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Lipoprotein(a), or Lp(a), levels and the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on Lp(a) during the peri-infarction and early postinfarction period are not well characterized. This study aimed to describe the trajectory of Lp(a), as well as the effect of PCSK9 inhibition on that trajectory during the peri-infarction and early postinfarction period. Lp(a) levels were obtained within 24 hours of hospital admission as well as within 24 hours of hospital discharge and at 30 days from 74 participants who presented with a NSTEMI (troponin I5 ng/ml) or with a STEMI and were enrolled in 2 randomized, double-blind trials of evolocumab and placebo (Evolocumab in Acute Coronary Syndrome [EVACS I]; ClinicalTrials.gov, NCT03515304 and Evolocumab in Patients With STEMI [EVACS II]; ClinicalTrials.gov Identifier: NCT04082442). There was a significant increase from the pretreatment level in the placebo-treated patients, from 64 (41,187) nmol/L to 80 (47, 172) nmol/L at hospital discharge and to 82 (37, 265) at 30 days. This was primarily driven by the results from participants with high Lp(a) at hospital admission (75 nmol/L) in whom the median increase was 28% as compared with a 10% increase in those with pretreatment Lp(a) of75 nmol/L. In contrast, there was no significant change from the pretreatment level in the evolocumab-treated patients regardless of pretreatment Lp(a) levels. In conclusion, Lp(a) rises during the peri-infarction and early postinfarction period in patients with acute myocardial infarction. The increase was prevented by a single dose of subcutaneous evolocumab given within 24 hours of hospital admission.

Aims Lipoprotein(a) [Lp(a)] levels are generally constant throughout an individual’s lifetime, and current guidelines recommend that a single measurement is sufficient to assess the risk of coronary artery disease (CAD). However, it is unclear whether a single measurement of Lp(a) in individuals with acute myocardial infarction (MI) is indicative of the Lp(a) level six months following the event. Methods and results Lp(a) levels were obtained from individuals with non–ST-elevation myocardial infarction (NSTEMI) or ST-elevation myocardial infarction (STEMI) (n = 99) within 24 h of hospital admission and after six months, who were enrolled in two randomized trials of evolocumab and placebo, and in individuals with NSTEMI or STEMI (n = 9) who enrolled in a small observation arm of the two protocols and did not receive study drug, but whose levels were obtained at the same time points. Median Lp(a) levels increased from 53.5 nmol/L (19, 165) during hospital admission to 58.0 nmol/L (14.8, 176.8) six months after the acute infarction (P = 0.02). Subgroup analysis demonstrated no difference in the baseline, six-month, or change between the baseline and six-month Lp(a) values between the STEMI and NSTEMI groups and between the group which received evolocumab and the group that did not. Conclusion This study demonstrated that Lp(a) levels in individuals with acute MI are significantly higher six months after the initial event. Therefore, a single measurement of Lp(a) in the peri-infarction setting is not sufficient to predict the Lp(a)-associated CAD risk in the post-infarction period. Registration Evolocumab in Acute Coronary Syndrome Trial [EVACS I] NCT03515304, Evolocumab in Patients with Acute Myocardial Infarction [EVACS II], NCT04082442

Preeclampsia is associated with decreased maternal low-density lipoprotein cholesterol (LDL-c), which is essential for fetal growth. The underlying mechanisms for decreased LDL-c in preeclampsia remain unknown. Proprotein convertase subtillisin/kexin type 9 (PCSK9) regulates serum LDL-c via LDL receptor (LDL-R) degradation. We describe the possible role of PCSK9 in lipid metabolism in all compartments of the parturient (maternal blood, placental tissue, and fetal blood) in pregnancies with and without preeclampsia.This is an observational study examining PCSK9 levels in maternal sera, umbilical cord blood, and PCSK9 protein content in placental tissue in three different locations (maternal placental interface, fetal placental interface, and umbilical cord) in women with and without preeclampsia at23 weeks gestation.68 parturients with preeclampsia and 55 without preeclampsia were enrolled. Maternal serum LDL-c (116.6 ± 48.9 mg/dL vs 146.1 ± 47.1 mg/dL, p = 0.0045) and PCSK9 (83 [61.8127.6] ng/mL vs 105.3 [83.5142.9] ng/mL, p = 0.011) were also reduced in the preeclamptics versus controls. There were no differences in PCSK9 protein content between preeclamptics and controls at comparative placental interfaces. However, PCSK9 protein content increased between the preeclampsia maternal placental interface (1.87 ± 0.62) and the preeclampsia umbilical cord (2.67 ± 1.08, p = 0.0243).PCSK9 levels are lower in maternal sera in preeclampsia when compared to controls. Placental PCSK9 protein content in preeclampsia increases from the maternal interface to the umbilical cord; however, this is not seen in controls. This suggests a potential compensatory mechanism for PCSK9 which allows for higher circulating fetal LDL-c levels in preeclampsia.

High lipoprotein(a) [Lp(a)] levels are associated with the development of atherosclerotic cardiovascular disease (ASCVD) and with calcific aortic valve stenosis (CAVS) both observationally and causally from human genetic studies. The mechanisms are not well characterized but likely involve its role as a carrier of oxidized phospholipids (OxPLs), which are known to be increased in pro-inflammatory states, to induce pro-inflammatory changes in monocytes leading to plaque instability, and to impair vascular endothelial cell function, a driver of acute and recurrent ischemic events. In addition, Lp(a) itself has prothrombotic activity. Current lipid-lowering strategies do not sufficiently lower Lp(a) serum levels. Lp(a)-specific-lowering drugs, targeting apolipoprotein(a) synthesis, lower Lp(a) by up to 90% and are being evaluated in ongoing clinical outcome trials. This review summarizes the current knowledge on the associations of Lp(a) with ASCVD and CAVS, the current role of Lp(a) assessment in the clinical setting, and emerging Lp(a)-specific-lowering therapies.

Cardiac PET/MR imaging is an integrated imaging approach that requires less radiation than PET/computed tomography and combines the high spatial resolution and morphologic data from MR imaging with the physiologic information from PET. This hybrid approach has the potential to improve the diagnostic and prognostic evaluation of several cardiovascular conditions, such as ischemic heart disease, infiltrative diseases such as sarcoidosis, acute and chronic myocarditis, and cardiac masses. Herein, the authors discuss the strengths of PET and MR imaging in several cardiovascular conditions; the challenges and potential; and the current data on the application of this powerful hybrid imaging modality.

Introduction: Elevated lipoprotein(a) [Lp(a)] is associated with atherosclerotic cardiovascular disease (ASCVD), yet little is known about Lp(a) testing patterns in real-world practice. We hypothesized that Lp(a) testing occurs in a different population than calculated low density lipoprotein (LDL-C) testing alone, and that elevated Lp(a) is associated with greater lipid-lowering therapy (LLT) initiation and cardiovascular (CV) events. Methods: We used data from 11 health systems participating in the National Patient-Centered Clinical Research Network. We created two cohorts based on lab tests from Jan 1, 2015 to Dec 31, 2019: 1) the Lp(a) cohort, of adults with an Lp(a) test and 2) the LDL-C cohort, of 4:1 date- and site-matched adults with an LDL-C test, but no Lp(a) test. We used logistic regression to assess the relationship between Lp(a) levels (< 50, 50-100, and > 100mg/dL) and initiation of LLT within 3 months; and cox proportional hazards to evaluate Lp(a) levels and time to all-cause hospitalization and the composite of MI, revascularization and ischemic stroke hospitalization. Results: Overall, 20,551 patients (0.06% per year) had Lp(a) tests, with median Lp(a) value 17.5mg/dL (Q1, Q3: 7.0, 56.0). Compared with the LDL-C cohort (N=82,204), the Lp(a) cohort more frequently had ASCVD (24.3% vs. 8.5%) or multiple prior CV events (8.6% vs. 2.6%). Elevated Lp(a) was associated with greater odds of LLT initiation (Figure 1). Elevated Lp(a) was not significantly associated with all-cause hospitalization; however, Lp(a) > 100mg/dL was correlated with composite CV hospitalization compared with Lp(a) < 50mg/dL [adj HR (95% CI): 1.24 (1.06-1.44), p=0.006]. Conclusions: Lp(a) testing occurs more often in adults with ASCVD and multiple CV events, but testing is infrequent. Elevated Lp(a) was associated with LLT initiation, including niacin, despite lack of evidence of CV benefit. There was an association between elevated Lp(a) and CV hospitalization outcomes.

Introduction: Impaired coronary endothelial function (CEF) is a known predictor of cardiovascular (CV) events and occurs in people living with HIV. HIV+ women compared to men have worse CV outcomes, but prior studies include very few women. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is related to endothelial cell inflammation and is elevated in HIV+ men. CEF and PCSK9 are not well studied in women with HIV. Hypothesis: We hypothesize that HIV+ women have worse CEF and higher PCSK9 levels compared to risk factor matched HIV- women, and that CEF will be associated with PCSK9 in HIV+ women, similar to prior findings in HIV+ men. Methods: A total of 34 HIV+ women and 75 HIV+ men on stable highly active antiretroviral therapy and 17 HIV- women and 8 HIV- men underwent MRI to measure CEF (%change in coronary artery cross-sectional area (%CSA) and coronary blood flow (CBF) during isometric handgrip exercise, an endothelial dependent stressor). Serum PCSK9 samples were obtained on the day of MRI. Comparisons were performed using student’s t-test for normally distributed and Kruskal-Wallis test for data not normally distributed. Robust regression was used for the association of PCSK9 with CEF. Results: CEF was significantly reduced in HIV+ women compared to age-, race- and BMI-matched HIV- women (p Conclusions: Coronary endothelial dysfunction is present among HIV+ women as compared to risk factor matched HIV- women. HIV+ women have similarly depressed CEF as HIV+ men. With HIV, PCSK9 is not significantly associated with CEF, suggesting potential alternative mechanisms of impaired CEF in men and women with HIV.

This case report describes a 50-year-old-woman from Southeast Asia with extensive atherosclerotic cardiovascular disease, found to have homozygous familial hypercholesterolemia caused by variants of uncertain significance in both the APOB and LDLR genes. Medications were insufficient, and thus LDL apheresis was initiated to further decrease LDL-C. (Level of Difficulty: Beginner.), Graphical abstract, This case report describes a 50-year-old-woman from Southeast Asia with extensive atherosclerotic cardiovascular disease, found to have homozygous…

Infective endocarditis remains a diagnostic challenge. Although echocardiography is still the mainstay imaging test, it misses up to 30% of cases. Newer imaging tests--4-dimensional computed tomography (4D CT), fluorodeoxy-glucose positron emission tomography (FDG-PET), and leukocyte scintigraphy--are increasingly used as alternative or adjunct tests for select patients. They improve the sensitivity of clinical diagnosis of infective endocarditis when appropriately used, especially in the setting of a prosthetic valve.

The objective of this study was to investigate whether baseline low-density lipoprotein cholesterol (LDL-C) levels influence total and cardiovascular mortality reduction associated with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy.In this meta-analysis, 9 randomized controlled trials were selected using Medline, Embase, and CENTRAL until November 2018. Analyses were stratified by mean baseline LDL-C (100 mg/dL and ≥ 100 mg/dL). Stepwise prespecified sensitivity analyses were performed after excluding the SPIRE trials and by regrouping ODYSSEY OUTCOME mortality data according to the baseline LDL-C (and ≥100 mg/dL).In 83,321 patients, PCSK9 inhibitor therapy was not associated with a reduction in the risk of all-cause mortality (relative risk [RR], 0.94, 95% confidence interval [CI], 0.81-1.09, P = .41). These results remained consistent after excluding the SPIRE trials (RR, 0.89, 95% CI, 0.75-1.05, P = .18). However, the RR varied by baseline LDL-C, with significant RR reduction only in patients with LDL-C ≥ 100 mg/dL (RR, 0.39, 95% CI, 0.20-0.76) (P-interaction = .01). Meta-regression showed RR of 0.97 for all-cause mortality per 1 mg/dL higher baseline LDL-C (95% CI, 0.94-0.99). PCSK9 inhibitor therapy showed no significant effect on cardiovascular mortality, with no effect when excluding the SPIRE trials. However, after regrouping ODYSSEY OUTCOME estimates, there was a significant reduction in cardiovascular mortality restricted to patients with LDL-C ≥ 100 mg/dL (RR, 0.67, 95% CI, 0.51-0.87) (P-interaction = .006).PCSK9 inhibitor therapy on a background statin treatment may reduce the risk of total and cardiovascular mortality in patients with baseline LDL-C ≥ 100 mg/dL. These results support current guidelines reserving PCSK9 inhibitors for high-risk patients with residually high LDL-C.

The impact of the antiplatelet regimen and the extent of associated platelet inhibition on cerebrovascular microembolic events during transcatheter aortic valve implantation (TAVI) are unknown. Our aim was to evaluate the effects of ticagrelor versus clopidogrel and of platelet inhibition on the number of cerebrovascular microembolic events in patients undergoing TAVI. Patients scheduled for TAVI were randomized previous to the procedure to either aspirin and ticagrelor or to aspirin and clopidogrel. Platelet inhibition was expressed in P2Y12 reaction units (PRU) and percentage of inhibition. High intensity transient signals (HITS) were assessed with transcranial Doppler (TCD). Safety outcomes were recorded according to the VARC-2 definitions. Among 90 patients randomized, 6 had an inadequate TCD signal. The total number of procedural HITS was lower in the ticagrelor group (416.5 [324.8, 484.2]) (42 patients) than in the clopidogrel group (723.5 [471.5, 875.0]) (42 patients), p0.001. After adjusting for the duration of the procedure, diabetes, extra-cardiac arteriopathy, BMI, hypertension, aortic valve calcium content, procedural ACT, and pre-implantation balloon valvuloplasty, patients on ticagrelor had on average 256.8 (95% CI: [-335.7, -176.5]) fewer total procedural HITS than patients on clopidogrel. Platelet inhibition was greater with ticagrelor 26 [10, 74.5] PRU than with clopidogrel 207.5 (120 to 236.2) PRU, p0.001, and correlated significantly with procedural HITS (r = 0.5, p0.05). In conclusion, ticagrelor resulted in fewer procedural HITS, compared with clopidogrel, in patients undergoing TAVI, while achieving greater platelet inhibition.

Vascular endothelial cell (EC) dysfunction is a pathological mediator of the development, progression, and clinical manifestations of atherosclerotic disease. Inflammation is associated with EC dysfunction, but the responsible mechanisms are not well characterized. There is substantial evidence that serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is increased in pro-inflammatory states and that elevated PCSK9 levels are associated with adverse cardiovascular outcomes after controlling for traditional risk factors, including low-density lipoprotein (LDL) cholesterol. Here we investigate PCSK9 as a novel link between inflammation and vascular EC dysfunction, as assessed by nitric oxide (NO) bioavailability. Tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, increased PCSK9 mRNA expression (1.98 [0.7, 3.4]-fold increase, p=0.02 vs. control) and PCSK9 protein levels (1.52±0.1-fold increase, p Our results demonstrate that PCSK9 is increased in human aortic ECs exposed to a pro-inflammatory stimulus and that this increase is associated with EC dysfunction. Silencing of TNFα-mediated augmentation of PCSK9 protein expression utilizing a small interfering RNA against PCSK9 rescued the inflammation-induced EC dysfunction. These results indicate that PCSK9 is a causal link between inflammation and EC dysfunction, a potent driver of atherosclerotic cardiovascular disease. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Career Development Award from the American Heart Association, OAIC pilot Award

ObjectivesTo evaluate the effects of ticagrelor versus clopidogrel and of platelet inhibition on the number of cerebrovascular microembolic events, in patients undergoing transcatheter aortic valve replacement (TAVR).BackgroundThe impact of the antiplatelet regimen and the extent of associated platelet inhibition on cerebrovascular microembolic events during TAVR are unknown.MethodsPatients scheduled for TAVR were randomized prior to the procedure to either aspirin and ticagrelor or to aspirin and clopidogrel. Platelet inhibition was expressed in P2Y12 Reaction Units (PRU) and percentage of inhibition. High intensity transient signals (HITS) were assessed with transcranial Doppler (TCD). Safety outcomes were recorded according to the VARC-2 definitions.ResultsAmong 90 patients randomized, six had inadequate TCD signal. The total number of procedural HITS was lower in the ticagrelor group (416.5 [324.8, 484.2]) (42 patients) than in the clopidogrel group (723.5 [471.5, 875.0]) (42 patients), p< 0.001. After adjusting for the duration of the procedure, diabetes, extra-cardiac arteriopathy, BMI, and aortic valve calcium content, patients on ticagrelor had on average 255.9 (95% CI: [-335.4, -176.4]) fewer total procedural HITS, than did patients on clopidogrel. Platelet inhibition was greater in those randomized to ticagrelor 26 [10, 74.5] PRU than in those randomized to clopidogrel 207.5 [120-236.2] PRU, pConclusionsTicagrelor resulted in fewer procedural HITS, compared to clopidogrel, in patients undergoing TAVR, while achieving greater platelet inhibition, without increasing the risk for complications.Clinical Trial(ClinicalTrials.gov Identifier: NCT02989558)CONDENSED ABSTRACTWe conducted a two-center, prospective, open label, randomized, controlled clinical trial to compare the efficacy of ticagrelor vs clopidogrel in preventing cerebrovascular embolic events as assessed by transcranial Doppler during TAVR.The total number of procedural HITS was lower in the ticagrelor group (416.5 [324.8, 484.2]) than in the clopidogrel group (723.5 [471.5, 875.0]), p< 0.001. Patients on ticagrelor had on average 255.9 (95% CI: [-335.4, -176.4]) fewer total procedural HITS than those on clopidogrel. This protective effect was not associated with an increase in complications.

Introduction: Although data up to 2016 suggests that mortality from cardiovascular disease (CVD) in the US appears to be on a decreasing trend, there is evidence of stagnation in progress among young adults, especially women. Sex differences in the trends for control of CVD risk factors have been described, but the temporal trends in the age at which CVD and its risk factors are diagnosed in the US, and whether there are sex-specific differences in these trends is unknown. Methods: We used the Medical Expenditure Panel Survey (MEPS) 2008-2017, a nationally representative sample of the US population. Individuals ≥18 years, with a diagnosis of hypercholesterolemia, hypertension, coronary heart disease (CHD) or stroke and reported the age at which these conditions were diagnosed were included. The trend in the age at diagnosis was calculated from the annual change overall and by sex, using a linear regression model. Results: There were 100,709 participants (50.2% women), representing 91.9 million US adults with the above disease conditions. The mean age at diagnosis of CVD risk factors has decreased over time, with steeper declines among women [(Hypercholesterolemia: women - annual decrease of 0.31 years, men-annual decrease of 0.24 years, all Ps Conclusion: The decreasing trend in the age at diagnosis for CVD and its risk factors in the US appears to be more pronounced among women. While earlier identification of CVD risk factors may provide an opportunity to initiate preventive treatment, younger age at diagnosis of CVD highlights the need for the prevention of CVD at the earliest opportunity and sex-specific interventions may be needed.

Introduction: Elevated Lipoprotein(a) [Lp(a)] is associated with an increased risk of coronary heart disease (CHD). Although Lp(a) is mostly heritable, and controlled by the apo(a) gene, acute increases are described in small studies following acute coronary syndrome (ACS). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition modestly reduces Lp(a) in people with stable CHD but its effects during the early phase of an ACS are unknown. Hypothesis: Early administration of a PCSK9 inhibitor prevents a rise in Lp(a) following an ACS/NSTEMI. Methods: Participants from the EVACS trial (Evolocumab in Acute Coronary Syndrome; NCT03515304), all with a NSTEMI and a troponin-I of > 5 ng/ml were randomized to placebo or to evolocumab. Serum Lp(a) was obtained at study entry prior to study drug and at 30 days. Normally distributed data were summarized using means and standard deviations and non-normally distributed data using medians and interquartile ranges. Results: Fifty-six participants were randomized to placebo (27) or to evolocumab (29). Mean age was 55±13 years, 41% were women and 27% were African American. The Scatterplots (Fig.1) demonstrate for those with a baseline Lp(a) of ≤75 nmol/L (the previously described optimal level) there was no increase in Lp(a) over the 30-day study period in either group. However, for those with a baseline Lp(a) of >75 nmol/L there was a significant increase in the placebo group (Panel A), from a baseline of 176.5 nmol/L [131.5, 245.0] to 266 nmol/L [195.8, 302.5] at 30 days, p=0.02, but no increase in the evolocumab group (Panel B; baseline of 142 nmol/L [93, 177] to 137 nmol/L [96.8, 178.3], p=NS). The baseline values of those with Lp(a) of >75 nmol/L did not differ between the groups; at 30 days, however, Lp(a) was higher in the placebo than in the evolocumab group (p=0.02; Panel C). Conclusions: Early administration of evolocumab prevents the acute increase in Lp(a) in those with a baseline Lp(a) of over 75 nmol/L following an ACS/NSTEMI.

Inflammation constitutes a complex, highly conserved cascade of molecular and cellular events. Inflammation has been labeled as "the fire within," is highly regulated, and is critical to host defense and tissue repair. In general, inflammation is beneficial and has evolved to promote survival. However, inflammation can also be maladaptive when chronically activated and sustained, leading to progressive tissue injury and reduced survival. Examples of a maladaptive response include rheumatologic disease and atherosclerosis. Despite evidence gathered by Virchow over 100 years ago showing that inflammatory white cells play a role in atherogenesis, atherosclerosis was until recently viewed as a disease of passive cholesterol accumulation in the subendothelial space. This view has been supplanted by considerable basic scientific and clinical evidence demonstrating that every step of atherogenesis, from the development of endothelial cell dysfunction to foam cell formation, plaque formation and progression, and ultimately plaque rupture stemming from architectural instability, is driven by the cytokines, interleukins, and cellular constituents of the inflammatory response. Herein we provide an overview of the role of inflammation in atherosclerotic cardiovascular disease, discuss the predictive value of various biomarkers involved in inflammation, and summarize recent clinical trials that evaluated the capacity of various pharmacologic interventions to attenuate the intensity of inflammation and impact risk for acute cardiovascular events.

Background Whether right and left heart hemodynamics are associated with myocardial injury in the acute respiratory distress syndrome (ARDS) is not known. Methods We performed a retrospective cohort study of subjects who had right heart catheterization within the ALVEOLI trial and Fluid and Catheter Treatment Trial. Myocardial injury was assessed using a highly sensitive troponin assay (hsTn; Abbot ARCHITECT). Hemodynamic variables included right atrial pressure, pulmonary artery wedge pressure, cardiac index and stroke volume, pulmonary vascular resistance, pulmonary arterial compliance, and pulmonary effective arterial elastance. We performed linear, logistic, and Cox regression to determine the association of hemodynamic variables with myocardial injury and to determine if hemodynamics mediated the association between myocardial injury and death. Results Among 252 ARDS patients, median day 0 troponin was 65.4 (13.8–397.8) ng/L. Lower cardiac index (β −0.23 SE 0.10; P

Background/Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) is well recognized for its importance in cholesterol metabolism. Elevated levels are associated with increased cardiovascular risk and inhibition with PCSK9 antibodies lowers cardiovascular events in patients with known coronary disease. PCSK9 levels are also elevated in people living with HIV (PLWH), and we previously reported that increased PCSK9 in PLWH is associated with impaired coronary endothelial function (CEF), a major driver for the development, progression, and clinical manifestations of coronary artery disease. Purpose Here we investigate the hypothesis that PCSK9 inhibition improves impaired CEF in PLWH and in patients with dyslipidemia (DL). Methods Cine 3T MRI was used to noninvasively measure CEF, assessed as the change in coronary cross-sectional area (CSA) from rest to isometric handgrip exercise (IHE), a known endothelial-dependent vasodilator. Eight HIV+ subjects on stable highly active antiretroviral therapy and with undetectable HIV RNA (mean age 53±9 yrs, LDLC 98±18 mg/dL, 38% on statins) and ten patients with dyslipidemia (DL) without HIV receiving evolocumab for clinical reasons (mean age 56±10 yrs, LDLC 130±28 mg/dL, 50% on statins) underwent MRI studies before and six weeks following the initiation of evolocumab 420 mg. MRI readers were blinded to group and timepoint. MRI data are presented as mean±SD for % change rest vs IHE. Results Prior to evolucumab, resting CSA in the two groups did not differ and IHE did not induce normal coronary vasodilation in either group; mean stress-induced CSA changes were −2.1±6.4% in HIV (p=0.27) and −0.6±4.1% in DL (p=0.46). Notably, CEF significantly improved following six weeks of evolocumab with IHE-induced CSA changes of 7.6±5.7% (p=0.006) and 5.0±3.6% (p=0.002) in the HIV and DL groups, respectively. The %-LDLC reduction with evolocumab was profound and comparable in the HIV and DL groups, 73±5% and 60±6% (p=0.19 HIV vs. DL). There was no significant correlation between the extents of LDLC reduction and of CEF improvement in either of these modest sized groups. Conclusion PCSK9 inhibition with evolocumab significantly improves abnormal coronary endothelial function after only six weeks in HIV+ people with normal LDLC and in HIV- people with DL. To our knowledge, these data represent the earliest (6 weeks) evidence for improvement in human coronary artery health by PCSK9 inhibition. Acknowledgement/Funding Amgen provided the PCSK9 monoclonal antibody (evolocumab) for this study.

Aims The effect of therapeutic lowering of apolipoprotein B (apoB) on mortality and major adverse cardiovascular events is uncertain. It is also unclear whether these potential effects vary by different lipid-lowering strategies. Methods A total of 29 randomized controlled trials were selected using PubMed, Cochrane Library and EMBASE through 2018. We selected trials of therapies which ultimately clear apolipoprotein B particles by upregulating low-density lipoprotein receptor (LDL-R) expression (statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bile acid sequestrants) or therapies which reduce apolipoprotein B independent of LDL-R (cholesteryl ester transfer protein inhibitor, fibrates, niacin, omega-3 fatty acids) with sample size of ≥1000 patients and follow-up of ≥1 year. The meta-regression and meta-analyses were constructed using a random effects model. Results In 332,912 patients, meta-regression analyses showed relative risks of 0.95 for all-cause mortality (95% confidence interval 0.92–0.99) and 0.93 (0.88–0.98) for cardiovascular mortality for every 10 mg/dL decrease in apolipoprotein B by all interventions combined. Reduction in all-cause mortality was limited to statins (0.92 (0.86–0.98)). For MACE, the relative risk per 10 mg/dL reduction in apolipoprotein B was 0.93 (0.90–0.97) for all therapies combined, with both statin (0.88 (0.83–0.93)) and non-statin therapies (0.96 (0.94–0.99)). which clear apolipoprotein B by upregulating LDL-R showing significant reductions; whereas interventions which lower apolipoprotein B independent of LDL-R did not demonstrate this effect (1.02 (0.81–1.30)). Conclusion While both statin and established non-statin therapies (PCSK9 inhibitor and ezetimibe) reduced cardiovascular risk per decrease in apolipoprotein B, interventions which reduce apolipoprotein B independently of LDL-R were not associated with cardiovascular benefit.

Background It is estimated that less than 10% of cases of familial hypercholesterolemia (FH) in the United States have been diagnosed. Low rates of diagnosis may in part be attributable to affected patients not meeting the clinical diagnostic criteria of the Dutch Lipid Clinic Network (DLCN), Simon Broome, or US MEDPED diagnostic criteria. Objective The objective of this study was to assess the utility of incorporating genetic testing into a patient's evaluation for FH. Methods We retrospectively reviewed patients seen in the Advanced Lipids Disorders Clinic at Johns Hopkins Hospital between January 2015 and May 2018. Between June 2018 and December 2018, patients were consented to a prospective registry. DLCN, Simon Broome, and MEDPED criteria were applied to each patient, before and after genetic testing. Genetic testing included sequencing and deletion duplication analysis of four genes (LDLR, PCSK9, APOB, and LDLRAP1). Results The retrospective review and prospective study identified 135 adult probands who were seen in our clinic for evaluation of heterozygous FH. Twenty-nine individuals (21%) were heterozygous for a pathogenic or likely pathogenic monogenic variant. Before genetic testing, using the DLCN criteria, 35 (26%) individuals met criteria for a definite diagnosis of FH. Thirty patients (22%) met criteria using Simon Broome, and 29 (21%) patients met criteria using US MEDPED before genetic analysis. Depending on the criteria, incorporating genetic testing identified 11–14 additional patients with FH. Conclusions Incorporating genetic testing diagnosed almost 50% more patients with definite FH in comparison to classification solely on clinical grounds.

In reply : The letter from Drs. Araj and Luna regarding the utilization of intracardiac echocardiography (ICE) raises several interesting points. Indeed, for patients with infective endocarditis with inconclusive findings on transthoracic echocardiography (TTE) and contraindications to use of

About 1% of all outpatient visits are related to chest pain, and of these patients, 1.5% will have unstable angina or an acute myocardial infarction. Chest pain represents a wide spectrum of disease, from benign to life-threatening conditions. The primary care provider has an essential role in the initial evaluation of such patients with a focus on a quick rule out of potential life-threatening conditions and further appropriately triaging the patient. The evaluation of patients with stable symptoms should focus on risk assessment for coronary artery disease and appropriate downstream noninvasive stress testing.

We describe the case of a 67-year-old man presenting with ventricular tachycardia (VT) and systolic heart failure secondary to a left adrenal phaeochromocytoma. After treatment with amiodarone, the patient's VT resolved. However, his course was complicated by femoral deep venous thrombosis secondary to an incidentally discovered dedifferentiated liposarcoma of the thigh, for which he was prescribed a course of enoxaparin. The patient was discharged with plans for adrenalectomy following achievement of sufficient preoperative heart rate and blood pressure control with alpha-adrenergic receptor blockade, but re-presented to an outside facility in haemorrhagic shock, where he ultimately expired. Autopsy determined his death to be caused by spontaneous haemorrhage of the phaeochromocytoma. Cardiac manifestations, complications and oncological associations of phaeochromocytoma are discussed.

Objective— KLF15 (Kruppel-like factor 15) has recently been shown to suppress activation of proinflammatory processes that contribute to atherogenesis in vascular smooth muscle, however, the role of KLF15 in vascular endothelial function is unknown. Arginase mediates inflammatory vasculopathy and vascular injury in pulmonary hypertension. Here, we tested the hypothesis that KLF15 is a critical regulator of hypoxia-induced Arg2 (arginase 2) transcription in human pulmonary microvascular endothelial cells (HPMEC). Approach and Results— Quiescent HPMEC express ample amounts of full-length KLF15. HPMECs exposed to 24 hours of hypoxia exhibited a marked decrease in KLF15 protein levels and a reciprocal increase in Arg2 protein and mRNA. Chromatin immunoprecipitation indicated direct binding of KLF15 to the Arg2 promoter, which was relieved with HPMEC exposure to hypoxia. Furthermore, overexpression of KLF15 in HPMEC reversed hypoxia-induced augmentation of Arg2 abundance and arginase activity and rescued nitric oxide (NO) production. Ectopic KLF15 also reversed hypoxia-induced endothelium-mediated vasodilatation in isolated rat pulmonary artery rings. Mechanisms by which hypoxia regulates KLF15 abundance, stability, and compartmentalization to the nucleus in HPMEC were then investigated. Hypoxia triggered deSUMOylation of KLF15 by SENP1 (sentrin-specific protease 1), and translocation of KLF15 from nucleus to cytoplasm. Conclusions— KLF15 is a critical regulator of pulmonary endothelial homeostasis via repression of endothelial Arg2 expression. KLF15 abundance and nuclear compartmentalization are regulated by SUMOylation/deSUMOylation—a hypoxia-sensitive process that is controlled by SENP1. Strategies including overexpression of KLF15 or inhibition of SENP1 may represent novel therapeutic targets for pulmonary hypertension.

We report the case of a 67-year-old patient who presented with anginal symptoms to the hospital. Computed tomographic angiography, to rule out a pulmonary embolism, showed a left ventricular apical outpouching. The patient underwent further imaging modalities, including contrast echocardiography (TTE) and cardiovascular magnetic resonance imaging (CMR), which were suggestive of a true left ventricular aneurysm (LVA). The absence of obstructive coronary artery disease on coronary angiography, absence of late enhancement on the CMR, and ultimately the intraoperative findings during surgical resection of the aneurysm, were strong indicators of a non-ischemic etiology of the patient's LVA. Additionally, the patient denied any previous history of cardiac instrumentation to rule out iatrogenic causes of LVA and congenital causes were excluded by a previous echocardiogram. Finally, history and presenting electrocardiogram did not reveal any other underlying obvious causes for the LVA. Excluding all common causes for the LVA an idiopathic cause seemed most likely.

Transcatheter aortic valve replacement (TAVR) via the transfemoral (TF), transapical (TA), or even the transaortic (TAO) approach in high-risk or inoperable patients is quickly becoming a safe and effective modality for the treatment of symptomatic severe aortic stenosis (AS). However, in this selected group of patients, those with anatomical or physiologic constraints preventing TF, TA, and conventional TAO TAVR, alternative sites of access must be explored. Here, we report a successful TAVR in an inoperable patient with severe AS using a distal abdominal TAO approach via a synthetic graft-conduit.