Aggregation and combination of cardiovascular risk factors and their association with 10-year all-cause mortality: the PERU MIGRANT Study.

OBJECTIVE: To estimate the association between the aggregation and pair-wise combination of selected cardiovascular risk factors (CVRF) and 10-year all-cause mortality. METHODS: Secondary data analysis of the PERU MIGRANT study, a prospective population-based cohort. Ten-year all-cause mortality was determined for participants originally enrolled in the PERU MIGRANT Study (baseline in 2007) through the National Registry of Identification and Civil Status. The CVRF included hypertension, type 2 diabetes mellitus, hypercholesterolemia, and overweight/obesity. Exposures were composed of both the aggregation of the selected CVRF (one, two, and three or more CVRF) and pair-wise combinations of CVRF. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (95% CI). FINDINGS: Of the 989 participants evaluated at baseline, 976 (98.8%) had information about vital status at 10 years of follow-up (9992.63 person-years), and 63 deaths were recorded. In the multivariable model, adjusting for sociodemographic and lifestyle variables, participants with two CVRF (HR: 2.48, 95% CI: 1.03-5.99), and those with three or more CVRF (HR: 3.93, 95% CI: 1.21-12.74) had higher all-cause mortality risk, compared to those without any CVRF. The pair-wise combinations associated with the highest risk of all-cause mortality, compared to those without such comorbidities, were hypertension with type 2 diabetes (HR: 11.67, 95% CI: 3.67-37.10), and hypertension with overweight/obesity (HR: 2.76, 95% CI: 1.18-6.71). CONCLUSIONS: The aggregation of two or more CVRF and the combination of hypertension with type 2 diabetes or overweight/obesity were associated with an increased risk of 10-year all-cause mortality. These risk profiles will inform primary and secondary prevention strategies to delay mortality from cardiovascular risk factors.

HDL-C, longitudinal change and risk of mortality in a Chinese cohort study.

BACKGROUND AND AIMS: High-density lipoprotein cholesterol (HDL-C) concentration and variability are both important factors of cardiovascular disease (CVD) and mortality. We aimed to explore the associations of HDL-C and longitudinal change in HDL-C with risk of mortality. METHODS AND RESULTS: We recruited a total of 69,163 participants aged ≥40 years and had medical examination records of HDL-C during 2010-2014 from the Yinzhou District, Ningbo, China. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression models. We observed a non-linear association of HDL-C with risks of non-accidental and CVD mortality. Compared with the moderate concentration group (1.4-1.6 mmol/L), HDL-C <1 mmol/L was associated with a higher risk of non-accidental mortality (HR: 1.13 (95% CI: 1.01-1.27)) and both HDL-C <1 mmol/L and ≥2 mmol/L were associated with a higher risk of CVD mortality (HRs: 1.23 (95% CI: 1.01-1.50) and 1.37 (95% CI: 1.03-1.82), respectively). Compared with the stable group ([-0.1, +0.1 mmol/L]), a large decrease ([-0.5, -0.3 mmol/L]) and very large decrease (<-0.5 mmol/L) in HDL-C were associated with a higher risk of non-accidental mortality (HRs: 1.40 (95% CI: 1.21-1.63) and 1.78 (95% CI: 1.44-2.20), respectively). Similar results were observed for CVD mortality and cancer mortality. CONCLUSION: Extremely low or high HDL-C and a large decrease or very large decrease in HDL-C were associated with a higher risk of cause-specific mortality. Monitoring of HDL-C may have utility in identifying individuals at higher risk of mortality.

Risk Differences in Secondary Prevention Patients Who Present With Acute Coronary Syndrome and Implications of Guideline-Directed Cholesterol Management.

The 2018 American College of Cardiology/American Heart Association cholesterol guidelines for secondary prevention identified a group of "very high risk" (VHR) patients, those with multiple major atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk features. A second group, "high risk" (HR), was defined as patients without any of the risk features in the VHR group. The incidence and relative risk differences of these 2 groups in a nontrial population has not been well characterized. Using the Northwestern Medicine Enterprise Data Warehouse, we compared the incidence of VHR and HR patients as well as their relative risk for cardiovascular morbidity and mortality in a single-center, large, academic, retrospective cohort study. Total 1,483 patients with acute coronary events from January 2014 to December 2016 were risk stratified into VHR and HR groups. International Classification of Diseases versions 9 and 10 were used to assess for composite events of unstable angina pectoris, non-ST elevation myocardial infarction, or ST-elevation myocardial infarction, ischemic stroke, or all-cause death with a median follow-up of 3.3 years. VHR patients were found to have 87 ± 5.4 composite events per 1,000 patient-years compared with HR patients who had 33 ± 5.1 events per 1,000 patient-years (p <0.001). VHR group had increased risk of future events as compared to the HR group (multivariable adjusted hazard ratio 1.66 [1.01 to 2.74], p = 0.047). In conclusion, these results support the stratification of patients into the VHR and HR risk groups for secondary prevention.

Phase 1 trial of vorolanib (CM082) in combination with everolimus in patients with advanced clear-cell renal cell carcinoma.

BACKGROUND: Vorolanib (X-82, CM082) is a multi-target tyrosine kinase inhibitor. This study aimed to evaluate the tolerability, safety, pharmacokinetics and antitumor activities of vorolanib plus everolimus (an inhibitor of mammalian target of rapamycin). METHODS: Patients had histologically or cytologically confirmed advanced RCC and failed with standard therapy were eligible for this study. Dose-escalated combinations of vorolanib (100, 150 or 200 mg once daily) with everolimus (5 mg once daily) were administered on 28-day cycles until disease progression or unacceptable toxicity using a conventional 3 + 3 dose-escalation design. FINDINGS: 22 patients (100 mg n = 4, 150 mg n = 3, 200 mg n = 15) were enrolled. Only one patient experienced dose-limiting toxicity (DLT, grade 4 thrombocytopenia) in the vorolanib 200 mg combination cohort, and the maximum tolerated dose (MTD) was not reached. The most common treatment-related adverse events were proteinuria (100%), leukopenia (77%), hypercholesterolaemia (77%), increased low-density lipoprotein (68%), hypertriglyceridaemia (64%), hyperglycaemia (59%), and fatigue (55%). Most treatment-related adverse events were grade 1 to 2, with grade 3 or higher toxicities mostly seen in the 200 mg cohort. Single dosing of vorolanib demonstrated dose-proportional increases in the Cmax and AUC, and observed short t1/2z ranging from 4.74±1.44 to 12.89±7.49 h. The pharmacokinetic parameters for everolimus were similar among all cohorts. Of 19 evaluable patients, the ORR and DCR was 32% (n = 6, 95% CI, 13-57%) and 100% (95% CI, 82-100%), respectively. INTERPRETATION: Combination therapy of vorolanib 200 mg plus everolimus 5 mg once daily is potentially effective with potential activity. Further evaluation of the combination in advanced RCC patients is ongoing (NCT03095040). FUNDING: Betta Pharmaceutical Co., Ltd., Hangzhou, China.

The Legacy Effect in Treating Hypercholesterolemia.

BACKGROUND: The duration of randomized controlled clinical trials usually is approximately 3 to 5 years although hypercholesterolemia and other risk factors for atherosclerotic cardiovascular disease (ASCVD) are lifelong conditions. OBJECTIVES: The legacy effect, defined as the persistence of benefit of pharmacologic interventions in clinical trials after the end of the randomized phase when all participants receive active therapy, is used to examine the long-term benefit. We summarize the evidence for the existence of the legacy effect as it pertains to hypercholesterolemia, describe underlying mechanisms, and discuss its relevance to clinical practice. METHODS: We examined all published (n = 13) randomized clinical trials of lipid-lowering agents compared to placebo or usual care with follow-up after the randomized phase for the presence or absence of a legacy effect. RESULTS: A legacy effect was demonstrated in all studies. The current US and European guidelines recommend treatment with high-intensity statins for patients with manifest ASCVD and that individualized approach be used for primary prevention. CONCLUSION: The legacy effect results in significant long-term clinical benefits by preventing fatal and nonfatal events. This implies that early therapy would result in lower event rates. Long-term follow-up should be a part of clinical trial design in order to evaluate the presence or absence of a legacy effect.

Predictive validity of the risk SCORE model in a Mediterranean population with dyslipidemia.

BACKGROUND AND AIMS: Cholesterol treatment for the primary prevention of cardiovascular disease is based on cardiovascular risk, as assessed by the SCORE (Systematic COronary Risk Evaluation) scale. This study aimed to assess the predictive value and clinical utility of the SCORE scale for preventing cardiovascular events and all-cause mortality in people with dyslipidemia and no lipid-lowering treatment. METHODS: Patients with dyslipidemia and no lipid-lowering treatment were included from the ESCARVAL-RISK cohort. Cardiovascular risk was calculated by means of the SCORE scale. All deaths and cardiovascular events were recorded for up to five years of follow-up. We calculated sensitivity, specificity and other predictive values for different cut-off points and assessed the effect of different risk factors on the diagnostic accuracy of the SCORE charts. RESULTS: In the final cohort of 18,853 patients, there were 1565 cardiovascular events and 268 deaths. The risk value recommended to initiate pharmacological treatment (5%) presented a specificity of 86% for death and 90% for cardiovascular events, and a sensitivity of 53% for death and 32% for cardiovascular events. In addition, the scale classified as low risk 62.8% of the patients who suffered a cardiovascular event and 46.6% of those who died. Antithrombotic treatment, diabetes, hypertension, heart failure, peripheral artery disease and chronic kidney disease were associated with a reduction in the predictive capability of the SCORE scale, whereas metabolic syndrome was related to better risk prediction. CONCLUSIONS: The predictive capability of the SCORE scale for cardiovascular disease and total mortality in patients with dyslipidemia is limited.

Influence of hypercholesterolemia and diabetes on long-term outcome in patients with stable coronary artery disease receiving percutaneous coronary intervention.

Coronary artery disease (CAD) is a life-threatening medical emergency which needs urgent medical attention. Percutaneous coronary intervention (PCI) is common and necessary for patients with CAD. The effect of hypercholesterolemia and diabetes on long-term outcomes in patients with stable CAD receiving PCI is unclear.In this study, patients with stable CAD who underwent PCI were prospectively divided into 4 groups according to the presence or absence of diabetes or hypercholesterolemia. Clinical characteristics, risk factors, medications, angiographic findings, and outcome predictors were analyzed and long-term outcomes compared between groups.Of the 1676 patients studied, those with hypercholesterolemia and diabetes had the highest all-cause mortality rate after PCI (P < .01); those with diabetes only had the highest cardiovascular (CV) mortality (P < .01). However, the 4 groups did not differ in rates of myocardial infarction (MI) or repeated PCI. In Kaplan-Meier survival analysis, patients with diabetes only had the highest rates of all-cause mortality and CV mortality (both P < .001). In the Cox proportional hazard model, patients with both hypercholesterolemia and diabetes had the highest risk of all-cause mortality (hazard ratio: 1.70), but groups did not differ in rates of MI, CV mortality, and repeated PCI.With or without hypercholesterolemia, diabetes adversely impacts long-term outcomes in patients receiving PCI. Diabetes mellitus seemed to be a more hazardous outcome predictor than hypercholesterolemia. Hypercholesterolemia and diabetes seemed to have an additive effect on all-cause mortality in patients after receiving PCI.

Repeated measures of extremely high levels of high-density lipoprotein cholesterol and subsequent all-cause mortality and cardiovascular events: A longitudinal study.

BACKGROUND AND AIMS: Extremely high level high-density lipoprotein (HDL) cholesterol had been cautioned as risk factor for all-cause mortality and cardiovascular disease. However, both the physician and the patient may underestimate the risk due to the emphasis on "good cholesterol", resulting in passive treatment or adoption of a less healthy lifestyle. The aim of this study is to re-evaluate the association with longitudinal data to account for fluctuations in HDL cholesterol and covariates. METHODS: We conducted a retrospective longitudinal study at a large teaching hospital in Tokyo, Japan, from 2005 to 2016. We included all adults who participated in health check-ups. Outcomes were all-cause mortality and cardiovascular events. HDL cholesterol was repeatedly measured at each visit and categorized into five groups. The time-varying Cox model was applied to longitudinal analyses. RESULTS: We included a total of 83,100 participants; the mean age was 45.5 (standard deviation:12.4) years; 41,013 (49.4%) were male, and 4475 participants belonged to the extremely high level HDL cholesterol group (>90 mg/dl). During a median follow-up of 1746 (interquartile range:740-3112.5) days, 382 (0.5%) participants died, and 2023 (2.4%) experienced cardiovascular events. Although the extremely high level HDL cholesterol group had significantly lower hazard ratios (HRs) for all-cause mortality (HR:0.49, 95%confidence interval(CI):0.26-0.90) and cardiovascular events (HR:0.71, 95%CI:0.54-0.94) compared to the low group (<40 mg/dl), HRs were higher than in the very high level HDL cholesterol group. CONCLUSIONS: Our study demonstrated that extremely high level HDL cholesterol has significantly lower risks of all-cause mortality and cardiovascular events compared to low level, but higher risks compared to very high level, as previously reported.

Effect of Alirocumab on Mortality After Acute Coronary Syndromes.

BACKGROUND: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. METHODS: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. RESULTS: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths ( P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events ( P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). CONCLUSIONS: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01663402.

Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT.

BACKGROUND: In time-to-first-event analyses, icosapent ethyl significantly reduced the risk of ischemic events, including cardiovascular death, among patients with elevated triglycerides receiving statins. These patients are at risk for not only first but also subsequent ischemic events. OBJECTIVES: Pre-specified analyses determined the extent to which icosapent ethyl reduced total ischemic events. METHODS: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) randomized 8,179 statin-treated patients with triglycerides ≥135 and <500 mg/dl (median baseline of 216 mg/dl) and low-density lipoprotein cholesterol >40 and ≤100 mg/dl (median baseline of 75 mg/dl), and a history of atherosclerosis (71% patients) or diabetes (29% patients) to icosapent ethyl 4 g/day or placebo. The main outcomes were total (first and subsequent) primary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) and total key secondary composite endpoint events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). As a pre-specified statistical method, we determined differences in total events using negative binomial regression. We also determined differences in total events using other statistical models, including Andersen-Gill, Wei-Lin-Weissfeld (Li and Lagakos modification), both pre-specified, and a post hoc joint frailty analysis. RESULTS: In 8,179 patients, followed for a median of 4.9 years, 1,606 (55.2%) first primary endpoint events and 1,303 (44.8%) subsequent primary endpoint events occurred (which included 762 second events, and 541 third or more events). Overall, icosapent ethyl reduced total primary endpoint events (61 vs. 89 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.70; 95% confidence interval: 0.62 to 0.78; p < 0.0001). Icosapent ethyl also reduced totals for each component of the primary composite endpoint, as well as the total key secondary endpoint events (32 vs. 44 per 1,000 patient-years for icosapent ethyl versus placebo, respectively; rate ratio: 0.72; 95% confidence interval: 0.63 to 0.82; p < 0.0001). CONCLUSIONS: Among statin-treated patients with elevated triglycerides and cardiovascular disease or diabetes, multiple statistical models demonstrate that icosapent ethyl substantially reduces the burden of first, subsequent, and total ischemic events. (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial [REDUCE-IT]; NCT01492361).

Hypercholesterolemia after conversion to sirolimus as primary immunosuppression and cardiac allograft vasculopathy in heart transplant recipients.

BACKGROUND: Sirolimus (SRL) attenuates cardiac allograft vasculopathy (CAV) progression after heart transplantation (HT) but often results in hyperlipidemia. In this study we investigated the differential effects of SRL-based and calcineurin inhibitor (CNI)-based immunosuppression on CAV progression and clinical outcomes in HT recipients. METHODS: CAV progression was assessed by coronary intravascular ultrasound (IVUS) as changes in volumetric measurements after correction to time between the first and last follow-up IVUS exams. CAV progression rate and CAV-associated events were compared between patients with mean follow-up low-density lipoprotein (LDL) <100 mg/dl (lower level or LL) and ≥100 mg/dl (higher level or HL) in the SRL and CNI groups. RESULTS: We identified 227 patients on SRL (LL: 118; HL: 109) and 96 on CNI (LL: 56; HL: 40), with a median follow-up of 6.7 years. Clinical characteristics did not differ between the LL and HL groups and all patients were on statins. In the SRL arm, there were no significant differences in CAV progression rate and there were no differences in all-cause mortality and CAV-associated events between the LL and HL groups. In the CNI arm, the Δ change in plaque volume normalized to segment length and time of follow-up (PV/SL/year) (0.55 ± 0.53 vs 1.53 ± 2.32, p = 0.003) and Δ change in plaque index per year (defined as PV/vessel volume ratio) (3.1 ± 3.7% vs 6.3 ± 10.4%; p = 0.034) were significantly lower in the LL than the HL group. After adjusting for patient characteristics, HL was associated with higher rates of advanced CAV requiring coronary angioplasty (hazard ratio [HR] 3.0, 95% confidence interval [CI] 1.05 to 9.40, p = 0.040) and higher rates of all CAV-associated events (HR 2.2, 95% CI 1.10 to 4.54, p = 0.026) in these CNI-treated subjects. CONCLUSION: Unlike CNI-based immunosuppression, the effects of SRL on attenuating CAV progression are independent of LDL cholesterol levels post-HT.

Long-term mortality after blood pressure-lowering and lipid-lowering treatment in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year follow-up results of a randomised factorial trial.

BACKGROUND: In patients with hypertension, the long-term cardiovascular and all-cause mortality effects of different blood pressure-lowering regimens and lipid-lowering treatment are not well documented, particularly in clinical trial settings. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy Study reports mortality outcomes after 16 years of follow-up of the UK participants in the original ASCOT trial. METHODS: ASCOT was a multicentre randomised trial with a 2 × 2 factorial design. UK-based patients with hypertension were followed up for all-cause and cardiovascular mortality for a median of 15·7 years (IQR 9·7-16·4 years). At baseline, all patients enrolled into the blood pressure-lowering arm (BPLA) of ASCOT were randomly assigned to receive either amlodipine-based or atenolol-based blood pressure-lowering treatment. Of these patients, those who had total cholesterol of 6·5 mmol/L or lower and no previous lipid-lowering treatment underwent further randomisation to receive either atorvastatin or placebo as part of the lipid-lowering arm (LLA) of ASCOT. The remaining patients formed the non-LLA group. A team of two physicians independently adjudicated all causes of death. FINDINGS: Of 8580 UK-based patients in ASCOT, 3282 (38·3%) died, including 1640 (38·4%) of 4275 assigned to atenolol-based treatment and 1642 (38·1%) of 4305 assigned to amlodipine-based treatment. 1768 of the 4605 patients in the LLA died, including 903 (39·5%) of 2288 assigned placebo and 865 (37·3%) of 2317 assigned atorvastatin. Of all deaths, 1210 (36·9%) were from cardiovascular-related causes. Among patients in the BPLA, there was no overall difference in all-cause mortality between treatments (adjusted hazard ratio [HR] 0·90, 95% CI 0·81-1·01, p=0·0776]), although significantly fewer deaths from stroke (adjusted HR 0·71, 0·53-0·97, p=0·0305) occurred in the amlodipine-based treatment group than in the atenolol-based treatment group. There was no interaction between treatment allocation in the BPLA and in the LLA. However, in the 3975 patients in the non-LLA group, there were fewer cardiovascular deaths (adjusted HR 0·79, 0·67-0·93, p=0·0046) among those assigned to amlodipine-based treatment compared with atenolol-based treatment (p=0·022 for the test for interaction between the two blood pressure treatments and allocation to LLA or not). In the LLA, significantly fewer cardiovascular deaths (HR 0·85, 0·72-0·99, p=0·0395) occurred among patients assigned to statin than among those assigned placebo. INTERPRETATION: Our findings show the long-term beneficial effects on mortality of antihypertensive treatment with a calcium channel blocker-based treatment regimen and lipid-lowering with a statin: patients on amlodipine-based treatment had fewer stroke deaths and patients on atorvastatin had fewer cardiovascular deaths more than 10 years after trial closure. Overall, the ASCOT Legacy study supports the notion that interventions for blood pressure and cholesterol are associated with long-term benefits on cardiovascular outcomes. FUNDING: Pfizer.

Redefining the histopathologic profile of acute aortic syndromes: Clinical and prognostic implications.

OBJECTIVES: The study objectives were to describe the aortic histopathologic substrates in patients with type A surgically treated acute aortic syndromes, to provide clinico-pathological correlations, and to identify the possible prognostic role of histology. METHODS: We assessed the aortic wall degenerative or inflammatory alterations of 158 patients according to the histopathologic consensus documents. Moreover, we correlated these histologic patterns with the patients' clinical data and long-term follow-up for mortality, major aorta-related events, and nonaorta-related events (including cardiovascular ones). RESULTS: We identified 2 histopathologic patterns: 122 patients (77%) with degenerative alterations and 36 patients (23%) with mixed degenerative-atherosclerotic lesions. Patients with mixed alterations were older (mean 69.6 ± 8.7 years vs 62.2 ± 12.4 years, P = .001) and more hypercholesterolemic (33.3% vs 13.9%, P = .017). The degenerative subgroup showed more intralamellar-mucoid extracellular matrix accumulation (86% vs 66.7%, P = .017) and a lower prevalence of translamellar collagen increase (9.8% vs 50%, P < .001). Patients with mixed degenerative-atherosclerotic abnormalities more frequently had long-term nonaorta-related events compared with those with degenerative abnormalities alone (P = .046); no differences were found between the groups with respect to mortality, major aorta-related events, and cardiovascular nonaorta-related events. CONCLUSIONS: Although degenerative lesions of the medial layer were present in all specimens, substantial atherosclerosis coexisted in approximately one quarter of cases. Patients with mixed degenerative-atherosclerotic abnormalities had a coherent clinical risk profile, a clinical presentation frequently mimicking acute coronary syndrome, and a higher incidence of nonaorta-related events during follow-up. Histopathologic characterization may improve the long-term prognostic stratification of patients after surgical treatment.

New Frontier in Lipids: PCSK9 Inhibitors and Implications for the Life Insurance Industry.

Since the Framingham Heart Study solidified cholesterol as a causative agent in the development of coronary heart disease there has been an explosion of research in the field of lipidology. Many therapeutic options have come and gone as we have been refining the goals of therapy to match the mortality outcome data of large clinical trials. A new frontier has emerged with the introduction of the PCSK9 inhibitors that are able with monthly injections to lower LDL cholesterol >60% with favorable side effect profiles and recently published favorable mortality data. This ushers in a whole new era of cholesterol management. Life insurance medical directors will need to be informed of how these drugs are being used and for conditions such as homozygous hypercholesterolemia, a condition with a very high mortality risk, and for new genetic analysis of affected patients, who are not as rare as once thought. This article provides the background about the development of these drugs, their expanded indications, how they may slip through the cracks of prescription drug (Rx) database inquiries, and touches on therapies in development beyond this class of medications. Medicine is an evolving field. With the new gene editing CRISPR technology it will truly be transformational for these genetically driven conditions with the potential for curative therapy. If curative therapy comes to pass it will, of course, have favorable implications for our evolving life insurance guidelines.

Changing clinical phenotypes of HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorder (HAND) remains a common cause of cognitive impairment and persists in 15-55% of HIV+ individuals in the combination antiretroviral therapy (CART) era. CART is now the primary treatment for HAND, but it is effective in only a subset of patients. In the pre-CART era, HIV-associated dementia was the most common form of HAND. However, in CART-treated patients, the prevalence of HIV-associated dementia has declined substantially, and milder stages of HAND, i.e., ANI and MND predominate. HIV+ patients with mild neurocognitive disorder (MND) can still have significant functional impairment in some activities of daily living. There have been several other significant changes in the clinical features of HAND in the CART era. The mean survival for an individual diagnosed with HIV dementia has increased dramatically. In HIV+ individuals on CART with a suppressed systemic viral load, the majority of individuals with HAND remain stable, with a small proportion showing deterioration. Extrapyramidal signs are now less common in patients with HAND on CART. In the CART era, HAND may have a mixed pattern of both cortical and subcortical features with greater deficits in executive functioning and working memory. Despite the milder clinical phenotype, in the CART era, patients with HAND still have persistent laboratory and neuroimaging abnormalities in the central nervous system even with systemic viral suppression. As the HIV+ patient population ages, cerebrovascular disease risk factors such as hypertension, diabetes, and hypercholesterolemia are increasingly recognized as risk factors for cognitive impairment in HIV+ patients on CART. HAND remains a common neurological condition globally in the CART era, necessitating the need for new animal models to examine pathogenesis and potential treatments for HAND.

Tenth categories of total and HDL cholesterol fail to independently predict death risk in middle-aged Turkish adults.

OBJECTIVE: The aim of this study was to delineate in detail the longitudinal association of total cholesterol (TC) and highdensity lipoprotein cholesterol (HDL-C) levels with overall mortality in middle-aged participants of the biennial Turkish Adult Risk Factor study. METHODS: Baseline lipid variables were analyzed in sex-specific deciles. A baseline age of 45 to 84 years as an inclusion criterion led to the enrollment of 2121 men and women. Cox regression analyses were performed. RESULTS: Deaths were recorded in 237 and 306 women and men, respectively, during a mean 8.85±4.4 years of follow-up. After adjustment for age, smoking status, lipid-lowering and antihypertensive drug usage, prevalent diabetes, and coronary heart disease, and using the lowest decile as referent, neither TC (p trend=0.94 and 0.96, respectively), nor HDL-C categories (p trend=0.20 and 0.31, respectively) were significantly predictive of mortality in either gender. TC deciles exhibited a gender difference insofar as hazard ratios in females tended to be reciprocal to those in males in deciles 2 through 5. CONCLUSION: The findings on TC deciles may be attributed to a comparatively higher death rate in the female (compared with male) bottom decile, reflecting the autoimmune process-induced elevated risk in the lowest decile. Observations on HDLC confirmed presumed pro-inflammatory conversion in levels >50 mg/dL. These results have important clinical implications.

Cholesterol: the debate should be terminated.

Here, I offer personal perspectives on cholesterol homeostasis that reflect my belief that certain aspects of the debate have been overstated.-Nathan, D. G. Cholesterol: the debate should be terminated.

Increasing proportion of ST elevation myocardial infarction patients with coronary atherosclerosis poorly explained by standard modifiable risk factors.

Aims Identification and management of the Standard Modifiable Cardiovascular Risk Factors (SMuRFs; hypercholesterolaemia, hypertension, diabetes and smoking) has substantially improved cardiovascular disease outcomes. However, cardiovascular disease remains the leading cause of death worldwide. Suspecting an evolving pattern of risk factor profiles in the ST elevation myocardial infarction (STEMI) population with the improvements in primary care, we hypothesized that the proportion of 'SMuRFless' STEMI patients may have increased. Methods/results We performed a single centre retrospective study of consecutive STEMI patients presenting from January 2006 to December 2014. Over the study period 132/695 (25%) STEMI patients had 0 SMuRFs, a proportion that did not significantly change with age, gender or family history. The proportion of STEMI patients who were SMuRFless in 2006 was 11%, which increased to 27% by 2014 (odds ratio 1.12 per year, 95% confidence interval: 1.04-1.22). The proportion of patients with hypercholesterolaemia decreased (odds ratio 0.92, 95% confidence interval 0.86-0.98), as did the proportion of current smokers (odds ratio 0.93, 95% confidence interval 0.86-0.99), with no significant change in the proportion of patients with diabetes and hypertension. SMuRF status was not associated with extent of coronary disease; in-hospital outcomes, or discharge prescribing patterns. Conclusion The proportion of STEMI patients with STEMI poorly explained by SMuRFs is high, and is significantly increasing. This highlights the need for bold approaches to discover new mechanisms and markers for early identification of these patients, as well as to understand the outcomes and develop new targeted therapies.

Effect on non-vascular outcomes of lowering LDL cholesterol in patients with chronic kidney disease: results from the Study of Heart and Renal Protection.

BACKGROUND: Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with chronic kidney disease (CKD), with no evidence of an excess risk of cancer or death from any non-vascular cause. However, non-randomized data have suggested that statin therapy may have effects (both adverse and beneficial) on particular non-vascular conditions that do not cause death. METHODS: The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to simvastatin 20 mg plus ezetimibe 10 mg (simvastatin/ezetimibe) daily versus matching placebo. Participants were followed up at least 6 monthly and all post-randomization serious adverse events (SAEs) were recorded. This supplementary analysis reports the effects of treatment on non-vascular SAEs, overall, by system of disease, by baseline characteristics, and by duration of follow-up. RESULTS: During a median of 4.9 years follow-up, similar numbers of participants in the two groups experienced at least one non-vascular SAE (3551 [76.4%] simvastatin/ezetimibe vs 3537 [76.6%] placebo; risk ratio [RR] 0.99, 95% confidence interval [CI] 0.95-1.04). There was no good evidence of any significant effect of simvastatin/ezetimibe on SAEs attributed to any particular nonvascular disease system (of 43 comparisons, only 3 yielded an uncorrected p value < 0.05, of which the smallest was p = 0.02). The relative risk of any nonvascular SAE did not vary significantly among particular prognostic subgroups or by duration of follow-up. CONCLUSIONS: In the SHARP trial, allocation to simvastatin/ezetimibe combination therapy was not associated with any significant non-vascular hazard. TRIALS REGISTRATION: SHARP was retrospectively registered after the first participant was enrolled in 2003 at ISRCTN (ISRCTN54137607 on 31 January 2005: http://www.isrctn.com/ISRCTN54137607) and ClinicalTrials.gov (NCT00125593 on 29 July 2005: https://clinicaltrials.gov/ct2/show/NCT00125593).