LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics.

Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk factor for cardiovascular disease (CVD). Lp(a) appears to induce inflammation, atherogenesis, and thrombosis. Approximately 20% of the world's population has increased Lp(a) levels, determined predominantly by genetics. Current clinical practices for the management of dyslipidemia are ineffective in lowering Lp(a) levels. Evolving RNA-based therapeutics, such as the antisense oligonucleotide pelacarsen and small interfering RNA olpasiran, have shown promising results in reducing Lp(a) levels. Phase III pivotal cardiovascular outcome trials [Lp(a)HORIZON and OCEAN(a)] are ongoing to evaluate their efficacy in secondary prevention of major cardiovascular events in patients with elevated Lp(a). The future of cardiovascular residual risk reduction may transition to a personalized approach where further lowering of either LDL-C, triglycerides, or Lp(a) is selected after high-intensity statin therapy based on the individual risk profile and preferences of each patient.

Development and Validation of the American Heart Association's PREVENT Equations.

BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. RESULTS: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P=0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.

Low-Density Lipoprotein Cholesterol Is Predominantly Associated With Atherosclerotic Cardiovascular Disease Events in Patients With Evidence of Coronary Atherosclerosis: The Western Denmark Heart Registry.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for atherosclerotic cardiovascular disease (ASCVD). However, a sizable proportion of middle-aged individuals with elevated LDL-C level have not developed coronary atherosclerosis as assessed by coronary artery calcification (CAC). Whether presence of CAC modifies the association of LDL-C with ASCVD risk is unknown. We evaluated the association of LDL-C with future ASCVD events in patients with and without CAC. METHODS: The study included 23 132 consecutive symptomatic patients evaluated for coronary artery disease using coronary computed tomography angiography (CTA) from the Western Denmark Heart Registry, a seminational, multicenter-based registry with longitudinal registration of patient and procedure data. We assessed the association of LDL-C level obtained before CTA with ASCVD (myocardial infarction and ischemic stroke) events occurring during follow-up stratified by CAC>0 versus CAC=0 using Cox regression models adjusted for baseline characteristics. Outcomes were identified through linkage among national registries covering all hospitals in Denmark. We replicated our results in the National Heart, Lung, and Blood Institute-funded Multi-Ethnic Study of Atherosclerosis. RESULTS: During a median follow-up of 4.3 years, 552 patients experienced a first ASCVD event. In the overall population, LDL-C (per 38.7 mg/dL increase) was associated with ASCVD events occurring during follow-up (adjusted hazard ratio [aHR], 1.14 [95% CI, 1.04-1.24]). When stratified by the presence or absence of baseline CAC, LDL-C was only associated with ASCVD in the 10 792/23 132 patients (47%) with CAC>0 (aHR, 1.18 [95% CI, 1.06-1.31]); no association was observed among the 12 340/23 132 patients (53%) with CAC=0 (aHR, 1.02 [95% CI, 0.87-1.18]). Similarly, a very high LDL-C level (>193 mg/dL) versus LDL-C <116 mg/dL was associated with ASCVD in patients with CAC>0 (aHR, 2.42 [95% CI, 1.59-3.67]) but not in those without CAC (aHR, 0.92 [0.48-1.79]). In patients with CAC=0, diabetes, current smoking, and low high-density lipoprotein cholesterol levels were associated with future ASCVD events. The principal findings were replicated in the Multi-Ethnic Study of Atherosclerosis. CONCLUSIONS: LDL-C appears to be almost exclusively associated with ASCVD events over ≈5 years of follow-up in middle-aged individuals with versus without evidence of coronary atherosclerosis. This information is valuable for individualized risk assessment among middle-aged people with or without coronary atherosclerosis.

Brief report: U.S. trends in use of colchicine by cardiologists and other specialties, 2018 to 2024.

Colchicine has emerged as an effective agent for reducing ASCVD based on recent large cardiovascular outcome trials and exerts its benefit through targeting inflammation. In light of the robust body of data and FDA approval of low-dose colchicine for ASCVD prevention, this paper aimed to use the National Prescription Audie to quantify the volume and trends of colchicine prescriptions dispensed rough U.S. retail pharmacies between March 2018 and February 2024. Despite a 6% increase in total monthly prescriptions since 2020, driven primarily by cardiologists, this specialty still represents only 2.8-4% of the national monthly totals with small absolute numbers (i.e. estimated ∼4000 incremental prescriptions/month since 2020), suggesting limited cardiologist adoption of colchicine for ASCVD prevention despite favorable clinical trial data.

Unfavorable social determinants of health and mortality risk by cardiovascular disease status: Findings from a National Study of United States Adults.

BACKGROUND: The association between cumulative burden of unfavorable social determinants of health (SDoH) and all-cause mortality has not been assessed by atherosclerotic cardiovascular disease (ASCVD) status on a population level in the United States. METHODS: We assessed the association between cumulative social disadvantage and all-cause mortality by ASCVD status in the National Health Interview Survey, linked to the National Death Index. RESULTS: In models adjusted for established clinical risk factors, individuals experiencing the highest level of social disadvantage (SDoH-Q4) had over 1.5 (aHR = 1.55; 95%CI = 1.22, 1.96) and 2-fold (aHR = 2.21; 95% CI = 1.91, 2.56) fold increased risk of mortality relative to those with the most favorable social profile (SDoH-Q1), respectively for adults with and without ASCVD; those experiencing co-occurring ASCVD and high social disadvantage had up to four-fold higher risk of mortality (aHR = 3.81; 95%CI = 3.36, 4.32). CONCLUSIONS: These findings emphasize the importance of a healthcare model that prioritizes efforts to identify and address key social and environmental barriers to health and wellbeing, particularly in individuals experiencing the double jeopardy of clinical and social risk.

Use of E-Cigarette, Traditional Cigarettes, and C-Reactive Protein: The Cross Cohort Collaboration.

This cross-sectional study included 18,797 participants from six longitudinal cohorts (CARDIA, FHS Gen III, HCHS/SOL, MESA, MiHeart, and REGARDS). 5,806 of them were with high-sensitivity C-reactive protein (hs-CRP) measurements. We found that among exclusive electronic cigarette (EC) use was associated with significantly lower high-sensitivity C-reactive protein (hs-CRP) levels compared to exclusive combustible cigarette use, suggesting a potentially lower inflammatory burden. hs-CRP levels in dual users and former smokers currently using EC were comparable to those observed in exclusive cigarette smokers. In contrast, individuals who exclusively used ECs showed no significant difference in hs-CRP levels compared to never smokers. These findings have important implications for tobacco regulation, public health, and clinical practice, highlighting the need for continued monitoring of EC-related health impacts.

Beyond the Agatston calcium score: role of calcium density and other calcified plaque markers for cardiovascular disease prediction.

PURPOSE OF REVIEW: To review the current evidence and highlight future strategies regarding consideration of coronary artery calcium (CAC) density in cardiovascular disease (CVD) risk stratification. RECENT FINDINGS: Expressed as the product of plaque area and a peak calcium density weighting factor, the Agatston method is the gold-standard for measuring CAC on noncontrast cardiac computed tomography. Over the last decade, observational data have suggested that calcium density is inversely associated with CVD events and confers additional prognostic information independent of traditional risk factors and Agatston CAC scores. Specific density measures have been assessed including peak calcium density, mean CAC density, and CAC area-density discordance. Beyond calcium density, the number of affected arteries and regional distribution of CAC which may be correlated with CAC density have also improved the predictive utility of the Agatston score. SUMMARY: Calcium density is inversely associated with CVD risk after considering plaque area and/or volume. Calcium markers including density, vessel involvement, and regional distribution confer additional prognostic information for the prediction of incident CVD among those with prevalent subclinical atherosclerosis. A future area of study includes calcium radiomics ('calcium-omics') and whether the artificial intelligence-derived automated measurement of calcium markers beyond the Agatston score may be of value in CVD risk stratification among individuals with early to advanced subclinical atherosclerosis.

Subclinical Atherosclerosis to Guide Treatment in Dyslipidemia and Diabetes Mellitus.

PURPOSE OF REVIEW: Dyslipidemia and type 2 diabetes mellitus are two common conditions that are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). In this review, we aimed to provide an in-depth and contemporary review of non-invasive approaches to assess subclinical atherosclerotic burden, predict cardiovascular risk, and guide appropriate treatment strategies. We focused this paper on two main imaging modalities: coronary artery calcium (CAC) score and computed tomography coronary angiography. RECENT FINDINGS: Recent longitudinal studies have provided stronger evidence on the relationship between increased CAC, thoracic aorta calcification, and risk of cardiovascular events among those with primary hypercholesterolemia, highlighting the beneficial role of statin therapy. Interestingly, resilient profiles of individuals not exhibiting atherosclerosis despite dyslipidemia have been described. Non-conventional markers of dyslipidemia have also been associated with increased subclinical atherosclerosis presence and burden, highlighting the contribution of apolipoprotein B-100 (apoB)-rich lipoprotein particles, such as remnant cholesterol and lipoprotein(a), to the residual risk of individuals on-target for low-density lipoprotein cholesterol (LDL-C) goals. Regarding type 2 diabetes mellitus, variability in atherosclerotic burden has also been found, and CAC testing has shown significant predictive value in stratifying cardiovascular risk. Non-invasive assessment of subclinical atherosclerosis can help reveal the continuum of ASCVD risk in those with dyslipidemia and diabetes mellitus and can inform personalized strategies for cardiovascular disease prevention in the primary prevention setting.

Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health.

BACKGROUND: In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug-drug interactions, but also a potential cardioprotective effect of these drugs. AIM: In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease. METHOD: A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus. OUTCOMES: Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors. RESULTS: An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug-drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non-PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non-PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed. CLINICAL IMPLICATIONS: Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease. STRENGTHS AND LIMITATIONS: Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting. CONCLUSION: The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors.

Association between a diagnosis of diabetes mellitus and smoking abstinence: An analysis of the National Health Interview Survey (2006-2018).

OBJECTIVE: Both diabetes and smoking significantly increase the risk of cardiovascular disease (CVD). Understanding whether a diagnosis of diabetes can be leveraged to promote smoking cessation is a gap in the literature. METHODS: We used data from the US National Health Interview Survey, 2006 to 2018, to investigate the relationship between self-report of diagnosis of diabetes and subsequent smoking abstinence among 142,884 respondents who reported regular smoking at baseline. Effect sizes were presented as hazard ratios (HRs) derived from multivariable Cox regression models adjusted for potential confounders using diabetes as a time-dependent covariate. Subgroup-specific estimates were obtained using interaction terms between diabetes and variables of interest. RESULTS: A self-reported diagnosis of diabetes was associated with smoking abstinence (HR: 1.21; 95% CI: 1.16 to 1.27). The strength of the association varied based on race (P for interaction: 0.004), where it was strongest in African Americans (HR: 1.44; 95% CI: 1.29 to 1.60); income (P for interaction <0.001), where it was strongest in those with a yearly income less than $35,000 (HR: 1.45; 95% CI: 1.36 to 1.53); and educational attainment (P for interaction <0.001), where it was strongest in those who did not attend college (HR: 1.48; 95% CI: 1.40 to 1.57). CONCLUSION: Among adults who smoke, a diagnosis of diabetes is significantly associated with subsequent smoking abstinence. The association is strongest in socially disadvantaged demographics, including African Americans, low-income individuals, and those who did not attend college.

Predictors of incident stroke among individuals without coronary artery calcification: A pooled cohort analysis from the Multi-Ethnic Study of Atherosclerosis, Jackson Heart Study, and Framingham Heart Study.

INTRODUCTION: The absence of coronary artery calcium (CAC = 0) is associated with low risk of stroke events; however, predictors of incident stroke among those with CAC = 0 are not known. METHODS: Individual participant-level data were pooled from three prospective cohorts (Multi-Ethnic Study of Atherosclerosis, Jackson Heart Study, and Framingham Heart Study). Multivariable-adjusted Cox proportional hazards models were used to study the association between cardiovascular risk factors and incident adjudicated stroke among individuals with CAC = 0 who were free of clinical atherosclerotic cardiovascular disease at baseline. RESULTS: Among 6180 participants (mean age 53 [SD 11] years, 62% women, and 44% White, 36% Black, and 20% other individuals), over a median (IQR) follow up of 15 (12-16) years, there were 122 strokes (95 ischemic, 27 hemorrhagic) with an overall unadjusted event rate of 2.0 per 1000 person-years. After multivariable adjustment, risk factors associated with overall stroke included (hazard ratio [95% CI]) systolic blood pressure (SBP): 1.19 (1.05-1.36) per 10-mmHg increase and carotid intima-media thickness (CIMT): 1.21 (1.04-1.42) per 0.1-mm increment. Current cigarette smoking: 2.68 (1.11-6.50), SBP: 1.23 (1.06-1.42) per 10-mmHg increase, and CIMT: 1.25 (1.04-1.49) per 0.1-mm increment were associated with ischemic stroke, whereas C-reactive protein was associated with hemorrhagic stroke risk (0.49, 0.25-0.93). CONCLUSION: In a large cohort of individuals with CAC = 0, the rate for incident stroke was low (2.0 per 1000-person years) and was associated with modifiable risk factors.

Association of cardiovascular risk profile with premature all-cause and cardiovascular mortality in US adults: findings from a national study.

OBJECTIVE: To assess the association between cardiovascular risk factor (CRF) profile and premature all-cause and cardiovascular disease (CVD) mortality among US adults (age < 65). METHODS: This study used data from the National Health Interview Survey from 2006 to 2014, linked to the National Death Index for non-elderly adults aged < 65 years. A composite CRF score (range = 0-6) was calculated, based on the presence or absence of six established cardiovascular risk factors: hypertension, diabetes, hypercholesterolemia, smoking, obesity, and insufficient physical activity. CRF profile was defined as "Poor" (≥ 3 risk factors), "Average" (1-2), or "Optimal" (0 risk factors). Age-adjusted mortality rates (AAMR) were reported across CRF profile categories, separately for all-cause and CVD mortality. Cox proportional hazard models were used to evaluate the association between CRF profile and all-cause and CVD mortality. RESULTS: Among 195,901 non-elderly individuals (mean age: 40.4 ± 13.0, 50% females and 70% Non-Hispanic (NH) White adults), 24.8% had optimal, 58.9% average, and 16.2% poor CRF profiles, respectively. Participants with poor CRF profile were more likely to be NH Black, have lower educational attainment and lower income compared to those with optimal CRF profile. All-cause and CVD mortality rates were three to four fold higher in individuals with poor CRF profile, compared to their optimal profile counterparts. Adults with poor CRF profile experienced 3.5-fold (aHR: 3.48 [95% CI: 2.96, 4.10]) and 5-fold (aHR: 4.76 [3.44, 6.60]) higher risk of all-cause and CVD mortality, respectively, compared to those with optimal profile. These results were consistent across age, sex, and race/ethnicity subgroups. CONCLUSIONS: In this population-based study, non-elderly adults with poor CRF profile had a three to five-fold higher risk of all-cause and CVD mortality, compared to those with optimal CRF profile. Targeted prevention efforts to achieve optimal cardiovascular risk profile are imperative to reduce the persistent burden of premature all-cause and CVD mortality in the US.

Circulating ketone bodies and cardiovascular outcomes: the MESA study.

AIMS: Ketone bodies (KB) are an important alternative metabolic fuel source for the myocardium. Experimental and human investigations suggest that KB may have protective effects in patients with heart failure. This study aimed to examine the association between KB and cardiovascular outcomes and mortality in an ethnically diverse population free from cardiovascular disease (CVD). METHODS AND RESULTS: This analysis included 6796 participants (mean age 62 ± 10 years, 53% women) from the Multi-Ethnic Study of Atherosclerosis. Total KB was measured by nuclear magnetic resonance spectroscopy. Multivariable-adjusted Cox proportional hazard models were used to examine the association of total KB with cardiovascular outcomes. At a mean follow-up of 13.6 years, after adjusting for traditional CVD risk factors, increasing total KB was associated with a higher rate of hard CVD, defined as a composite of myocardial infarction, resuscitated cardiac arrest, stroke, and cardiovascular death, and all CVD (additionally included adjudicated angina) [hazard ratio, HR (95% confidence interval, CI): 1.54 (1.12-2.12) and 1.37 (1.04-1.80) per 10-fold increase in total KB, respectively]. Participants also experienced an 87% (95% CI: 1.17-2.97) increased rate of CVD mortality and an 81% (1.45-2.23) increased rate of all-cause mortality per 10-fold increase in total KB. Moreover, a higher rate of incident heart failure was observed with increasing total KB [1.68 (1.07-2.65), per 10-fold increase in total KB]. CONCLUSION: The study found that elevated endogenous KB in a healthy community-based population is associated with a higher rate of CVD and mortality. Ketone bodies could serve as a potential biomarker for cardiovascular risk assessment.

Assessment of cardiovascular disease risk: a 2023 update.

PURPOSE OF REVIEW: The aim of this study was to highlight the current best practice for atherosclerotic cardiovascular disease (CVD) risk evaluation, including selective use of adjunctive tools for risk stratification [e.g. coronary artery calcium (CAC) scoring] and risk enhancement [e.g. lipoprotein(a) [Lp(a)], polygenic risk scoring (PRS)]. RECENT FINDINGS: New studies have evaluated the efficacy of various risk assessment tools. These studies demonstrate the role of Lp(a) as a risk-enhancing factor ready for more widespread use. CAC is the gold standard method of assessing subclinical atherosclerosis, enabling true risk stratification of patients, and informing net benefit assessment for initiating or titrating lipid-lowering therapy (LLT). SUMMARY: Lp(a) concentration and CAC scoring, apart from the traditional risk factors, add the most value to the current CVD risk assessment approaches of all available tools, especially in terms of guiding LLT. In addition to new integrative tools such as the MESA CHD Risk Score and Coronary Age calculator, the future of risk assessment may include PRS and more advanced imaging techniques for atherosclerosis burden. Soon, polygenic risk scoring may be used to identify the age at which to begin CAC scoring, with CAC scores guiding preventive strategies.

Determinants of Incident Atherosclerotic Cardiovascular Disease Events Among Those With Absent Coronary Artery Calcium: Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The 2018 American Heart Association/American College of Cardiology/Multisociety cholesterol guideline states that statin therapy may be withheld or delayed among intermediate-risk individuals in the absence of coronary artery calcium (CAC=0). We evaluated whether traditional cardiovascular risk factors are associated with incident atherosclerotic cardiovascular disease (ASCVD) events among individuals with CAC=0 over long-term follow-up. METHODS: We included participants with CAC=0 at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of clinical ASCVD at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between cardiovascular risk factors (cigarette smoking, diabetes, hypertension, preventive medication use [aspirin and statin], family history of premature ASCVD, chronic kidney disease, waist circumference, lipid and inflammatory markers) and adjudicated incident ASCVD outcomes. RESULTS: We studied 3416 individuals (mean [SD] age 58 [9] years; 63% were female, 33% White, 31% Black, 12% Chinese American, and 24% Hispanic). Over a median follow-up of 16 years, there were 189 ASCVD events (composite of coronary heart disease and stroke) of which 91 were coronary heart disease, 88 were stroke, and 10 were both coronary heart disease and stroke events. The unadjusted event rates of ASCVD were ≤5 per 1000 person-years among individuals with CAC=0 for most risk factors with the exception of current cigarette smoking (7.3), diabetes (8.9), hypertension (5.4), and chronic kidney disease (6.8). After multivariable adjustment, risk factors that were significantly associated with ASCVD included current cigarette smoking: hazard ratio, 2.12 (95% CI, 1.32-3.42); diabetes: hazard ratio, 1.68 (95% CI, 1.01-2.80); and hypertension: hazard ratio, 1.57 (95% CI, 1.06-2.33). CONCLUSIONS: Current cigarette smoking, diabetes, and hypertension are independently associated with incident ASCVD over a 16-year follow-up among those with CAC=0.

Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development.

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.

Risk factor associations with individual myocardial infarction subtypes and acute non-ischemic myocardial injury in the Multi-Ethnic Study of Atherosclerosis (MESA): Design and rationale.

BACKGROUND: Despite different prevalence, pathobiology, and prognosis between etiologically distinct myocardial infarction (MI) subtypes, prospective study of risk factor for MI in large NHLBI-sponsored cardiovascular cohorts is limited to acute MI as a singular entity. Therefore, we sought to utilize the Multi-Ethnic Study of Atherosclerosis (MESA), a large prospective primary prevention cardiovascular study, to define the incidence and risk factor profile of individual myocardial injury subtypes. METHODS: We describe the rationale and design of re-adjudicating 4,080 events that occurred over the first 14 years of follow-up in MESA for the presence and subtype of myocardial injury as defined by the Fourth Universal Definition of MI: MI type 1 to 5, acute non-ischemic myocardial injury, and chronic myocardial injury. The project utilizes a 2-physician adjudication process via examination of medical records, abstracted data collection forms, cardiac biomarker results, and electrocardiograms of all relevant clinical events. Comparison of the magnitude and direction of associations between baseline traditional and novel cardiovascular risk factors with incident and recurrent acute MI subtypes and acute non-ischemic myocardial injury events will be made. CONCLUSIONS: This project will result in one of the first large prospective cardiovascular cohort with modern classification of acute MI subtypes, as well as a full accounting of non-ischemic myocardial injury events, with implications for numerous ongoing and future studies in MESA. By creating precise MI phenotypes, and defining their epidemiology, this project will allow for discovery of novel pathobiology-specific risk factors, allow for development of more accurate risk prediction, and suggest more targeted preventive strategies.

Coronary artery calcium testing in young adults.

PURPOSE OF REVIEW: To provide a summary of recent literature on coronary artery calcium testing (CAC) for risk stratification in young adults <45 years old. RECENT FINDINGS: One of every ten young adults in the general population, and one out of every three young adults with traditional atherosclerotic cardiovascular disease (ASCVD) risk factors, have CAC. While the definition of premature CAC has yet to be formally defined in guidelines, it has become increasingly clear that any prevalent CAC among adults <45 years old should be considered premature. Traditional risk factors are strong predictors of CAC in young adults; however, this association has been found to wane over the life course which suggests that the onset and severity of risk factors for calcific atherosclerosis varies as individuals age. Though CAC is a robust predictor of both ASCVD and cancer-related mortality in old age, CAC in young adults confers a stepwise higher risk uniquely for incident ASCVD mortality, and not for non-ASCVD causes. New tools are available to assist in interpretation of CAC in the young, and for estimating the ideal age to initiate CAC scoring. SUMMARY: The identification of premature CAC is important because it suggests that calcific plaque can be detected with modern imaging earlier in the natural history than previously thought. Taken together, these findings underline a utility of selective use of CAC scoring on non-contrast computed tomography among at-risk young adults to facilitate timely lifestyle modification and pharmacotherapies for the prevention of later life ASCVD.

Coronary artery calcium and sudden cardiac death: current evidence and future directions.

PURPOSE OF REVIEW: To provide a summary of the current evidence and highlight future directions regarding coronary artery calcium (CAC) and risk of sudden cardiac death (SCD). RECENT FINDINGS: Although up to 80% of all SCD is attributed to coronary heart disease (CHD), the subclinical atherosclerosis markers that help to improve SCD risk prediction are largely unknown. Recent observational data have demonstrated that, after adjustment for traditional risk factors, there is a stepwise higher risk for SCD across increasing CAC burden such that asymptomatic patients without overt atherosclerotic cardiovascular disease (ASCVD) experience a three-fold to five-fold higher SCD risk beginning at CAC at least 100 when compared with CAC = 0. Although the mechanisms underlying increasing CAC and SCD risk have yet to be fully elucidated, risk for myocardial infarction and scar, and/or exercise-induced ischemia may be potential mediators. SUMMARY: High CAC burden is an important risk factor for SCD in asymptomatic middle-aged adults, suggesting that SCD risk stratification can begin in the early stages of CHD via measurement of calcific plaque on noncontrast computed tomography. Despite the clinical inertia for downstream functional cardiac testing after detecting high CAC, comprehensive ASCVD prevention strategies should be the primary focus for SCD risk reduction.

Multimodality cardiovascular imaging in hypertension.

PURPOSE OF THE REVIEW: Hypertension accounts for the largest proportion of cardiovascular (CV) mortality worldwide and its prevalence continues to rise. While prominent CV societies have offered strong recommendations on the management of hypertension in adults, the role of noninvasive CV imaging in the evaluation of hypertensive patients remains incompletely defined. RECENT FINDINGS: Noninvasive imaging is a rapidly expanding field with a growing number of sophisticated and readily applicable modalities to assess how cardiac structure and function changes after periods of sustained, elevated blood pressure. Echocardiography remains the initial modality to screen these patients while developments in nuclear, computed tomography and cardiac magnetic resonance complement and expand investigations for alternative diagnoses that may complement or conflict with the diagnosis of left ventricular hypertrophy. SUMMARY: In this review article, we summarize the application of echocardiography, nuclear imaging, cardiac computed tomography, and cardiac magnetic resonance imaging in the evaluation and management of hypertensive heart disease.