trend level only. CONCLUSIONS: Further research is warranted to replicate our findings and to determine whether XR-NTX effect is relatively specific to blood pressure or generalizes to other components of metabolic syndrome. Distinguishing between heroin and prescription opioid users could shed light on the unique clinical and pharmacological profiles of opioid drugs, particularly regarding their cardiovascular safety. This information can be useful in developing personalized therapeutic strategies based on the route of opioid administration.

Blood lipid levels and treatment following an acute coronary syndrome or coronary intervention - Journey from hospital to cardiac rehabilitation.

Background: A significant number of coronary artery disease patients do not attain guideline recommended LDL levels. Participating in a cardiac rehabilitation (CR) program has been shown to improve adherence to medical therapy. Objectives: Evaluate the specific lipid lowering therapy (LLT) prescribed and percent of subjects achieving LDL levels of <70 mg/dL before and after 3 months following CR program initiation. Methods: From May 2017 to April 2019, we prospectively recruited patients referred to our CR program and compared 1015 of them at 4 time points; (P1) just prior to the index hospitalization, (P2) during the index hospitalization, (P3) upon entering the CR program, roughly 3 months after the index hospitalization, and (P4) 3 months into the CR program. Included in the analysis were parameters of lipid levels, the dispensed medication given, as well as patient adherence to treatment. Results: At CR intake, LDL goals were partially achieved with 57% of patients below 70 mg/dL. After completion of 3 months of CR, 63% of patients had LDL levels below 70 mg/dL, despite the fact that the majority (95%) were prescribed high-dose potent statins. Aside from the LDL levels at CR intake, we found no other independent predictors for not attaining the lipid goals at 6 months. Conclusions: A significant treatment gap is present even in a selected population participating in CR, with the vast majority receiving guideline recommended LLT. In order to improve goals, we need to intensify LLT treatment, and increase patient adherence to therapy.

The insulin sensitivity Mcauley index (MCAi) is associated with 40-year cancer mortality in a cohort of men and women free of diabetes at baseline.

BACKGROUND: The association between insulin resistance and cancer-mortality is not fully explored. We investigated the association between several insulin sensitivity indices (ISIs) and cancer-mortality over 3.5 decades in a cohort of adult men and women. We hypothesized that higher insulin resistance will be associated with greater cancer-mortality risk. METHODS: A cohort of 1,612 men and women free of diabetes during baseline were followed since 1979 through 2016 according to level of insulin resistance (IR) for cause specific mortality, as part of the Israel study on Glucose Intolerance, Obesity and Hypertension (GOH). IR was defined according to the Mcauley index (MCAi), calculated by fasting insulin and triglycerides, the Homeostatic Model Assessment (HOMA), the Matsuda Insulin Sensitivity Index (MISI), and the Quantitative Insulin Sensitivity Check Index (QUICKI), calculated by plasma glucose and insulin. RESULTS: Mean age at baseline was 51.5 ± 8.0 years, 804 (49.9%) were males and 871 (54.0%) had prediabetes. Mean follow-up was 36.7±0.2 years and 47,191 person years were accrued. Cox proportional hazard model and competing risks analysis adjusted for age, sex, country of origin, BMI, blood pressure, total cholesterol, smoking and glycemic status, revealed an increased risk for cancer-mortality, HR = 1.5 (95% CI: 1.1-2.0, p = 0.005) for the MCAi Q1 compared with Q2-4. No statistically significant associations were observed between the other ISIs and cancer-mortality. CONCLUSION: The MCAi was independently associated with an increased risk for cancer-mortality in adult men and women free of diabetes and should be further studied as an early biomarker for cancer risk.

The association between insulin sensitivity indices, ECG findings and mortality: a 40-year cohort study.

BACKGROUND: Type 2 Diabetes is a major risk factor for cardiovascular (CV) mortality. Insulin resistance can be evaluated non-invasively by insulin sensitivity indices (ISI) such as the Mcauley index (MCAi), which is a function of the fasting insulin and triglycerides. Currently, the association between ISIs and ECG findings and all-cause and CV mortality is still not established in a large scale and heterogeneous population. METHOD: In a prospective study of the Israel cohort on Glucose Intolerance, Obesity and Hypertension (GOH) second phase (1979-1982) 1830 men and women were followed until December-2016 for CV-mortality and December-2019 for all-cause mortality. ECGs were recorded and OGTTs performed during baseline. ISIs were categorized into quartiles and evaluated against ECG findings and all-cause and CV-mortality. RESULTS: Mean age at baseline was 52.0 ± 8.1 years, and 75 (15.2%) and 47 (25.3%) participants in the upper quartiles (Q2-4) and the lower quartile (Q1) of the MCAi, presented with Ischemic changes on ECG respectively (p = 0.02). Multivariable analysis showed higher odds for ECG ischemic changes, for individuals in Q1-MCAi (adjusted-OR = 1.7, 95% CI 1.02-2.8), compared with Q2-4-MCAi, which attenuated when excluding individuals with diabetes (adjusted-OR = 1.6, 95% CI 0.9-2.7, p = 0.09). Median follow up for all-cause and for cardiovascular mortality was 31 years and 37 years, respectively. Cox proportional-hazards regression showed an increased risk for all-cause mortality for individuals in Q1-MCAi (HR = 1.2, 95% CI 1.02-1.3) as well as an increased risk for CV-mortality (HR = 1.4, 95%CI 1.1-1.8) compared with Q2-4-MCAi. Individuals in Q4-Ln Homeostatic model assessment- Insulin Resistance (HOMA-IR) and Q1- Quantitative Insulin Sensitivity Check Index (QUICKI) also presented with increased risk for all-cause-mortality (HR = 1.2, 95%CI 1.04-1.4; and HR = 1.2, 95% CI 1.04-1.4, respectively). Other ISIs did not show significant associations with CV-mortality. CONCLUSION: Higher insulin-resistance, according to the MCAi, associated with ECG-changes, and with greater risk for all-cause and CV-mortality over a 40-year follow-up. The MCAi may be considered as an early predictive and prognostic biomarker for CV-morbidity and mortality in adults.

Congestive heart failure treated with peritoneal dialysis or hemodialysis: Typical patient profile and outcomes in real-world setting.

BACKGROUND: Peritoneal dialysis (PD) is increasingly used for the long-term management of hypervolemic refractory congestive heart failure (CHF) patients, in particular when complicated by renal insufficiency. While PD has many advantages over hemodialysis (HD) in those patients, there is a controversy concerning survival superiority of PD compared with HD in this population. The aim of the study was to define typical patient profile and to compare outcomes of patients with CHF and renal failure treated with HD or PD. METHODS: This retrospective cohort study enrolled CHF patients treated with chronic PD or HD between the years 2009-2018. Information at dialysis initiation included age, gender, body weight, blood pressure, cause of renal disease, comorbidities, hospitalisations, echocardiographic and laboratory parameters. Survival was compared between PD and HD patients using a Kaplan-Meier model and Cox regression analysis. RESULTS: CHF patients treated with PD had significantly higher eGFR and lower systolic blood pressure compared with HD treated patients. Median survival time was 13.32 (7.08, 23.28) months in the PD group and 19.68 (9.48, 39.24) months in the HD group, P = .013. After adjustment for confounders the mortality risk amongst PD and HD patients was not significantly different: adjusted HR for death in PD vs HD patients was 1.44, P = .35 for 1- year and 1.69, P = .10 for 2-year mortality. Number of hospitalisations was similar in both groups. CONCLUSIONS: CHF patient profile was different in PD and HD. Two modalities were equally effective in the treatment of patients with CHF and renal failure considering different patient characteristics.

Author Correction: Metabolic and Addiction Indices in Patients on Opioid Agonist Medication-Assisted Treatment: A Comparison of Buprenorphine and Methadone.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Metabolic and Addiction Indices in Patients on Opioid Agonist Medication-Assisted Treatment: A Comparison of Buprenorphine and Methadone.

Metabolic hormones stabilize brain reward and motivational circuits, whereas excessive opioid consumption counteracts this effect and may impair metabolic function. Here we addressed the role of metabolic processes in the course of the agonist medication-assisted treatment for opioid use disorder (OUD) with buprenorphine or methadone. Plasma lipids, hemoglobin A1C, body composition, the oral glucose tolerance test (oGTT) and the Sweet Taste Test (STT) were measured in buprenorphine- (n = 26) or methadone (n = 32)- treated subjects with OUD. On the whole, the subjects in both groups were overweight or obese and insulin resistant; they displayed similar oGTT and STT performance. As compared to methadone-treated subjects, those on buprenorphine had significantly lower rates of metabolic syndrome (MetS) along with better values of the high-density lipoproteins (HDL). Subjects with- vs. without MetS tended to have greater addiction severity. Correlative analyses revealed that more buprenorphine exposure duration was associated with better HDL and opioid craving values. In contrast, more methadone exposure duration was associated with worse triglycerides-, HDL-, blood pressure-, fasting glucose- and hemoglobin A1C values. Buprenorphine appears to produce beneficial HDL- and craving effects and, contrary to methadone, its role in the metabolic derangements is not obvious. Our data call for further research aimed at understanding the distinctive features of buprenorphine metabolic effects vis-à-vis those of methadone and their potential role in these drugs' unique therapeutic profiles.

Clinically significant incidental QTc prolongation is subject to within-individual variability.

BACKGROUND: Prolonged QTc interval observed in daily practice is often deemed to be drug induced and might result in drug discontinuation, with possible therapeutic consequences. However, whether clinically significant prolonged QTc may be due to within-individual variability occurs has yet to be described. METHODS: A retrospective cohort study documenting within-individual QTc variability in subjects attending annual routine medical evaluation. At each visit, QT interval was measured and corrected for heart rate using Bazett and three other commonly used formulae. Outcome measures were rates of ΔQTc ≥60 msec, absolute QTc ≥500 msec and QTc ≥25% from baseline. RESULTS: A total of 188 subjects [54 (29%)] females were recruited. Mean age at first ECG was 54 ± 12.8 years with mean time interval of 12.2 ± 1.1 months between measurements. Mean Bazett QTc was higher compared to the other 3 formulae: 412 ± 20 vs. 400 ± 16 msec. Using Bazett formula, 18/188 (9.6%) and 5/188 (2.7%) subjects showed at least one measurement with ΔQTc ≥60 msec and QTc ≥500 msec, respectively. Of the former, 5/18 (27.8%) showed QTc ≥25% prolongation. In multivariate analysis, QTc ≥500 msec was significantly associated with number of measurements (HR: 5.01, 95%CI: 1.21-20.78, p = .026) with no effect of other known confounders. Lower rates were demonstrated with the other three formulae. CONCLUSION: In clinical practice, significant prolonged QTc may be attributed to within-individual variability, particularly when adjusting the QT interval with Bazett correction. This should be taken into consideration when decisions on changing current drug regimens are to be made.

Participation in an Exercise-Based Cardiac Rehabilitation Program and Functional Improvement of Heart Failure Patients with Preserved Versus Reduced Left Ventricular Systolic Function.

BACKGROUND: About half of all patients with heart failure are diagnosed with heart failure preserved ejection fraction (HFpEF). Until now, studies have failed to show that medical treatment improves the prognosis of patients with HFpEF. OBJECTIVES: To evaluate changes in exercise capacity of patients with HFpEF compared to those with heart failure with reduced ejection fraction (HFrEF) following an exercise training program. METHODS: Patient data was retrieved from a multi-center registry of patients with heart failure who participated in a cardiac rehabilitation program. Patients underwent exercise testing and an echocardiogram prior to entering the program and were retested6  months later. RESULTS: Of 216 heart failure patients enrolled in the program, 170 were diagnosed with HFrEF and 46 (21%) with HFpEF. Patients with HFpEF had lower baseline exercise capacity compared to those with HFrEF. Participating in a 6 month exercise program resulted in significant and similar improvement in exercise performance of both HFpEF and HFrEF patients: an absolute metabolic equivalent (MET) change (1.45 METs in HFrEF patients vs. 1.1 in the HFpEF group, P = 0.3). CONCLUSIONS: An exercise training program resulted in similar improvement of exercise capacity in both HFpEF and HFrEF patients. An individualized, yet similarly structured, cardiac rehabilitation program may serve both heart failure groups, providing safety and efficacy.

The prognostic significance of improvement in exercise capacity in heart failure patients who participate in cardiac rehabilitation programme.

Introduction There are limited contemporary data regarding the association between improvement in cardiovascular fitness in heart failure patients who participate in a cardiac rehabilitation programme and the risk of subsequent hospitalisations. Methods The study population comprised 421 patients with heart failure who participated in our cardiac rehabilitation programme between the years 2009 and 2016. All were evaluated by a standard exercise stress test before initiation, and underwent a second exercise stress test on completion of 3 ± 1 months of training. Participants were dichotomised by fitness level at baseline, according to the percentage of predicted age and sex norms achieved. Each group was further divided according to its degree of functional improvement, between the baseline and the follow-up exercise stress test. Major improvement was defined as improvement above the median value in each group. The combined primary endpoint was cardiac hospitalisation or all-cause mortality. Results A total of 211 (50%) patients had low baseline fitness (<73% (median)) for age and sex-predicted metabolic equivalents of task value. Compared to patients with higher fitness, those with a low baseline fitness were more commonly smokers, had diabetes and were obese ( P < 0.05 for all). Multivariable Cox proportional hazard regression analysis showed that, independent of baseline capacity, an improvement of 5% of predicted fitness was associated with a corresponding 10% reduced risk of cardiac hospitalisation or all-cause mortality ( P < 0.001). Conclusion In heart failure patients participating in a cardiac rehabilitation programme, improved cardiovascular fitness is associated with reduced mortality or cardiac hospitalisation risk during long-term follow-up, independent of baseline fitness.

Early Referral to Coronary Artery Bypass Grafting Following Acute Coronary Syndrome, Trends and Outcomes from the Acute Coronary Syndrome Israeli Survey (ACSIS) 2000-2010.

BACKGROUND: Limited information exists on whether changes in medical practices over the study decades have affected the outcomes of acute coronary syndrome (ACS) patients who undergo early coronary artery bypass surgery (CABG) during index hospitalisation. METHODS: Data on trends for early CABG referral and associated outcomes were obtained among 11,485 ACS patients enrolled in the biennial Acute Coronary Syndrome Israeli Surveys (ACSIS) 2000-2010. RESULTS: Among 11,485 patients, 566 (5%) were referred to early CABG. These patients displayed higher risk characteristics, including Killip class >II, anterior myocardial infarction, greater left ventricular dysfunction, and more frequent use of mechanical ventilation and intra-aortic balloon pump (all p<0.01). Nevertheless, mortality rates of patients referred to early CABG vs. treated with percutaneous coronary intervention (PCI) or medically, was similar (11.4% vs. 10.2%; log-rank p-value=0.40). There was a significant decline in the referral trend over the study decade (6.7% - 1.7%; p<0.001). One year survival was similar between patients referred to early CABG during the late (years: 2006-2010) vs. early (years: 2000-2005) period (85.7% vs. 90%; log-rank p-value=0.15), whereas, among patients who didn't undergo early CABG, and underwent percutaneous coronary intervention (PCI) or medical management only, enrolment during the late periods was associated with a significant survival benefit (91.5% vs. 88.1%; log-rank p-value<0.001). CONCLUSIONS: Over the study decade there was a significant decline in referral for early CABG, without a difference in the one-year mortality between the early and non-early CABG group.

Serum Cardiac Troponin T Levels in Asymptomatic Elderly Nursing Home Residents.

BACKGROUND: The definition of myocardial infarction relies on elevated troponin levels. However, elevated levels of high sensitive cardiac troponin (hs-cTnT) assays have been reported in elderly patients without acute myocardial infarction. We sought to determine whether elevated hs-cTnT levels have a prognostic value in stable elderly subjects without any acute illness. METHODS: The study cohort included residents of a nursing home who were asymptomatic without any acute medical problem. Serum hs-cTnT levels were measured, and participants were divided into high and low hs-cTnT groups. We measured hs-cTnT levels of young healthy volunteers as well and compared them with hs-cTnT levels of those nursing home residents. RESULTS: Fifty-seven nursing home residents and 14 young volunteers were included in the study. The average age of nursing home residents was 83 ± 14 years, compared with 37 ± 3 years of the volunteers. Levels of hs-cTnT were significantly higher in the elderly compared with the volunteers (0.02 ± 0.016 ng/mL vs 0.005 ± 0.0003 ng/mL; P < .001); accordingly, we chose a cutoff of 0.02 ng/mL hs-cTnT and divided the 57 patients into 2 subgroups for further evaluation. After adjustment for age, gender, and glomerular filtration rate, the hs-cTnT was still an independent predictor of 1-year mortality (relative risk 2.04 [95% conficence interval, 2.009-29.45], P = .003). CONCLUSIONS: Mild elevations of hs-cTnT levels are common in elderly patients, and hs-cTnT level is an independent marker of mortality risk in this population. For patients older than 70 years, a different hs-cTnT cutoff is required (eg, higher than 0.014 ng/mL).

Short- and Long-Term Prognostic Implications of Jugular Venous Distension in Patients Hospitalized With Acute Heart Failure.

The present study was designed to assess the role of jugular venous distension (JVD) as a predictor of short- and long-term mortality in a "real-life" setting. The independent association between the presence of admission JVD and the 30-day, 1- and 10-year mortality was assessed among 2,212 patients hospitalized with acute heart failure (HF) who were enrolled in the Heart Failure Survey in Israel (2003). Independent predictors of JVD finding in study patients included: the presence of significant hyponatremia (odds ratio [OR] 1.48; p = 0.03), reduced left ventricular ejection fraction ([LVEF] OR 1.24; p = 0.03), anemia (OR 1.3; p = 0.01), New York Heart Association III to IV (OR 1.34; p <0.01) and age >75 years (OR 1.32; p = 0.01). The presence of JVD versus its absence at the time of HF hospitalization was associated with increased 30-day mortality (7.2% vs 4.9%, respectively; p = 0.02), 1-year (33% vs 28%, respectively; p <0.001), and greater 10-year mortality (91.8% vs 87.2%, respectively; p <0.001). Consistently, interaction term analysis demonstrated that the presence of JVD at the time of the index HF hospitalization was independently associated with a significant increased risk for 10-year mortality, with a more pronounced effect among younger patients, patients with reduced LVEF, preserved renal function, and chronic HF. In conclusion, in patients admitted with HF, JVD is associated with specific risk factors and is independently associated with increased risk of both short- and long-term mortality. These findings can be used for improved risk assessment and management of this high-risk population.

Temporal trends in the outcomes of patients with acute myocardial infarction associated with renal dysfunction over the past decade.

BACKGROUND: Patients with renal dysfunction (RD) who present with acute myocardial infarction (AMI) are at a high risk for subsequent cardiovascular morbidity and mortality. We sought to evaluate changes in the short and long term mortality of AMI patients with RD compared to patients with normal renal function over the last decade. METHODS: This study based on 4 bi-annually surveys was performed from 2002 to 2010 and included 9468 AMI patients, that were followed for 1year, of whom 2770 (29%) had reduced estimated GFR ([eGFR]<60ml/min/m(2)). Among patients with reduced eGFR: 1251 patients (45%) were included in the 2002-2005 surveys (early period) and 1519 (55%) in the 2006-2010 surveys (late period). RESULTS: Patients with RD were more likely to have advanced cardiovascular disease, multiple comorbidities and higher in-hospital, 30-day, and 1-year mortality rates (8.1%,12.3% and 23% vs. 0.7%, 1.7% and 4%, respectively; all p<0.001). Patients with RD enrolled during the late survey periods were more likely to undergo primary PCI and be discharged with current evidence based medical treatment. 1-year mortality rates were significantly lower among patients with RD who were enrolled during the late vs. early survey periods: 22% vs. 25% respectively; (Log-rank P-value <0.001). Consistently, multivariate analysis showed that patients with RD who were enrolled during the late survey periods displayed a lower adjusted risk for 1-year mortality (HR 0.83; CI[0.70-0.94] P=0.01). CONCLUSIONS: Prognosis of patients with RD admitted with AMI has significantly improved over the last decade, possibly due to an improvement of pharmacological and non-pharmacological management.

Cholesterol Levels Decrease soon after Acute Myocardial Infarction.

BACKGROUND: While earlier studies indicated that cholesterol levels decrease significantly after an acute myocardial infarction (MI), a more recent study refuted this observation. OBJECTIVES: To assess changes in plasma lipid levels after onset of acute MI, and determine important predictors of lipid dynamics. METHODS: We prospectively measured lipid levels of patients who presented with an acute MI. Blood samples were drawn on admission to the hospital (day 1), after fasting at least 12 hours overnight (day 2), and on the 4th day of hospitalization (day 4). RESULTS: Of 67 acute MI patients, 30 were admitted for ST elevation MI (STEMI) and 37 for non-STEMI. Both total cholesterol and low density lipoprotein cholesterol (LDL-C) levels decreased significantly (by 9%) in the 24 hours after admission and by 13% and 17% respectively on day 4. High density lipoprotein cholesterol (HDL-C) levels as well as triglycerides did not change significantly. Independent predictors of LDL-C decrease were the presence of diabetes mellitus [odds ratio (OR) 6.73, P = 0.01), and elevated cardiac troponin T (cTnT) levels (OR 1.81, P < 0.04). CONCLUSIONS: LDL-C levels decrease significantly after an acute MI. The reduction is correlated with cTnT levels. Diabetes is a strong independent predictor of LDL-C decrease. In acute MI patients only measurements taken within 24 hours of onset should be used to guide selection of lipid-lowering medication.

Correlation between participation in a cardiac rehabilitation program and quality of life of patients with coronary artery disease.

PURPOSE: To examine the correlation between participation in a cardiac rehabilitation (CR) program and quality of life (QoL). DESIGN: A prospective study of patients with coronary artery disease (CAD). METHODS: Participants completed questionnaires before and after a 3-month CR program. Patients were surveyed using a cardiac history evaluation and the MacNew Heart Disease Health-Related QoL questionnaire. FINDINGS: Of those eligible, only 14% of the participants were women and 7% were of Arab ethnicity. Patients' QoL significantly improved following participation. Higher level of education was associated with improved QoL. Conversely, cardiac risk factor burden was associated with a decline in QoL. No association was found between cardiac risk stratification, age or religiosity and QoL. CONCLUSIONS: Improved QoL after CR program participation should raise awareness of the significant benefits of CR among healthcare professionals. CLINICAL RELEVANCE: CR for those patients with CAD should be implemented, with a focus on women and minorities.