Life expectancy in the US is now the lowest it has been since 1996, with young- and middle-aged adults seeing the most rapid declines. These declines began in 2014 and have accelerated over the past ...3 years of the pandemic. While COVID-19 represents a significant proportion, increases in heart disease between 2020 and 2021 explain more than 4% of the most recent shortening in life expectancy. These increases in cardiovascular mortality reflect recent disturbing trends in cardiovascular risk determinants and events in younger adults. Although overall cardiovascular disease mortality declined until 2020, hospitalization and death rates flattened or in some cases increased among specific racial and ethnic subgroups of young adults during this time. In particular, hypertensive heart disease, heart failure, and endocarditis have increased in young adults, particularly among Black individuals, through 2018.7 Consequently, young adults make up a growing proportion of cardiovascular disease events, with the proportion of premature myocardial infarction among adults younger than 40 years increasing by 2% every year. The increasing event rates observed among younger adults can be attributed to the increasing prevalence and onset of risk factors such as obesity and hypertension at younger ages, which exacerbate cumulative exposure and cardiovascular disease risk over near- and long-term time horizons.
IMPORTANCE Single measures of blood pressure (BP) levels are associated with the development of atherosclerosis; however, long-term patterns in BP and their effect on cardiovascular disease risk are ...poorly characterized. OBJECTIVES To identify common BP trajectories throughout early adulthood and to determine their association with presence of coronary artery calcification (CAC) during middle age. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort data from 4681 participants in the CARDIA study, who were black and white men and women aged 18 to 30 years at baseline in 1985-1986 at 4 urban US sites, collected through 25 years of follow-up (2010-2011). We examined systolic BP, diastolic BP, and mid-BP (calculated as SBP+DBP/2, an important marker of coronary heart disease risk among younger populations) at baseline and years 2, 5, 7, 10, 15, 20, and 25. Latent mixture modeling was used to identify trajectories in systolic, diastolic, and mid-BP over time. MAIN OUTCOMES AND MEASURES Coronary artery calcification greater than or equal to Agatston score of 100 Hounsfield units (HU) at year 25. RESULTS We identified 5 distinct mid-BP trajectories: low-stable (21.8%; 95% CI, 19.9%-23.7%; n=987), moderate-stable (42.3%; 40.3%-44.3%; n=2085), moderate-increasing (12.2%; 10.4%-14.0%; n=489), elevated-stable (19.0%; 17.1%-20.0%; n=903), and elevated-increasing (4.8%; 4.0%-5.5%; n=217). Compared with the low-stable group, trajectories with elevated BP levels had greater odds of having a CAC score of 100 HU or greater. Adjusted odds ratios were 1.44 (95% CI, 0.83-2.49) for moderate-stable, 1.86 (95% CI, 0.91-3.82) for moderate-increasing, 2.28 (95% CI, 1.24-4.18), for elevated-stable, and 3.70 (95% CI, 1.66-8.20) for elevated-increasing groups. The adjusted prevalence of a CAC score of 100 HU or higher was 5.8% in the low-stable group. These odds ratios represent an absolute increase of 2.7%, 5%, 6.3%, and 12.9% for the prevalence of a CAC score of 100 HU or higher for the moderate-stable, moderate-increasing, elevated-stable and elevated-increasing groups, respectively, compared with the low-stable group. Associations were not altered after adjustment for baseline and year 25 BP. Findings were similar for trajectories of isolated systolic BP trajectories but were attenuated for diastolic BP trajectories. CONCLUSIONS AND RELEVANCE Blood pressure trajectories throughout young adulthood vary, and higher BP trajectories were associated with an increased risk of CAC in middle age. Long-term trajectories in BP may assist in more accurate identification of individuals with subclinical atherosclerosis.
Background
Despite the availability of effective drug therapies that reduce low‐density lipoprotein (LDL)‐cholesterol (LDL‐C), cardiovascular disease (CVD) remains an important cause of mortality and ...morbidity. Therefore, additional LDL‐C reduction may be warranted, especially for people who are unresponsive to, or unable to take, existing LDL‐C‐reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) reduce LDL‐C and CVD risk.
Objectives
Primary
To quantify the effects of PCSK9 inhibitors on CVD, all‐cause mortality, myocardial infarction, and stroke, compared to placebo or active treatment(s) for primary and secondary prevention.
Secondary
To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention.
Search methods
We identified studies by systematically searching CENTRAL, MEDLINE, Embase, and Web of Science in December 2019. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in August 2020 and screened the reference lists of included studies. This is an update of the review first published in 2017.
Selection criteria
All parallel‐group and factorial randomised controlled trials (RCTs) with a follow‐up of at least 24 weeks and adult participants with or without a history of CVD were eligible if they compared PCSK9 inhibitors alirocumab or evolocumab to placebo or active treatments such as statins, ezetimibe, or a combination of these.
Data collection and analysis
Two review authors independently reviewed and extracted data. Where data were available, we calculated pooled effect estimates. We used GRADE to assess certainty of evidence and in 'Summary of findings' tables.
Main results
We included 24 studies with data on 60,997 participants. Eighteen trials randomised participants to alirocumab and six to evolocumab. All participants received background lipid‐lowering treatment or lifestyle counselling. Six alirocumab studies used an active treatment comparison group (the remaining used placebo), compared to three evolocumab active comparison trials. Follow‐up ranged from 6 to 36 months for the comparisons with placebo and from 6 to 12 months for comparisons with active treatment. Most of the available studies preferentially enrolled people with either established CVD or at a high risk already, and evidence in low‐ to medium‐risk settings is minimal.
Alirocumab compared with placebo decreased the risk of CVD events, with an absolute risk difference (RD) of –2% (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.80 to 0.94; 10 studies, 23,868 participants; high‐certainty evidence), decreased the risk of mortality (RD –1%; OR 0.83, 95% CI 0.72 to 0.96; 12 studies, 24,797 participants; high‐certainty evidence), and MI (RD –2%; OR 0.86, 95% CI 0.79 to 0.94; 9 studies, 23,352 participants; high‐certainty evidence) and for any stroke (RD 0%; OR 0.73, 95% CI 0.58 to 0.91; 8 studies, 22,835 participants; high‐certainty evidence).
Alirocumab compared with ezetimibe and statins: for CVD, the RD was 1% (OR 1.37, 95% CI 0.65 to 2.87; 3 studies, 1379 participants; low‐certainty evidence); for mortality, RD was –1% (OR 0.51, 95% CI 0.18 to 1.40; 5 studies, 1333 participants; low‐certainty evidence); for MI, RD was 1% (OR 1.45, 95% CI 0.64 to 3.28, 5 studies, 1734 participants; low‐certainty evidence); and for any stroke, RD was less than 1% (OR 0.85, 95% CI 0.13 to 5.61; 5 studies, 1734 participants; low‐certainty evidence).
Evolocumab compared with placebo: for CVD, the RD was –2% (OR 0.84, 95% CI 0.78 to 0.91; 3 studies, 29,432 participants; high‐certainty evidence); for mortality, RD was less than 1% (OR 1.04, 95% CI 0.91 to 1.19; 3 studies, 29,432 participants; high‐certainty evidence); for MI, RD was –1% (OR 0.72, 95% CI 0.64 to 0.82; 3 studies, 29,432 participants; high‐certainty evidence); and for any stroke RD was less than –1% (OR 0.79, 95% CI 0.65 to 0.94; 2 studies, 28,531 participants; high‐certainty evidence).
Evolocumab compared with ezetimibe and statins: for any CVD event RD was less than –1% (OR 0.66, 95% CI 0.14 to 3.04; 1 study, 218 participants; very low‐certainty evidence); for all‐cause mortality, the RD was less than 1% (OR 0.43, 95% CI 0.14 to 1.30; 3 studies, 5223 participants; very low‐certainty evidence); and for MI, RD was less than 1% (OR 0.66, 95% CI 0.23 to 1.85; 3 studies, 5003 participants; very low‐certainty evidence). There were insufficient data on any stroke.
Authors' conclusions
The evidence for the clinical endpoint effects of evolocumab and alirocumab versus placebo were graded as high. There is a strong evidence base for the benefits of PCSK9 monoclonal antibodies to people who might not be eligible for other lipid‐lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials.
The evidence base of PCSK9 inhibitors compared with ezetimibe and statins is much weaker (low very‐ to low‐certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies.
Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.
A 'proteoform' is defined as one specific protein structural form that results from the combination of allelic variation, alternative RNA splicing, and/or posttranslational modifications (PTMs) in ...specific locations on the amino acid backbone. Apolipoproteins A1 and A2 are highly abundant apolipoproteins that mediate HDL structure and function. ApoA1 and apoA2 are known to undergo PTMs, which results in multiple proteoforms. However, the catalogue of apoA1 and apoA2 proteoforms as well as their associations with cardiometabolic health characteristics has not been described until recently. In this brief review, we discuss recent efforts to catalogue the spectrum of apoA1 and apoA2 proteoforms, to understand the relationships between the relative abundance of these proteoforms with cardiometabolic phenotypic characteristics, and we will discuss the implications of these findings to future research.
A broad spectrum of apoA1 and apoA2 proteoforms has been characterized. Although, the types of apoA1 and A2 proteoforms are consistent across individuals, the relative abundances of proteoforms can vary substantially between individuals. Proteoform-specific associations with cardiometabolic characteristics in humans, independent of absolute apolipoprotein abundance, have been described. These recent findings suggest multiple levels of protein structural variation that arise from known and unknown metabolic pathways may be important markers or mediators of cardiometabolic health.
Understanding the associations between apolipoprotein proteoforms and phenotype may lead to enhanced understanding of how apolipoproteins mediate lipid metabolism and affect atherosclerotic cardiovascular disease (ASCVD) risk, which may lead to discovery of novel markers of risk and/or key mechanistic insights that may drive further druggable targets for modifying lipid metabolism and reducing ASCVD risk.
The ultimate goal of lipid-lowering therapy is to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Current cholesterol guidelines recommend comprehensive assessment of all ASCVD ...risk factors and a focus on lifestyle counseling. Several patient groups also derive clear benefit from cholesterol-lowering drug therapy to reduce risk. Statins are first-line agents: initiation is recommended for all patients treated for secondary prevention, patients with familial hypercholesterolemia, and essentially all adults aged 40 to 75 years with diabetes. Consideration of statin initiation is recommended in patients treated for primary prevention with estimated 10-year ASCVD risk of 7.5% or more, or certain patients with estimated risk less than 7.5% and risk-enhancing factors. In patients with familial hypercholesterolemia who cannot achieve LDL-C lower than 100 mg/dL, or patients treated for secondary prevention who cannot achieve LDL-C lower than 70 mg/dL, drugs like ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors can be considered to reduce risk further.
IMPORTANCE: Although the associations between processed meat intake and cardiovascular disease (CVD) and all-cause mortality have been established, the associations of unprocessed red meat, poultry, ...or fish consumption with CVD and all-cause mortality are still uncertain. OBJECTIVE: To identify the associations of processed meat, unprocessed red meat, poultry, or fish intake with incident CVD and all-cause mortality. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed individual-level data of adult participants in 6 prospective cohort studies in the United States. Baseline diet data from 1985 to 2002 were collected. Participants were followed up until August 31, 2016. Data analyses were performed from March 25, 2019, to November 17, 2019. EXPOSURES: Processed meat, unprocessed red meat, poultry, or fish intake as continuous variables. MAIN OUTCOMES AND MEASURES: Hazard ratio (HR) and 30-year absolute risk difference (ARD) for incident CVD (composite end point of coronary heart disease, stroke, heart failure, and CVD deaths) and all-cause mortality, based on each additional intake of 2 servings per week for monotonic associations or 2 vs 0 servings per week for nonmonotonic associations. RESULTS: Among the 29 682 participants (mean SD age at baseline, 53.7 15.7 years; 13 168 44.4% men; and 9101 30.7% self-identified as non-white), 6963 incident CVD events and 8875 all-cause deaths were adjudicated during a median (interquartile range) follow-up of 19.0 (14.1-23.7) years. The associations of processed meat, unprocessed red meat, poultry, or fish intake with incident CVD and all-cause mortality were monotonic (P for nonlinearity ≥ .25), except for the nonmonotonic association between processed meat intake and incident CVD (P for nonlinearity = .006). Intake of processed meat (adjusted HR, 1.07 95% CI, 1.04-1.11; adjusted ARD, 1.74% 95% CI, 0.85%-2.63%), unprocessed red meat (adjusted HR, 1.03 95% CI, 1.01-1.06; adjusted ARD, 0.62% 95% CI, 0.07%-1.16%), or poultry (adjusted HR, 1.04 95% CI, 1.01-1.06; adjusted ARD, 1.03% 95% CI, 0.36%-1.70%) was significantly associated with incident CVD. Fish intake was not significantly associated with incident CVD (adjusted HR, 1.00 95% CI, 0.98-1.02; adjusted ARD, 0.12% 95% CI, −0.40% to 0.65%). Intake of processed meat (adjusted HR, 1.03 95% CI, 1.02-1.05; adjusted ARD, 0.90% 95% CI, 0.43%-1.38%) or unprocessed red meat (adjusted HR, 1.03 95% CI, 1.01-1.05; adjusted ARD, 0.76% 95% CI, 0.19%-1.33%) was significantly associated with all-cause mortality. Intake of poultry (adjusted HR, 0.99 95% CI, 0.97-1.02; adjusted ARD, −0.28% 95% CI, −1.00% to 0.44%) or fish (adjusted HR, 0.99 95% CI, 0.97-1.01; adjusted ARD, −0.34% 95% CI, −0.88% to 0.20%) was not significantly associated with all-cause mortality. CONCLUSIONS AND RELEVANCE: These findings suggest that, among US adults, higher intake of processed meat, unprocessed red meat, or poultry, but not fish, was significantly associated with a small increased risk of incident CVD, whereas higher intake of processed meat or unprocessed red meat, but not poultry or fish, was significantly associated with a small increased risk of all-cause mortality. These findings have important public health implications and should warrant further investigations.
IMPORTANCE: Cholesterol is a common nutrient in the human diet and eggs are a major source of dietary cholesterol. Whether dietary cholesterol or egg consumption is associated with cardiovascular ...disease (CVD) and mortality remains controversial. OBJECTIVE: To determine the associations of dietary cholesterol or egg consumption with incident CVD and all-cause mortality. DESIGN, SETTING, AND PARTICIPANTS: Individual participant data were pooled from 6 prospective US cohorts using data collected between March 25, 1985, and August 31, 2016. Self-reported diet data were harmonized using a standardized protocol. EXPOSURES: Dietary cholesterol (mg/day) or egg consumption (number/day). MAIN OUTCOMES AND MEASURES: Hazard ratio (HR) and absolute risk difference (ARD) over the entire follow-up for incident CVD (composite of fatal and nonfatal coronary heart disease, stroke, heart failure, and other CVD deaths) and all-cause mortality, adjusting for demographic, socioeconomic, and behavioral factors. RESULTS: This analysis included 29 615 participants (mean SD age, 51.6 13.5 years at baseline) of whom 13 299 (44.9%) were men and 9204 (31.1%) were black. During a median follow-up of 17.5 years (interquartile range, 13.0-21.7; maximum, 31.3), there were 5400 incident CVD events and 6132 all-cause deaths. The associations of dietary cholesterol or egg consumption with incident CVD and all-cause mortality were monotonic (all P values for nonlinear terms, .19-.83). Each additional 300 mg of dietary cholesterol consumed per day was significantly associated with higher risk of incident CVD (adjusted HR, 1.17 95% CI, 1.09-1.26; adjusted ARD, 3.24% 95% CI, 1.39%-5.08%) and all-cause mortality (adjusted HR, 1.18 95% CI, 1.10-1.26; adjusted ARD, 4.43% 95% CI, 2.51%-6.36%). Each additional half an egg consumed per day was significantly associated with higher risk of incident CVD (adjusted HR, 1.06 95% CI, 1.03-1.10; adjusted ARD, 1.11% 95% CI, 0.32%-1.89%) and all-cause mortality (adjusted HR, 1.08 95% CI, 1.04-1.11; adjusted ARD, 1.93% 95% CI, 1.10%-2.76%). The associations between egg consumption and incident CVD (adjusted HR, 0.99 95% CI, 0.93-1.05; adjusted ARD, −0.47% 95% CI, −1.83% to 0.88%) and all-cause mortality (adjusted HR, 1.03 95% CI, 0.97-1.09; adjusted ARD, 0.71% 95% CI, −0.85% to 2.28%) were no longer significant after adjusting for dietary cholesterol consumption. CONCLUSIONS AND RELEVANCE: Among US adults, higher consumption of dietary cholesterol or eggs was significantly associated with higher risk of incident CVD and all-cause mortality in a dose-response manner. These results should be considered in the development of dietary guidelines and updates.
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