Risk Of CV Death Research Articles

Salt intake and cardiovascular disease: why are the data inconsistent?

Effective population-based interventions are required to reduce the global burden of cardiovascular disease (CVD). Reducing salt intake has emerged as a leading target, with many guidelines recommending sodium intakes of 2.3 g/day or lower. These guideline thresholds are based largely on clinical trials reporting a reduction in blood pressure with low, compared with moderate, intake. However, no large-scale randomized trials have been conducted to determine the effect of low sodium intake on CV events. Prospective cohort studies evaluating the association between sodium intake and CV outcomes have been inconsistent and a number of recent studies have reported an association between low sodium intake (in the range recommended by current guidelines) and an increased risk of CV death. In the largest of these studies, a J-shaped association between sodium intake and CV death and heart failure was found. Despite a large body of research in this area, there are divergent interpretations of these data, with some advocating a re-evaluation of the current guideline recommendations. In this article, we explore potential reasons for the differing interpretations of existing evidence on the association between sodium intake and CVD. Similar to other areas in prevention, the controversy is likely to remain unresolved until large-scale definitive randomized controlled trials are conducted to determine the effect of low sodium intake (compared to moderate intake) on CVD incidence.

Relationship Between Healthy Diet and Risk of Cardiovascular Disease Among Patients on Drug Therapies for Secondary Prevention

Background— Diet quality is strongly related to cardiovascular disease (CVD) incidence, but little is known about its impact on CVD events in older people at high risk of CVD and receiving effective drugs for secondary prevention. This study assessed the association between diet quality and CVD events in a large population of subjects from 40 countries with CVD or diabetes mellitus with end-organ damage receiving proven medications. Methods and Results— Overall, 31 546 women and men 66.5±6.2 years of age enrolled in 2 randomized trials, the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and the Telmisartan Randomized Assessment Study in ACEI Intolerant Subjects With Cardiovascular Disease (TRANSCEND), were studied. We used 2 dietary indexes: the modified Alternative Healthy Eating Index and the Diet Risk Score. The association between diet quality and the primary composite outcome of CV death, myocardial infarction, stroke, or congestive heart failure was assessed with Cox proportional hazard regression with adjustment for age, sex, trial enrollment allocation, region, and other known confounders. During the 56-month follow-up, there were 5190 events. Patients in the healthier quintiles of modified Alternative Healthy Eating Index scores had a significantly lower risk of CVD (hazard ratio, 0.78; 95% confidence interval, 0.71–0.87, top versus lowest quintile of modified Alternative Healthy Eating Index). The reductions in risk for CV death, myocardial infarction, and stroke were 35%, 14%, and 19%, respectively. The protective association was consistent regardless of whether patients were receiving proven drugs. Conclusions— A higher-quality diet was associated with a lower risk of recurrent CVD events among people ≥55 years of age with CVD or diabetes mellitus. Highlighting the importance of healthy eating by health professionals would substantially reduce CVD recurrence and save lives globally. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00153101.

Patients with CKD are at High Risk for CV Death

An estimated 26 million American adults have chronic kidney disease (CKD) and millions of others are at increased risk for CKD [National Kidney Foundation]. Furthermore, as glomerular filtration rate falls, the risk of cardiovascular death increases [Go AS et al. N Engl J Med 2004].

How can we avoid the danger of hypoglycemia, one of the most serious complications of therapy of type 2 diabetes mellitus? The role of DPP-4 inhibitors

Optimal or near-optimal compensation of diabetes mellitus is almost inevitably fraught with the risk of hypoglycemia. In patients with type 2 diabetes (DM2), especially in those of old-age groups, the development of hypoglycemia increases the risk of CV death, cardiac rhythm disturbances, dementia, and depressive states. Whether absolutely all diabetic patients should be treated so as to ensure blood glucose levels close the physiological values thus far remains a matter of controversy. The results of large-scale clinical studies carried out in the recent years suggest the necessity to revise the existing algorithms for the treatment of patients with DM2. Highly efficacious agents for the purpose should be chosen with reference to both their glucose-normalizing activity and "the safety profile" (i.e. reduced risk of hypoglycemia). A panel of experts for the Russian Association of Endocrinologists (RAE) developed and published «Consensus Algorithm on the initiation and intensification of therapy of type 2 diabetes mellitus». Its main provisions emphasize the necessity of treating diabetics on an individual basis and establish target levels of glycemia for each patient. Special attention should be given to the patients belonging to high risk groups, i.e. those with manifest macrovascular pathology, unable to recognize hypoglycemia, and having serious concomitant diseases. The following first line preparations are recommended to enhance the safety of DM2 therapy: metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors and agonists of glucagon-like peptide-1 (GLP-1) receptors. The results of both national and international clinical studies of vildaglyptin give reason to recommend this DPP-4 inhibitor for a wider application to the treatment of patients with type 2 diabetes mellitus.

Abstract 5338: Universal Definition of Myocardial Infarction Classification and the Risk of Cardiovascular Death: Observations From the TRITON-TIMI 38 Trial

The prognostic implications of new or recurrent MI after an acute coronary syndrome have not been completely defined in the era of the Universal Definition of Myocardial Infarction and newer more sensitive biomarker assays. Therefore, we investigated the association between new or recurrent MI by MI Type and the risk of cardiovascular death among 13,608 patients with ACS undergoing coronary intervention in the TRITON-TIMI 38 Trial. METHODS : MI events were categorized on the basis of subtypes as defined by the AHA/ACC/ESC/WHF Task Force for the Redefinition of MI. The risk of CV death was evaluated by landmark analysis starting at the time of the new MI through the end of follow-up and adjusted for important clinical covariates. Outcomes were adjudicated by a blinded CEC. RESULTS : Pts who experienced a MI during follow up were at higher risk of CV death at 6 months than patients who did not experience a MI (6.5% vs 1.3% vs, p<0.001). This association was present across all subtypes of MI with the highest rate among Type 4b (stent thrombosis, 15.4%) and the lowest among Type 4a (non-stent thrombosis PCI related) (figure ). After adjusting for important clinical covariates, the occurrence of any MI was associated with a 4 fold higher risk of death at 6 months (95% CI 3.3–5.6) with similar increased risk across subtype (figure ). CONCLUSIONS : New or recurrent MI after ACS is associated with a significantly increased risk of CV death. This pattern is consistent across all types as defined by the Universal Classification System, including peri-procedural MI. These findings underscore the clinical relevance of these events and therapies aimed at attenuating this risk.

Abstract 5017: Osteoprotegerin and the Risk of Recurrent Events in Patients With Non-ST elevation Acute Coronary Syndromes (NSTE-ACS): Observations From MERLIN-TIMI 36

Osteoprotegerin (OPG) inhibits bone resorption and may also play a role in mediating vascular calcification. Recent studies have suggested that high plasma OPG is a strong predictor of cardiovascular disease (CV) and mortality. We hypothesized that OPG would be useful for risk assessment in patients presenting with NSTE-ACS. METHODS: We measured OPG at baseline in 4,463 pts with NSTE-ACS randomized to ranolazine or placebo in the MERLIN-TIMI 36 trial. Patients were followed for an average of one year. Endpoints were adjudicated by a blinded CEC. RESULTS: OPG at presentation showed a significant graded association with higher rates of recurrent CV events (Figure ). OPG > median (1632 pmol/L, IQR 1206–2242) was associated with a higher risk of CV death (HR 2.9; 95% CI 2.2 – 4.0), CV death or MI (HR 1.9; 95% CI 1.6 – 2.3), and CV death or CHF (HR 2.5; 95% CI 1.9 – 3.1). After adjustment for important covariates including age, gender, diabetes, smoking, HTN, index event, cTnI, CRP and BNP, OPG remained independently associated with the risk of death (adj HR 1.7; 95% CI 1.2 – 2.4), CVD or MI (adj HR 1.4; 95% CI 1.1 – 1.7) and CVD or CHF (adj HR 1.4; 95% CI 1.1 – 1.8). CONCLUSIONS: OPG was independently associated with long-term risk of recurrent CV events in patients with NSTE-ACS, adding to clinical predictors, cTnI, CRP and BNP. This finding in a large data set adds to the emerging evidence supporting OPG as a candidate prognostic marker in pts with ACS, and supports investigation of other therapies that might modify this risk. Event Rates at 1 Year by Quartile of OPG

Abstract 1439: Cytochrome P450 Genetic Variants Predict Cardiovascular Outcomes following Treatment with Clopidogrel but not with Prasugrel

Background : Prasugrel and clopidogrel require transformation into active metabolites by cytochrome P450 (CYP) enzymes. Variants in CYP genes, particularly CYP2C19 , are associated w/ reduced levels of metabolite and platelet inhibition w/ clopidogrel but not prasugrel. We investigated the impact of variants in CYP genes on clinical outcomes. Methods : TRITON-TIMI 38 randomized ACS patients w/ planned PCI to prasugrel (60 mg load, 10 mg qd) or clopidogrel (300 mg, 75 mg qd) for 6–15 mos. DNA was available in 2943 subjects who were genotyped for functional polymorphisms in CYP2C19 , 2C9 , 3A4/5 , 2B6 , and 1A2 and classified for each gene as carriers or non-carriers of ≥1 reduced function allele. Results : Among subjects treated with clopidogrel, CYP2C19 reduced function allele carriers (27% of population) had a 53% increased risk of the primary efficacy endpoint of CV death, MI, or stroke (HR 1.53, P=0.007, Fig ) and a 3-fold increased risk of ARC-defined definite or probable stent thrombosis (HR 3.09, P=0.038) compared w/ non-carriers. In contrast, with prasugrel CYP2C19 reduced function allele carriers were not at increased risk of CV death, MI, or stroke (HR 0.89, P=0.86) or stent thrombosis (HR 0.60, P=0.57). No association between genotype and bleeding was observed w/ either treatment. There were no statistically significant associations between any other tested CYP genotypes and outcomes. Conclusions : CYP2C19 genetic variants identify patients at significantly higher risk for CV death, MI, or stroke and for stent thrombosis among those treated with clopidogrel but not among those treated with prasugrel. CYP2C19 genotyping offers the potential to help tailor antiplatelet therapy.

Glomerular filtration rate < 45 mL/min/1.73 m^2 with microalbuminuria was associated with increased risk for CV death

Source Citation Hallan S, Astor B, Romundstad S, et al. Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: the HUNT II study. Arch Intern ...

Moderate alcohol consumption is associated with reduced long-term cardiovascular risk in patients following a complicated acute myocardial infarction

Background The impact on prognosis of alcohol use in patients with coronary artery disease remains uncertain. We related alcohol use to all-cause mortality, cardiovascular (CV)-mortality and hospitalization in patients following a complicated myocardial infarction (MI). Methods In the OPTIMAAL trial, 5477 patients from 7 Western European countries with heart failure and/or evidence of left ventricular dysfunction following MI were recruited. Following randomization median 3 days, patients were asked to assess their average alcohol consumption prior to the index infarction. Patients were stratified by the frequency of the use of alcohol into either non-users ( n = 2160), moderate users (1–7 drinks/week, n = 2753) and heavy users (> 7 drinks/week, n = 545) and related to prespecified clinical outcomes in the groups. Results A total of 5477 patients were included in the trial. During the follow-up period of 2.7 years 946 deaths were reported. Adjusted for age and smoking status, patients with moderate use of alcohol had 24% lower risk of all-cause death ( p < 0.001), 26% lower risk of CV-death ( p < 0.000) and 8% lower risk for hospitalization ( p = 0.030) than abstainers. There was no significant difference between non-drinkers and heavy drinkers with regard to survival following adjustment for age and smoking status. Conclusion Our results demonstrate a strong positive association between moderate alcohol use and survival in a cohort of patients following complicated MI. Both heavy drinkers and abstainers had poorer prognosis, with no significance difference between those 2 groups.

Abstract 1724: Elevated Levels of the Atherosclerotic Lesion Metalloproteinase PAPPA Are an Independent Predictor of Cardiovascular Death or CHF in STEMI: Results from the CLARITY-TIMI 28 Biomarker Study

Background : Pregnancy associated plasma proteinase A (PAPPA) is a metalloproteinase found in unstable atherosclerotic lesions. The prognostic value of PAPPA in ST-elevation myocardial infarction (STEMI) is unknown. Methods : We measured circulating PAPPA levels using an ELISA (Diagnostic Systems) in a case-cohort of 731 STEMI pts undergoing lysis in CLARITY-TIMI 28 and followed for 30 d. Multivariable Cox proportional hazards regression was used to adjust for demographics, comorbidities, infarct location, Killip class, and type of lytic. Results : The median level of PAPPA was 1.67 mIU/ml (IQR 0.18–9.89 mIU/ml). Patients with higher levels of PAPPA were more likely to be male, but tended to be less likely to have hypertension or diabetes, have an anterior MI, or present in Killip class II–IV. After multivariable adjustment, patients in the top 3 quartiles were at significantly higher risk for cardiovascular death or heart failure (Figure , left, P=0.03). PAPPA levels were not correlated with other biomarkers of death or CHF, including NT-proBNP and ST2 (r&lt;0.10 for both). In a multivariable model that adjusted for clinical covariates, all 3 biomarkers were independent predictors of CV death or CHF (Figure , right, P&lt;0.02 for each) and their addition to clinical risk factors significantly raised the c-statistic from 0.74 to 0.80 (P=0.003). Conclusion : Circulating levels of PAPPA at presentation are a significant predictor of a threefold increased risk of CV death or CHF in patients with STEMI. In a multimarker model, PAPPA, NT-proBNP, and ST2 were significant and complementary predictors of risk, and their addition to clinical risk factors significantly improved the c-statistic. Risk for CV Death or CHF

Abstract 1945: Levels Of Circulating Progenitor Cells In Patients With Chronic Heart Failure Predict Outcomes

Background: A low level of circulating endothelial progenitor cells (EPCs), a marker of reduced vascular regeneration, is related to worse outcome in patients with coronary heart disease, but little is known on pts with heart failure (HF). The aim was to assess the prognostic value of circulating EPCs in patients with HF. Methods: In 68 pts enrolled to GISSI-HF trial by 5 Italian Centers and 45 pts from Frankfurt, mononuclear cells from peripheral blood were isolated and plated; after 4 days, adherent cells were incubated with DiI-labeled acetylated LDL, stained with FITC-labeled Ulex europaeus agglutinin I (lectin), and counted as double positive at confocal microscopy. 66 patients had ischemic etiology, 12 were females, 26 had NYHA class &gt;II, median age 64 y (Q1–Q3 56–70y). Cutoffs for EPCs were assessed by ROC. Results: Mean EPCs in pts with HF 34 ± 7 EPCs/mm 2 , 2–3 fold lower than in age-matched controls. Over a median of 2.5 years, 12 CV deaths and 47 first hospitalizations for CV reasons were recorded. Levels of EPCs were unrelated to severity of HF, age or sex. After adjustment for clinical variables, creatinine and BNP, EPCs &lt;30/mm 2 were associated with a 2-fold higher risk of CV death and hospitalization, as shown by K-M curves (figure ) and by Cox multivariate regression. Pts with HF of ischemic etiology gave identical results. Conclusions : The level of circulating EPCs is an independent predictor of CV death and hospitalization in pts with chronic HF. The assay of this cellular marker of risk can be performed in blood samples collected in a multicenter setting under controlled conditions, and may offer an accessible tool to assess the role of vascular regeneration in the treatment of HF.

Contemporary Use of Digoxin in the Management of Cardiovascular Disorders

Digitalis is the oldest compound in cardiovascular medicine that continues to be used in contemporary clinical practice.1 Evidence supporting the beneficial effects of digoxin on hemodynamic, neurohormonal, and electrophysiological parameters has been accumulated from >200 years of clinical experience and research (Table 1).2 View this table: TABLE 1. Effects of Digoxin Digoxin was approved for heart failure in 1998 under current regulations by the Food and Drug Administration on the basis of the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED), Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE), and Digitalis Investigators Group (DIG) clinical trials.3–5 It was also approved for the control of ventricular response rate for patients with atrial fibrillation. The most recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend digoxin for symptomatic chronic heart failure for patients with reduced systolic function (Class IIa recommendation: weight of evidence/opinion is in favor of usefulness/efficacy), preserved systolic function (Class IIb: usefulness/efficacy is less well established by evidence/opinion), and/or rate control for atrial fibrillation with a rapid ventricular response (Class IIa).6 The new Heart Failure Society of America guidelines for heart failure provide similar recommendations.7 Despite its relatively recent approval by the Food and Drug Administration and the guideline recommendations, digoxin use is decreasing in patients with heart failure.8 In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry, only 30% of patients with left ventricular systolic dysfunction were being treated with digoxin before admission. Digoxin was added in only 8% of patients before discharge despite the fact that they had signs and symptoms of heart failure while receiving diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs) and β-blockers.9,10 This decrease in digoxin use is likely the result of several factors. …

Renal dysfunction as a novel risk factor: Microalbuminuria and cardiovascular risk

only for elevated glucose or BMI values; the correlation extends well into the range of normal values. Apparently, the metabolic syndrome and microalbuminuria are tightly correlated with each other. This relation is of considerable interest because in patients with renal disease insulin resistance is found even in the very early stages [10], and even when GFR is still within the normal range (unpublished observations). Conversely, in a population sample it was found that insulin resistance (according to the HOMA index) was associated with a higher risk of chronic kidney disease [11]. The information obtained from microalbuminuria cannot be replaced by estimating the glomerular filtration rate. Although the reports in the literature are not entirely consistent, the study in Groningen showed that with increasing quantiles of urinary albumin excretion, the creatinine clearance tended to be higher and was lower only in the uppermost quantiles [12]. Although the creatinine clearance is not a reliable index of glomerular filtration, this observation would be plausible in view of a similar relation between GFR and albuminuria noted previously in diabetic patients [13]. There has been much discussion whether microalbuminuria reflects primarily a generalized endothelial cell dysfunction, as suggested by the Steno hypothesis [14], or whether it reflects a podocyte defect, as proposed more recently [15]. The observation that the rate of albumin escape from the plasma space is increased in patients with microalbuminuria [16] argues for the former possibility. The observation that the risk of being microalbuminuric was significantly higher for carriers of the Q-genotype of the 229 polymorphism of the podocin gene at any given level of body mass index or other correlates of microalbuminuria is more in favor of a podocyte problem [15].