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Highlighted articles December

Volume 279 Issue December 2018

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

Clinical risk prediction rules play an important role for risk stratification and patient management in both primary and secondary prevention. Although the integration of clinical measures has superior prognostic performance compared to the use of single risk factors, they are limited in sensitivity and specificity. Typically, these limitations are addressed by imaging and liquid biomarkers. Novel algorithms and stratification for specific subgroups of patients, for example by age, gender, ethnicity, and comorbidities, is an alternative approach. Several articles of this issue of Atherosclerosis report such studies, as well as the development of novel clinical risk prediction rules for heart disease and other cardiovascular diseases such as aortic aneurysm.

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Highlighted articles

Discordance between 10-year cardiovascular risk estimates using the ACC/AHA 2013 estimator and coronary artery calcium in individuals from 5 racial/ethnic groups: Comparing MASALA and MESA

South Asian (SA) individuals currently represent the second fastest growing ethnic group in the US, with nearly 5 million residents. Several studies have reported a high prevalence of cardiovascular risk factors and atherosclerotic cardiovascular disease (ASCVD) in this group, the latter being higher among SAs than any other racial/ethnic group living in North America or Europe. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) ASCVD risk assessment guidelines included the pooled cohort equations (PCE), which allow estimating 10-year ASCVD risk by race/ethnicity [non-Hispanic Whites (NHWs) and African Americans (AAs)] and sex. However, the performance of the Pooled Cohort Equations (PCE) remains uncertain in SAs living in the US. Al Rifai et al. aimed to study the interplay between predicted 10-year ASCVD risk and coronary artery calcium (CAC) in SAs compared to other racial/ethnic groups.

The authors studied 536 SAs from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study, and 2073 NHWs, 1514 AAs, 1254 Hispanics, and 671 Chinese Americans (CAs) from the Multi-Ethnic Study of Atherosclerosis (MESA), who were not on statins. They used logistic regression models to assess the association between race/ethnicity and CAC within each ASCVD risk stratum.

SAs at low and intermediate estimated ASCVD risk were more likely to have CAC = 0 compared to NHWs, while SAs at high risk had a similar CAC burden to NHWs.

These results suggest that the extent of ASCVD risk overestimation using PCEs may be even greater among SAs considered at low and intermediate risk than among NHWs. Studies with incident ASCVD events are required to validate and/or recalibrate current ASCVD risk prediction tools in this group.

Development and validation of modified risk prediction models for cardiovascular disease and its subtypes: The Hisayama Study

To reduce the burden of cardiovascular mortality, it is important to detect a high-risk population for cardiovascular disease (CVD) and modify the cardiovascular risk factors. In addition, the recent guidelines place emphasis on risk-based decision-making to determine the initial treatment. Therefore, risk prediction algorithms based on multiple risk models would be a clinically useful tool to estimate future risk of development of CVD and its subtypes (i.e., stroke and coronary heart disease). Honda et al. aimed at developing and evaluating an updated risk prediction model for cardiovascular diseases and its subtypes, based on a previously developed risk prediction model by the same group.

A total of 2462 community residents aged 40–84 years were followed up for 24 years. A Cox proportional hazards regression model was used to develop risk prediction models for cardiovascular diseases, and for stroke and coronary heart diseases, separately. The risk assessment ability of the developed model was evaluated, and a bootstrapping method was used for internal validation. The predicted risk was translated into a simplified scoring system. A decision curve analysis was used to evaluate clinical usefulness.

The multivariable model for cardiovascular diseases included age, sex, systolic blood pressure, hemoglobin A1c, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, smoking habits, and regular exercise as predictors. The models for stroke and coronary heart diseases incorporated both shared and unique variables. The developed models showed good discrimination with little evidence of overfitting and calibrations. The decision curve analysis revealed that the predicted risk-based decision-making would have higher net benefit than a CVD intervention strategy for all individuals or no individuals.

In conclusion, the developed risk prediction models showed a good performance and satisfactory internal validity, indicating that predicted risk-based decision-making can be beneficial in primary prevention. 

Lipid accumulation product in relation to 10-year cardiovascular disease incidence in Caucasian adults: The ATTICA study

The lipid accumulation product (LAP) is an index describing lipid over-accumulation based on waist circumference (WC) and fasting triglycerides, and can outperform the body mass index (BMI) in recognizing cardiovascular disease (CVD) risk. To date, the existing epidemiological data from prospective, community-based studies on the predictive value of LAP for long-term CVD risk are very limited. Therefore, Kyrou et al. assessed LAP as a predictor of the 10-year CVD incidence in the ATTICA study cohort of Caucasian adults without previous CVD, and compared its discriminating ability against BMI and other commonly used anthropometric indices/ratios of central obesity.

ATTICA is a prospective, population-based cohort study performed in the Athens region that recruited 3042 adults without pre-existing CVD from the Greek general population. The 10-year study follow-up (2011–2012) captured the fatal/non-fatal CVD incidence in 2020 participants. Baseline LAP was calculated and analyzed in relation to the 10-year CVD incidence.

In total, 317 CVD cases were documented during follow-up. Baseline LAP showed a significant positive association with the 10-year CVD incidence, even after adjusting for hypertension, diabetes, hypercholesterolemia, smoking, physical activity, Mediterranean diet adherence, and key pro-inflammatory biomarkers. Moreover, LAP predicted the 10-year CVD study incidence better than common obesity indices (BMI, WC, waist-to-hip, waist-to-height ratio).

These findings support a positive association between LAP and long-term CVD incidence in CVD-free Caucasian adults from the general population.

Early onset ACS: An age based clinico-epidemiologic and angiographic comparison 

Acute coronary syndrome (ACS) is an umbrella term for conditions where blood supply to the cardiac muscle is suddenly reduced. The characteristics and clinical course of ACS have been studied extensively in older patients. However, this disease has rarely been analysed in younger patients, as the incidence of ACS is much lower in younger individuals. Chhabra et al. aimed to assess patterns and profile of ACS in patients aged 20–30 years in comparison with those above 30 years.

They conducted a retrospective record-based study where the demographic and clinical profile of all patients with ACS in the last 12 years was analysed, and patients were divided into two groups: group I (20–30 years) and group II (above 30 years). Patients in group II were selected by systematic sampling. Age, gender, domicile, body mass index (BMI), serum cholesterol, smoking, alcohol use, drug abuse, diabetes, hypertension, family history, type of ACS, angiographic findings and management strategies were recorded. Chi-square test and Fischer's exact test were used for data analysis.

Of 35,259 patients, 0.32% were from the younger age group, with a rising trend of prevalence over 12 years. Obesity, overweight, urban living, smoking, alcohol and drug abuse were significantly higher in group I. Diabetes mellitus and hypertension were more prevalent in group II. STEMI in group I and NSTEMI in group II were the common modes of presentation. 42.1% of group I patients had re-canalized coronaries with conservative management in comparison to 3% in group II.

The data show a rising trend in prevalence of ACS in very young patients. Overweight, obesity, urbanization and drug abuse are potential risk factors. The younger subset of ACS patients is different from the older population due to their thrombotic milieu, which could be more amenable to intensive pharmacologic management.


Effect of visit-to-visit LDL-, HDL-, and non-HDL-cholesterol variability on mortality and cardiovascular outcomes after percutaneous coronary intervention

Low-density lipoprotein cholesterol (LDL-C) is one of the most important risk factors for atherosclerotic cardiovascular disease (CVD). Increased LDL-C levels lead to atherosclerotic plaque formation in a dose-dependent manner. In contrast to LDL-C, high-density lipoprotein cholesterol (HDL-C) plays a protective role in the development of CVD by promoting reverse cholesterol transport and modulating inflammation. Visit-to-visit variability in biological measures has been suggested as an independent predictor of CVD. Although LDL-C and HDL-C are important risk factors of CVD, there are few studies investigating the effect of variability in LDL-C and HDL-C on cardiovascular outcomes. Lee et al. assessed the association between visit-to-visit variability in LDL-C, HDL-C, and non-HDL-C and major adverse cardiovascular and cerebrovascular events (MACCE) in patients who underwent percutaneous coronary intervention (PCI).

Data from 1792 subjects who underwent PCI from January 2004 to December 2009 were analyzed. Visit-to-visit variability was calculated using various indices: standard deviation (SD), coefficient of variation, and corrected variability independent of mean (cVIM). MACCE comprised all-cause death, non-fatal myocardial infarction, and stroke.

During a median follow-up of 65 months, 114 subjects experienced MACCE. Visit-to-visit variability in LDL-C, HDL-C, and non-HDL-C was significantly higher in the MACCE group compared to the non-MACCE group. In multiple regression analysis, all LDL-C, HDL-C, and non-HDL-C variability parameters were independent predictors for MACCE after adjusting for potential confounding factors. Each 1-SD increase of cVIM in LDL-C, HDL-C, and non-HDL-C increased the risk of MACCE by 34%, 50%, and 37%, respectively. These relationships were observed in various subgroups according to age, sex, and diabetes status.

These results suggest that visit-to-visit LDL-, HDL-, and non-HDL-cholesterol variability can predict MACCE, highlighting an important dynamic relationship between cholesterol levels and clinical outcomes.

Single and combined effects of peripheral artery disease and of type 2 diabetes mellitus on the risk of cardiovascular events: A prospective cohort study

Peripheral artery disease (PAD) and type 2 diabetes (T2DM) are frequently present together. Indeed, PAD is one of the most common cardiovascular complications of diabetes. However, it is unknown how the cardiovascular risk of PAD patients without T2DM compares to the cardiovascular risk of T2DM patients without PAD, because the individual and combined effects of PAD and T2DM on the cardiovascular event rate have not been investigated so far. These effects were therefore addressed by Saely et al. in the present investigation.

Cardiovascular events were prospectively recorded in 1049 subjects, divided into 4 groups: 558 with neither PAD nor diabetes, 153 with T2DM but without PAD, 192 with PAD but without T2DM and 146 with the combination of PAD and T2DM.

The result show that over a mean follow-up period of 7.2 ± 2.6 years, the cardiovascular event rate was lowest in patients with neither PAD nor T2DM. Compared to this group, the event rate was not significantly increased in T2DM patients without PAD, but it was higher in non-diabetic patients with PAD, and further increased in patients with both PAD and T2DM. Nondiabetic PAD patients were at a higher cardiovascular risk than T2DM patients without PAD.

PAD is a stronger risk factor for future cardiovascular events than T2DM, but T2DM in PAD patients accelerates atherothrombotic disease and strongly increases the incidence of cardiovascular events.


Chronic kidney disease measures and the risk of abdominal aortic aneurysm

 Chronic kidney disease (CKD), defined as reduced kidney function or kidney damage, is a major global public health problem, affecting 10–20% of adults worldwide. CKD increases the risk of various adverse outcomes such as cardiovascular disease (CVD) and infectious diseases. The investigation of the link between CKD and CVD is particularly important since up to half of the individuals with CKD die from CVD. Despite its strong link to cardiovascular outcomes, the association of CKD with abdominal aortic aneurysm (AAA), a CVD subtype, has not been explicitly and comprehensively investigated.

Matsushita et al. evaluated the associations of two key CKD measures - estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) - with incident AAA in 10,724 participants in the Atherosclerosis Risk in Communities Study (ARIC). Additionally, they performed a cross-sectional analysis for CKD measures and ultrasound-based abdominal aortic diameter in 4258 participants.

During a median follow-up of 13.9 years, 347 participants developed AAA. The demographically-adjusted hazard ratio (HR) was 4.44 for eGFR <30, 3.29 for 30–44, 2.03 for 45–59, and 1.62 for 60–74 compared to eGFR ≥90 mL/min/1.73 m2 and was 2.49 for ACR ≥300, 1.99 for 30–299, and 1.46 for 10–29 compared to ACR <10 mg/g. The associations were generally similar after accounting for additional confounders, such as smoking (although attenuated), or after stratifying by subgroups, including diabetes. The cross-sectional analysis also showed continuous positive associations of these CKD measures with aortic diameter, particularly at the distal aortic segment assessed. Reduced eGFR and elevated albuminuria were independently associated with greater incidence of AAA and greater abdominal aortic diameter.

The authors emphasize how these results suggest the potential usefulness of CKD measures to identify subjects at high risk of AAA and the need to investigate pathophysiological pathways linking CKD to AAA.

In their editorial discussing the above findings, Bellasi et al. concluded that although the results do not shed light on the causal association of AAA with CKD, they support the authors’ statement that CKD measures (creatinine, eGFR, albuminuria) are useful markers to identify individuals at particular risk of cardiovascular complications. However, at the current stage, it is unclear if renal function may guide target screening of AAA as well as timing of imaging testing in CKD

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