Scott M. Lilly

Resistive and Pulsatile Arterial Load as Predictors of Left Ventricular Mass and Geometry: The Multi-Ethnic Study of Atherosclerosis

Arterial load is composed of resistive and various pulsatile components, but their relative contributions to left ventricular (LV) remodeling in the general population are unknown. We studied 4145 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, who underwent cardiac MRI and radial arterial tonometry. We computed systemic vascular resistance (SVR=mean arterial pressure/cardiac output) and indices of pulsatile load including total arterial compliance (TAC, approximated as stroke volume/central pulse pressure), forward wave amplitude (Pf), and reflected wave amplitude (Pb). TAC and SVR were adjusted for body surface area to allow for appropriate sex comparisons. We performed allometric adjustment of LV mass for body size and sex and computed standardized regression coefficients (&bgr;) for each measure of arterial load. In multivariable regression models that adjusted for multiple confounders, SVR (&bgr;=0.08; P<0.001), TAC (&bgr;=0.44; P<0.001), Pb (&bgr;=0.73; P<0.001), and Pf (&bgr;=−0.23; P=0.001) were significant independent predictors of LV mass. Conversely, TAC (&bgr;=−0.43; P<0.001), SVR (&bgr;=0.22; P<0.001), and Pf (&bgr;=−0.18; P=0.004) were independently associated with the LV wall/LV cavity volume ratio. Women demonstrated greater pulsatile load than men, as evidenced by a lower indexed TAC (0.89 versus 1.04 mL/mm Hg per square meter; P<0.0001), whereas men demonstrated a higher indexed SVR (34.0 versus 32.8 Wood Units×m2; P<0.0001). In conclusion, various components of arterial load differentially associate with LV hypertrophy and concentric remodeling. Women demonstrated greater pulsatile load than men. For both LV mass and the LV wall/LV cavity volume ratio, the loading sequence (ie, early load versus late load) is an important determinant of LV response to arterial load.

Reflection Magnitude as a Predictor of Mortality The Multi-Ethnic Study of Atherosclerosis

Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P=0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P=0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P=0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P=0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P=0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis.Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P =0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P =0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P =0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P =0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P =0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis. # Novelty and Significance {#article-title-33}

Reflection Magnitude as a Predictor of MortalityNovelty and Significance: The Multi-Ethnic Study of Atherosclerosis

Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P=0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P=0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P=0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P=0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P=0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis.Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P =0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P =0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P =0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P =0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P =0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis. # Novelty and Significance {#article-title-33}

Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): A Phase 2, Randomized, Sham-Controlled Trial

Background: In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%. Methods: REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise. Results: A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group (P=0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group (P=1.0). Conclusions: In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02600234.

New targets and emerging therapies for reducing LDL cholesterol.

Purpose of review Effective therapies for lowering LDL-cholesterol reduce the incidence of cardiovascular disease and provide associated decreases in morbidity and mortality. Progress in our understanding of metabolism and innovations in drug design have jointly identified promising new drug targets and alternative approaches to old targets. This review focuses on the mechanism, safety and efficacy of emerging LDL-cholesterol lowering therapies. Recent findings Decreasing apolipoprotein B expression or preventing the formation of a stable lipoprotein structure by inhibiting microsomal triglyceride transfer protein attenuates the secretion of atherogenic lipoproteins containing apolipoprotein B into the plasma. Increases in LDL receptor-mediated cholesterol clearance occur when hepatic cholesterol stores are reduced secondary to inhibition of squalene synthase or LDL receptor degradation is disrupted by reduced activity of proprotein convertase subtilisin kexin type 9. Each of these developing therapies demonstrably reduces LDL-cholesterol levels. Summary The emergence of modalities that act in series and in parallel with available agents may allow more effective LDL-cholesterol lowering in those patients intolerant of current therapy, and may permit decremental reductions in LDL-cholesterol for those unable to achieve aggressive LDL-cholesterol goals using existing agents.

Extended-release Niacin Acutely Suppresses Postprandial Triglyceridemia

OBJECTIVE Postprandial triglyceridemia predicts cardiovascular events. Niacin might lower postprandial triglycerides by restricting free fatty acids. Immediate-release niacin reduced postprandial triglycerides, but extended-release niacin failed to do so when dosed the night before a fat challenge. The study aims were to determine whether extended-release niacin dosed before a fat challenge suppresses postprandial triglycerides and whether postprandial triglycerides are related to free fatty acid restriction. METHODS A double-blinded, placebo-controlled, random-order crossover experiment was performed, in which healthy volunteers took 2 g extended-release niacin or placebo 1 hour before heavy cream. We sampled blood over 12 hours and report triglycerides and free fatty acid as means ± standard deviation for incremental area under the curve (AUC) and nadir. RESULTS By combining 43 fat challenges from 22 subjects, postprandial triglycerides incremental AUC was +312 ± 200 mg/dL*h on placebo versus +199 ± 200 mg/dL*h on extended-release niacin (33% decrease, P=.02). The incremental nadir for free fatty acid was -0.07 ± 0.15 mmol/L on placebo versus -0.27 ± 0.13 mmol/L on extended-release niacin (P<.0001), and free fatty acid incremental AUC decreased from +2.9 ± 1.5 mmol/L*h to +1.5 ± 1.5 mmol/L*h on extended-release niacin (20% decrease, P=.0015). The incremental AUC for triglycerides was strongly related to the post-dose decrease in free fatty acid (r = +0.58, P=.0007). CONCLUSIONS Given right before a fat meal, even a single dose of extended-release niacin suppresses postprandial triglyceridemia. This establishes that postprandial triglycerides suppression is an acute pharmacodynamic effect of extended-release niacin, probably the result of marked free fatty acid restriction. Further study is warranted to determine whether mealtime dosing would augment the clinical efficacy of extended-release niacin therapy.

Cardiopulmonary bypass and intra‐aortic balloon pump use is associated with higher short and long term mortality after transcatheter aortic valve replacement: A PARTNER trial substudy

Transcatheter aortic valve replacement (TAVR) with the balloon‐expandable Sapien transcatheter heart valve improves survival compared to standard therapy in patients with severe aortic stenosis (AS) and is noninferior to surgical aortic valve replacement (AVR) in patients at high operative risk. Nonetheless, a significant proportion of patients may require pre‐emptive or emergent support with cardiopulmonary bypass (CPB) and/or intra‐aortic balloon pump (IABP) during TAVR due to pre‐existing comorbid conditions or as a result of procedural complications. Objectives: We hypothesized that patients who required CPB or IABP would have increased periprocedural complications and reduced long‐term survival. In addition, we sought to determine whether preprocedural variables could predict the need for CPB and IABP. Methods: The study population included 2,525 patients in the PARTNER Trial (Cohort A and B) and the continuing access registry (CAR). Patients that received CPB or IABP were compared to patients that did not receive either, and then further divided into those that received support pre‐TAVR and those that were placed on support emergently. Results: One‐hundred sixty‐three patients (6.5%) were placed on CPB and/or IABP. The use of CPB or IABP was associated with higher 1 year mortality (49.1% vs. 21.6%, P < 0.001). In multivariable analysis, utilization of CPB or IABP was an independent predictor of 30 day (HR 6.95) and 1‐year (HR 2.56) mortality. Although mortality was highest in emergent cases, mortality was also greater in planned CPB and IABP cases compared with non‐CPB/IABP cases (53.3% and 40.3% vs. 21.6%, P < 0.001). Conclusions: These findings indicate that CPB and IABP use in TAVR portends a poor prognosis and its utilization, particularly in the setting of pre‐emptive use, needs reconsideration.

Non-compressible arterial disease and the risk of coronary calcification in type-2 diabetes

OBJECTIVE Ankle-brachial index (ABI) screening is recommended for the detection of asymptomatic peripheral arterial disease (PAD) in at-risk populations, including diabetics. A low ABI identifies obstructive lower extremity vascular disease and predicts CVD events and increased mortality. A high ABI represents non-compressible arterial disease (NCAD), and is also associated with increased mortality and vascular events. Our objective is to investigate whether low and high ABI have distinct patterns of association with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis in individuals with type-II diabetes mellitus. METHODS The Penn Diabetes Heart Study (PDHS) is a prospective observational cohort of diabetic individuals without clinically evident CVD. Multivariate logistic and Tobit linear regression were used to compare CVD risk factors and coronary artery (CAC) among 1863 subjects with PAD (ABI ≤ 0.9), NCAD (ABI ≥ 1.4 or non-compressible) or normal ABI (0.91-1.39). RESULTS Compared to those with normal ABI, PAD was associated with smoking, obesity, and lower HDL-c; while diabetes duration and reduced renal function were associated with NCAD. Both PAD and NCAD were independently associated with increased CAC compared to those with normal ABI, and these relationships were not attenuated in multiply adjusted models. CONCLUSION NCAD bears a distinct relationship to traditional CVD risk factors among diabetics, though like PAD is independently associated with increased CAC. These findings support the recognition of NCAD as a high-risk phenotype and provide additional relevance to ABI screening in diabetics.

Personalized vascular medicine: Individualizing drug therapy

Personalized medicine refers to the application of an individual’s biological fingerprint – the comprehensive dataset of unique biological information – to optimize medical care. While the principle itself is straightforward, its implementation remains challenging. Advances in pharmacogenomics as well as functional assays of vascular biology now permit improved characterization of an individual’s response to medical therapy for vascular disease. This review describes novel strategies designed to permit tailoring of four major pharmacotherapeutic drug classes within vascular medicine: antiplatelet therapy, antihypertensive therapy, lipid-lowering therapy, and antithrombotic therapy. Translation to routine clinical practice awaits the results of ongoing randomized clinical trials comparing personalized approaches with standard of care management.

An In-Vitro Evaluation of Turbulence after Transcatheter Aortic Valve Implantation

Background This study aimed at assessment of post‐transcatheter aortic valve (TAV) replacement hemodynamics and turbulence when a same‐size SAPIEN 3 (Edwards Lifesciences Corp, Irvine, Calif) and Medtronic Evolut (Minneapolis, Minn) were implanted in a rigid aortic root with physiological dimensions and in a representative root with calcific leaflets obtained from patient computed tomography scans. Methods TAV hemodynamics were studied by placing a SAPIEN 3 26‐mm and an Evolut 26‐mm in rigid aortic roots and representative root with calcific leaflets under physiological conditions. Hemodynamics were assessed using high‐fidelity particle image velocimetry and high‐speed imaging. Transvalvular pressure gradients (PGs), pinwheeling indices, and Reynolds shear stress (RSS) were calculated. Results (1) PGs obtained with the Evolut and the SAPIEN 3 were comparable among the different models (10.5 ± 0.15 mm Hg vs 7.76 ± 0.083 mm Hg in the rigid model along with 13.9 ± 0.19 mm Hg vs 5.0 ± 0.09 mm Hg in representative root with calcific leaflets obtained from patient computed tomography scans respectively); (2) more pinwheeling was found in the SAPIEN 3 than the Evolut (0.231 ± 0.057 vs 0.201 ± 0.05 in the representative root with calcific leaflets and 0.366 ± 0.067 vs 0.122 ± 0.045 in the rigid model); (3) higher rates of RSS were found in the Evolut (161.27 ± 3.45 vs 122.84 ± 1.76 Pa in representative root with calcific leaflets and 337.22 ± 7.05 vs 157.91 ± 1.80 Pa in rigid models). More lateral fluctuations were found in representative root with calcific leaflets. Conclusions (1) Comparable PGs were found among the TAVs in different models; (2) pinwheeling indices were found to be different between both TAVs; (3) turbulence patterns among both TAVs translated according to RSS were different. Rigid aortic models yield more conservative estimates of turbulence; (4) both TAVs exhibit peak maximal RSS that exceeds platelet activation 100 Pa threshold limit.