When Does Primary Prevention Encroach on Secondary Prevention?

PURPOSE OF REVIEW: The risk of incident atherosclerotic cardiovascular disease (ASCVD) in primary prevention is typically lower than in secondary prevention. However, there is a spectrum of risk among individuals undergoing primary prevention with the risk in some individuals approaching those of secondary prevention. We review the clinical conditions wherein the risk in primary prevention is similar to that observed in secondary prevention. RECENT FINDINGS: Among individuals without established ASCVD, coronary artery calcium (CAC) scores ≥ 300 AU are associated with ASCVD event rates similar to secondary prevention populations. CAC score ≥ 1,000 AU are associated with an ASCVD risk seen in very high-risk secondary prevention populations. Interpretation of these observations must however consider differences in the risk reduction strategies. Current guidelines dichotomize ASCVD prevention into primary and secondary prevention, but certain primary prevention patients have an ASCVD risk equivalent to that of secondary prevention populations. Identifying higher risk primary prevention populations will allow for better risk mitigation strategies.

Severe hypercholesterolemia in a patient with very low albumin and normal renal function.

A 20-year-old male presented with severe elevation in low-density lipoprotein cholesterol (LDL-C). Initial genetic testing for familial hypercholesterolemia was negative. Patient also had low albumin, and further genetic testing showed homozygous variants in the ALB gene, suggesting congenital analbuminemia (CAA) causing severe hyperlipidemia. CAA is an autosomal recessive disorder with incidence of about 1:1,000,000. The gene for albumin is a single autosomal gene, and pathological variants that affect splicing lead to premature stop, nonsense variants, and deletions that result in a defect in albumin synthesis with CAA. CAA can be fatal in the prenatal period and cause infections in early childhood. CAA is tolerated better in adulthood because of compensatory increase in other plasma proteins. Plasma lipoproteins also increase, and CAA can cause gross hyperlipidemia with severe elevations in LDL-C and hypercholesterolemia. Genetic examination of ALB is mandatory to establish the diagnosis. Early diagnosis may be important to initiate lipid-lowering treatments to avoid premature coronary artery disease.

Genetic Testing for Hypertriglyceridemia in Academic Lipid Clinics: Implications for Precision Medicine-Brief Report.

BACKGROUND: Severe hypertriglyceridemia is often caused by variants in genes of triglyceride metabolism. These variants include rare, heterozygous pathogenic variants (PVs), or multiple common, small-effect single nucleotide polymorphisms that can be quantified using a polygenic risk score (PRS). The role of genetic testing to examine PVs and PRS in predicting risk for pancreatitis and severity of hypertriglyceridemia is unknown. METHODS: We examined the relationship of PVs and PRSs associated with hypertriglyceridemia with the highest recorded plasma triglyceride level and risk for acute pancreatitis in 363 patients from 3 academic lipid clinics who underwent genetic testing (GBinsight's Dyslipidemia Comprehensive Panel). Categories of hypertriglyceridemia included: normal triglyceride (<200 mg/dL), moderate (200-499 mg/dL), severe (500-999 mg/dL), or very severe (≥1000 mg/dL). RESULTS: PVs and high PRSs were identified in 37 (10%) and 59 (16%) individuals, respectively. Patients with both had increased risk for very severe hypertriglyceridemia compared with those with neither genetic risk factor. Risk for acute pancreatitis was also increased in individuals with both genetic risk factors (odds ratio, 5.1 [P=0.02] after controlling for age, race, sex, body mass index, and highest triglyceride level), but not in individuals with PV or high PRS alone. CONCLUSIONS: The presence of both PV and high PRS significantly increased risk for very severe hypertriglyceridemia and acute pancreatitis, whereas PV or PRS alone only modestly increased risk. Genetic testing may help identify patients with hypertriglyceridemia who have the greatest risk for developing pancreatitis and may derive the greatest benefit from novel triglyceride-lowering therapies.

Temporal Trends in Lipoprotein(a) Concentrations: The Atherosclerosis Risk in Communities Study.

Background Plasma lipoprotein(a) (Lp[a]) concentrations are primarily determined by genetic factors and are believed to remain stable throughout life. However, data are scarce on longitudinal trends in Lp(a) concentrations over time. Therefore, it is unclear whether measurement of Lp(a) once in a person's life is sufficient for cardiovascular risk assessment in all adults. Methods and Results Lp(a) concentrations, specifically apolipoprotein(a) concentrations, were measured at visits 4 and 5, ≈15 years apart, in 4734 adult participants of the ARIC (Atherosclerosis Risk in Communities) study (mean age at visits 4 and 5, 60.7±5.1 and 75.5±5.2 years, respectively). Participants were categorized by baseline (visit 4) Lp(a) concentrations as normal (<30 mg/dL), borderline-high (30-49 mg/dL), or high (≥50 mg/dL). We compared adults with Lp(a) change ≥20 mg/dL between visits and those with Lp(a) change <20 mg/dL. Multivariable logistic regression analysis was used to identify covariates associated with change in Lp(a) over time. At visit 5, 58.1% of participants with borderline-high Lp(a) concentrations of 30 to 49 mg/dL at visit 4 had high Lp(a) concentrations ≥50 mg/dL. Participants with low Lp(a) (<30 mg/dL) or high Lp(a) (≥50 mg/dL) at visit 4 tended to stay in these respective categories. Black race, female sex, diabetes, hypertension, total cholesterol, and albuminuria were associated with significantly greater probability for Lp(a) change ≥20 mg/dL over time. Conclusions Our results suggest that adults with borderline-high Lp(a) concentrations may be considered for repeat monitoring of Lp(a) over time, particularly if they are Black, women, or have diabetes, hypertension, and/or elevated albuminuria.

A Comprehensive Review of the Pleiotropic Effects of Ticagrelor.

AIMS: This review summarizes the findings of preclinical studies evaluating the pleiotropic effects of ticagrelor. These include attenuation of ischemia-reperfusion injury (IRI), inflammation, adverse cardiac remodeling, and atherosclerosis. In doing so, it aims to provide novel insights into ticagrelor's mechanisms and benefits over other P2Y12 inhibitors. It also generates viable hypotheses for the results of seminal clinical trials assessing ticagrelor use in acute and chronic coronary syndromes. METHODS AND RESULTS: A comprehensive review of the preclinical literature demonstrates that ticagrelor protects against IRI in the setting of both an acute myocardial infarction (MI), and when MI occurs while on chronic treatment. Maintenance therapy with ticagrelor also likely mitigates adverse inflammation, cardiac remodeling, and atherosclerosis, while improving stem cell recruitment. These effects are probably mediated by ticagrelor's ability to increase local interstitial adenosine levels which activate downstream cardio-protective molecules. Attenuation and augmentation of these pleiotropic effects by high-dose aspirin and caffeine, and statins respectively may help explain variable outcomes in PLATO and subsequent randomized controlled trials (RCTs). CONCLUSION: Most RCTs and meta-analyses have not evaluated the pleiotropic effects of ticagrelor. We need further studies comparing cardiovascular outcomes in patients treated with ticagrelor versus other P2Y12 inhibitors that are mindful of the unique pleiotropic advantages afforded by ticagrelor, as well as possible interactions with other therapies (e.g., aspirin, statins, caffeine).

Lipid Monitoring After Initiation of Lipid-Lowering Therapies: Return of Performance Measures?

PURPOSE OF REVIEW: The 2015 American College of Cardiology (ACC)/American Heart Association (AHA) Focused Update of Secondary Prevention Lipid Performance Measures removed low-density lipoprotein cholesterol (LDL-C) assessment as a performance measure. This review discusses the evidence supporting the importance of lipid monitoring in the secondary prevention of atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS: The 2018 AHA/ACC Multisociety cholesterol guideline (as did the 2013 guideline) recommends a lipid panel after initiating lipid-lowering therapy to monitor adherence and medication efficacy. The 2018 guideline also recommends adding nonstatin therapy in very-high-risk ASCVD patients with LDL-C ≥70 mg/dL despite maximally tolerated statin therapy. The removal of LDL-C monitoring as a performance measure is not consistent with the 2018 cholesterol guidelines. Given the importance of monitoring lipid-lowering medication efficacy and adherence and optimally reducing LDL-C in very-high-risk patients with additional evidence-based nonstatin therapy, LDL-C assessment after initiating lipid-lowering therapy should be reinstated as a performance measure for patients with ASCVD.

Challenges and Controversies in the Management of ACS in Elderly Patients.

PURPOSE OF REVIEW: Elderly patients presenting with acute coronary syndrome (ACS) represent a challenging patient population. A high index of suspicion is needed for their diagnosis, as they are less likely to present with typical anginal symptoms compared to their younger counterparts. RECENT FINDINGS: Disrupted coronary plaques with superimposed thrombosis are the predominant pathophysiology of ACS; however, an increased proportion of calcified nodules is encountered in elderly patients. Emergent reperfusion and revascularization remain the mainstay treatment for ST-elevation myocardial infarction or cardiogenic shock. In elderly patients with NSTE-ACS, a routine invasive strategy is generally superior to an ischemia-guided strategy, and the safety of an early invasive strategy has also been recently demonstrated. When treating elderly ACS patients with antiplatelet and antithrombotic therapies, close attention to co-morbidities, frailty and the balance of ischemia-bleeding risk should be undertaken, and medication doses should be carefully adjusted. Overall, elderly patients with ACS remain undertreated with evidence-based therapies, experience worse outcomes, and represent an opportunity for enhancing and mitigating healthcare disparities.

The significance of electrocardiographic changes without echocardiographic evidence of segmental wall motion abnormalities in patients undergoing dobutamine stress echocardiography.

Ischemic ECG changes during dobutamine stress echocardiography (DSE) have been reported to have low sensitivity and specificity for detecting myocardial ischemia in the absence of wall motion abnormalities on echocardiography. We present a case of a renal transplant candidate with severe multivessel disease who had ST depressions without any wall motion abnormalities on DSE. Certain studies have shown the sensitivity of DSE is lower in patients with left ventricular hypertrophy and/or end stage renal disease, but the significance of ischemic ECG changes with no evidence of wall motion abnormalities in these patients has not been well studied.

Total sulfane sulfur bioavailability reflects ethnic and gender disparities in cardiovascular disease.

Hydrogen sulfide (H2S) has emerged as an important physiological and pathophysiological signaling molecule in the cardiovascular system influencing vascular tone, cytoprotective responses, redox reactions, vascular adaptation, and mitochondrial respiration. However, bioavailable levels of H2S in its various biochemical metabolite forms during clinical cardiovascular disease remain poorly understood. We performed a case-controlled study to quantify and compare the bioavailability of various biochemical forms of H2S in patients with and without cardiovascular disease (CVD). In our study, we used the reverse-phase high performance liquid chromatography monobromobimane assay to analytically measure bioavailable pools of H2S. Single nucleotide polymorphisms (SNPs) were also identified using DNA Pyrosequencing. We found that plasma acid labile sulfide levels were significantly reduced in Caucasian females with CVD compared with those without the disease. Conversely, plasma bound sulfane sulfur levels were significantly reduced in Caucasian males with CVD compared with those without the disease. Surprisingly, gender differences of H2S bioavailability were not observed in African Americans, although H2S bioavailability was significantly lower overall in this ethnic group compared to Caucasians. We also performed SNP analysis of H2S synthesizing enzymes and found a significant increase in cystathionine gamma-lyase (CTH) 1364 G-T allele frequency in patients with CVD compared to controls. Lastly, plasma H2S bioavailability was found to be predictive for cardiovascular disease in Caucasian subjects as determined by receiver operator characteristic analysis. These findings reveal that plasma H2S bioavailability could be considered a biomarker for CVD in an ethnic and gender manner. Cystathionine gamma-lyase 1346 G-T SNP might also contribute to the risk of cardiovascular disease development.

Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism.

Angiotensin-converting enzyme type 2 (ACE2) is a pivotal component of the renin-angiotensin system, promoting the conversion of angiotensin II (Ang-II) to Ang-(1-7). We previously reported that decreased ACE2 expression and activity contributes to the development of Ang-II-mediated hypertension in mice. The present study aimed to investigate the mechanisms involved in ACE2 downregulation during neurogenic hypertension. In ACE2-transfected Neuro-2A cells, Ang-II treatment resulted in a significant attenuation of ACE2 enzymatic activity. Examination of the subcellular localization of ACE2 revealed that Ang-II treatment leads to ACE2 internalization and degradation into lysosomes. These effects were prevented by both the Ang-II type 1 receptor (AT1R) blocker losartan and the lysosomal inhibitor leupeptin. In contrast, in HEK293T cells, which lack endogenous AT1R, Ang-II failed to promote ACE2 internalization. Moreover, this effect could be induced after AT1R transfection. Furthermore, coimmunoprecipitation experiments demonstrated that AT1R and ACE2 form complexes, and these interactions were decreased by Ang-II treatment, which also enhanced ACE2 ubiquitination. In contrast, ACE2 activity was not changed by transfection of AT2 or Mas receptors. In vivo, Ang-II-mediated hypertension was blunted by chronic infusion of leupeptin in wildtype C57Bl/6, but not in ACE2 knockout mice. Overall, this is the first demonstration that elevated Ang-II levels reduce ACE2 expression and activity by stimulation of lysosomal degradation through an AT1R-dependent mechanism.