Association of Aortic Stiffness and Pressure Pulsatility With Noninvasive Estimates of Hepatic Steatosis and Fibrosis: The Framingham Heart Study.

BACKGROUND: Arterial stiffening may contribute to the pathogenesis of metabolic dysfunction-associated steatotic liver disease. We aimed to assess relations of vascular hemodynamic measures with measures of hepatic steatosis and fibrosis in the community. METHODS: Our sample was drawn from the Framingham Offspring, New Offspring Spouse, Third Generation, Omni-1, and Omni-2 cohorts (N=3875; mean age, 56 years; 54% women). We used vibration-controlled transient elastography to assess controlled attenuation parameter and liver stiffness measurements as measures of liver steatosis and liver fibrosis, respectively. We assessed noninvasive vascular hemodynamics using arterial tonometry. We assessed cross-sectional relations of vascular hemodynamic measures with continuous and dichotomous measures of hepatic steatosis and fibrosis using multivariable linear and logistic regression. RESULTS: In multivariable models adjusting for cardiometabolic risk factors, higher carotid-femoral pulse wave velocity (estimated ß per SD, 0.05 [95% CI, 0.01-0.09]; P=0.003), but not forward pressure wave amplitude and central pulse pressure, was associated with more liver steatosis (higher controlled attenuation parameter). Additionally, higher carotid-femoral pulse wave velocity (ß=0.11 [95% CI, 0.07-0.15]; P<0.001), forward pressure wave amplitude (ß=0.05 [95% CI, 0.01-0.09]; P=0.01), and central pulse pressure (ß=0.05 [95% CI, 0.01-0.09]; P=0.01) were associated with more hepatic fibrosis (higher liver stiffness measurement). Associations were more prominent among men and among participants with obesity, diabetes, and metabolic syndrome (interaction P values, <0.001-0.04). Higher carotid-femoral pulse wave velocity, but not forward pressure wave amplitude and central pulse pressure, was associated with higher odds of hepatic steatosis (odds ratio, 1.16 [95% CI, 1.02-1.31]; P=0.02) and fibrosis (odds ratio, 1.40 [95% CI, 1.19-1.64]; P<0.001). CONCLUSIONS: Elevated aortic stiffness and pressure pulsatility may contribute to hepatic steatosis and fibrosis.

Longitudinal Hemodynamic Correlates of and Sex Differences in the Evolution of Blood Pressure Across the Adult Lifespan: The Framingham Heart Study.

Background Systolic blood pressure increases with age after midlife, particularly in women, and contributes to development of wide pulse pressure hypertension in middle-aged and older adults. Relative contributions of aortic stiffness and premature wave reflection to increases in pulse pressure remain controversial. Methods and Results We evaluated visit-specific values and change in key correlates of pulse pressure, aortic characteristic impedance, forward and backward wave amplitude, and global reflection coefficient, at 3 sequential examinations of the Framingham Generation 3 (N=4082), Omni-2 (N=410), and New Offspring Spouse (N=103) cohorts (53% women). Data were analyzed using repeated-measures linear mixed models adjusted for age, sex, and risk factor exposures. Pulse pressure increased markedly with age after midlife (age and age-squared terms, P<0.0001), particularly in women (age slope 3.1±0.2 mm Hg/decade higher in women, P<0.0001). In sex-specific models, change in pulse pressure was closely related (all P<0.0001) to baseline (6.7±0.2 and 7.3±0.2 mm Hg/SD in men and women, respectively) and change (11.8±0.1 and 11.7±0.1 mm Hg/SD) in forward wave amplitude, whereas relations with baseline (2.1±0.15 and 2.0±0.14 mm Hg/SD) and change (4.0±0.13 and 3.4±0.11 mm Hg/SD) in global reflection coefficient were weaker. Global reflection coefficient fell as aortic characteristic impedance increased (P<0.0001), consistent with the hypothesis that impedance matching reduces relative wave reflection in the arterial system. Conclusions Proximal aortic stiffening, as assessed by higher aortic characteristic impedance and larger forward wave amplitude, is strongly associated with longitudinal increase in pulse pressure, especially in women, whereas wave reflection has more modest relations.

Relations of postural change in blood pressure with hypertension-mediated organ damage in middle-aged adults of the Framingham heart study: A cross-sectional study.

Background: Dysregulation of compensatory mechanisms to regulate blood pressure (BP) upon postural change is a phenotype of BP variability and an emerging risk factor for cardiovascular outcomes. Materials and methods: We assessed postural change in BP (starting 2 min after standing from a supine position), carotid-femoral pulse wave velocity (cfPWV), and markers of hypertension-mediated organ damage (HMOD) in the heart, kidney, and brain in Framingham Third Generation, Omni-2, and New Offspring Spouse Cohort participants. We related vascular measures (postural change in BP measures and cfPWV) with HMOD in 3,495 participants (mean age 47 years, 53% women) using multivariable logistic and linear regression models. Results: In multivariable-adjusted models, we did not observe significant associations of vascular measures with presence of left ventricular hypertrophy, albuminuria, covert brain infarcts, or white matter hyperintensities (Bonferroni-adjusted P-values > 0.05/20 > 0.0025). In multivariable models, greater cfPWV (est. ß = 0.11 ± 0.03; P < 0.001), but not postural change in BP measures (Bonferroni-adjusted P-values > 0.05/20 > 0.0025), was associated with higher white matter free water using brain magnetic resonance imaging. In multivariable models, greater postural change in pulse pressure was associated with higher urinary albumin-creatinine ratio (est. ß = 0.07 ± 0.02; P < 0.001). No other postural change in BP measure was associated with urinary albumin-creatinine ratio (Bonferroni-adjusted P-values > 0.05/20 > 0.0025). In sex-specific analyses, higher cfPWV was associated with higher urinary albumin-creatinine ratio in men (est. ß: 0.11 ± 0.04; P = 0.002) but not in women (est. ß: 0.03 ± 0.03; P = 0.44). We also observed marginal to strong effect modification by above vs. at/below median postural change in BP for the association of cfPWV with urinary albumin-creatinine ratio (Bonferroni-adjusted interaction P < 0.001-0.01). Vascular measures were not related to left ventricular mass index or fractional anisotropy (Bonferroni-adjusted P-values > 0.05/20 > 0.0025). Conclusion: Baroreflex dysfunction is associated with greater subclinical kidney damage. Additionally, relations of higher aortic stiffness with greater kidney damage may be modified by associated baroreflex dysregulation.

Controlling the shape and topology of two-component colloidal membranes.

Changes in the geometry and topology of self-assembled membranes underlie diverse processes across cellular biology and engineering. Similar to lipid bilayers, monolayer colloidal membranes have in-plane fluid-like dynamics and out-of-plane bending elasticity. Their open edges and micrometer-length scale provide a tractable system to study the equilibrium energetics and dynamic pathways of membrane assembly and reconfiguration. Here, we find that doping colloidal membranes with short miscible rods transforms disk-shaped membranes into saddle-shaped surfaces with complex edge structures. The saddle-shaped membranes are well approximated by Enneper's minimal surfaces. Theoretical modeling demonstrates that their formation is driven by increasing the positive Gaussian modulus, which in turn, is controlled by the fraction of short rods. Further coalescence of saddle-shaped surfaces leads to diverse topologically distinct structures, including shapes similar to catenoids, trinoids, four-noids, and higher-order structures. At long timescales, we observe the formation of a system-spanning, sponge-like phase. The unique features of colloidal membranes reveal the topological transformations that accompany coalescence pathways in real time. We enhance the functionality of these membranes by making their shape responsive to external stimuli. Our results demonstrate a pathway toward control of thin elastic sheets' shape and topology-a pathway driven by the emergent elasticity induced by compositional heterogeneity.

Association of Aortic Stiffness and Pressure Pulsatility With Global Amyloid-ß and Regional Tau Burden Among Framingham Heart Study Participants Without Dementia.

Importance: Aortic stiffness is associated with clinical hallmarks of Alzheimer disease and related dementias and could be a modifiable target for disease prevention. Objective: To assess associations of aortic stiffness and pressure pulsatility with global amyloid-ß plaques and regional tau burden in the brain of middle-aged and older adults without dementia. Design, Setting, and Participants: The sample for this cross-sectional study was drawn from the Framingham Heart Study Third Generation Cohort at examination 3 (N = 3171; 2016-2019), of whom 3092 successfully underwent comprehensive hemodynamic evaluations. In a supplemental visit (2015-2021), a subset of 270 participants without dementia who represented the spectrum of vascular risk also underwent positron emission tomography. Thirteen participants were excluded for missing covariate data. The final sample size was 257 participants. Exposures: Three measures of aortic stiffness and pressure pulsatility (carotid-femoral pulse wave velocity, central pulse pressure [CPP], and forward wave amplitude [FWA]) were evaluated using arterial tonometry. Main Outcomes and Measures: Global amyloid-ß plaques and regional tau were assessed using 11C-Pittsburgh compound B and 18F-flortaucipir positron emission tomography tracers, respectively. Results: The mean (SD) age of the 257 participants was 54 (8) years, and 126 were women (49%). All participants were White Western European race. In multivariable models, higher CPP (ß per SD = 0.17; 95% CI, 0.00-0.35; P = .045) and FWA (ß per SD = 0.16; 95% CI, 0.00-0.31; P = .04) were associated with greater entorhinal tau burden. In similar models, higher CPP (ß per SD = 0.19; 95% CI, 0.02-0.36; P = .03) and FWA (ß per SD = 0.17; 95% CI, 0.01-0.32; P = .03) were associated with greater rhinal tau burden. Aortic stiffness and pressure pulsatility measures were not associated with amygdala, inferior temporal, precuneus tau burden, or global amyloid-ß plaques. Associations for entorhinal and rhinal tau outcomes were more prominent in older participants (≥60 years). For example, higher levels of all aortic stiffness and pressure pulsatility measures (ß per SD = 0.40-0.92; P = .001-.02) were associated with higher entorhinal tau burden among older but not younger participants in stratified analyses. Conclusions and Relevance: In this cross-sectional study, abnormal central vascular hemodynamics were associated with higher tau burden in specific brain regions. Findings suggest that aortic stiffness, which is potentially modifiable, may be a probable independent target for prevention of tau-related pathologies.

A Retrospective Study of Psychotropic Drug Use and Prescription Opioid Initiation Among Older Adults.

Individuals with mental health problems may be more vulnerable to using prescription opioids than their counterparts. Therefore, the main objective of this study was to assess the initiation of prescription opioids in older adults who used psychotropic drugs compared with those who did not. The authors used a retrospective cohort design and included a sample of older adults enrolled in Pennsylvania's Pharmaceutical Assistance Contract for the Elderly program who did not use prescription opioids in 2013. Using pharmacy claims, patients who used anxiolytics/sedatives/hypnotics (n = 13,512) or antidepressants (n = 17,492) between October and December 2013 were identified and compared with those who did not use anxiolytics/sedatives/hypnotics (n = 114,091) or antidepressants (n = 110,111) during that period, to determine the incidence of prescription opioid use in 2014. Chi-square tests and multivariate logistic regressions were performed for analyses. Compared with patients who did not use anxiolytics/sedatives/hypnotics, those who used were more likely to initiate prescription opioids (15.0% versus 22.0%, P < .0001). Similarly, compared with patients who did not use antidepressants, those who used were more likely to initiate prescription opioids (14.7% versus 21.9%, P < .0001). Multivariate logistic regression indicated that the odds of prescription opioid initiation increased with anxiolytic/sedative/hypnotic use by 44% (AOR = 1.44; P < .0001) and antidepressant use by 48% (AOR = 1.48; P < .0001) among older adults after adjusting for potential confounding variables. Results showed that prescription opioid initiation is associated with prior anxiolytic/sedative/hypnotic or antidepressant use among older adults. Patients with mental health problems should also be queried about pain experiences for effective treatment.

Kidney Function and Aortic Stiffness, Pulsatility, and Endothelial Function in African Americans: The Jackson Heart Study.

RATIONALE & OBJECTIVE: The relation of vascular stiffness, endothelial function, and kidney function is incompletely elucidated in African Americans. Our hypothesis was that increased vascular stiffness and endothelial dysfunction are associated with low estimated glomerular filtration rate (eGFR) and albuminuria in African Americans. STUDY DESIGN: Cross-sectional cohort analysis of data from the Jackson Heart Study. SETTINGS & PATIENTS: 2,244 Jackson Heart Study participants (2012-2017 after Exam 3) who had undergone noninvasive hemodynamic assessment using arterial tonometry. PREDICTORS: Baseline carotid-femoral pulse wave velocity, pulsatile hemodynamics forward wave amplitude, and hyperemic brachial artery flow were measured. Reduced eGFR was defined as eGFR between 15 and 60 mL/min/1.73 m2. OUTCOMES: Prevalent albuminuria, urinary albumin-creatinine ratio. ANALYTICAL APPROACH: 2-sample t test for continuous variables and χ2 test for categorical variables in addition to logistic and linear regression models to assess the risk for chronic kidney disease with each proposed hemodynamic variable. RESULTS: Among 2,244 participants, mean age was 66 ± 11 years and 64% were women. Reduced eGFR was present in 233 (10.4%), and elevated urinary albumin-creatinine ratio, in 232 (10.4%). In multivariable-adjusted analyses, higher carotid-femoral pulse wave velocity was associated with the presence of reduced eGFR (OR, 1.37 [95% CI, 1.08-1.75] per SD; P = 0.01) and with prevalent albuminuria (OR, 1.66 [95% CI, 1.32-2.11]; P < 0.001). Higher forward wave amplitude was significantly associated with prevalent albuminuria (OR, 1.37 [95% CI, 1.14-1.65]; P = 0.001). LIMITATIONS: Cross-sectional analyses cannot inform causality. CONCLUSIONS: Higher arterial stiffness and pulsatility are associated with higher odds of reduced eGFR in African Americans. Future studies should focus on whether improving arterial stiffness contributes to kidney protection in African Americans.

Discrepancies in Observed and Predicted Longitudinal Change in Central Hemodynamic Measures: The Framingham Heart Study.

[Figure: see text].

Axisymmetric membranes with edges under external force: buckling, minimal surfaces, and tethers.

We use theory and numerical computation to determine the shape of an axisymmetric fluid membrane with a resistance to bending and constant area. The membrane connects two rings in the classic geometry that produces a catenoidal shape in a soap film. In our problem, we find infinitely many branches of solutions for the shape and external force as functions of the separation of the rings, analogous to the infinite family of eigenmodes for the Euler buckling of a slender rod. Special attention is paid to the catenoid, which emerges as the shape of maximal allowable separation when the area is less than a critical area equal to the planar area enclosed by the two rings. A perturbation theory argument directly relates the tension of catenoidal membranes to the stability of catenoidal soap films in this regime. When the membrane area is larger than the critical area, we find additional cylindrical tether solutions to the shape equations at large ring separation, and that arbitrarily large ring separations are possible. These results apply for the case of vanishing Gaussian curvature modulus; when the Gaussian curvature modulus is nonzero and the area is below the critical area, the force and the membrane tension diverge as the ring separation approaches its maximum value. We also examine the stability of our shapes and analytically show that catenoidal membranes have markedly different stability properties than their soap film counterparts.

Digital Peripheral Arterial Tonometry and Cardiovascular Disease Events: The Framingham Heart Study.

Background and Purpose: Novel noninvasive measures of vascular function are emerging as subclinical markers for cardiovascular disease (CVD) and may be useful to predict CVD events. The purpose of our prospective study was to assess associations between digital peripheral arterial tonometry (PAT) measures and first-onset major CVD events in a sample of FHS (Framingham Heart Study) participants. Methods: Using a fingertip PAT device, we assessed pulse amplitude in Framingham Offspring and Third Generation participants (n=3865; mean age, 55±14 years; 52% women) at baseline and in 30-second intervals for 4 minutes during reactive hyperemia. The PAT ratio (relative hyperemia index) was calculated as the post-to-pre occlusion pulse signal ratio in the occluded arm, relative to the same ratio in the control (nonoccluded) arm, and corrected for baseline vascular tone. Baseline pulse amplitude and PAT ratio during hyperemia are measures of pressure pulsatility and microvascular function in the finger, respectively. We used Cox proportional hazards regression to relate PAT measures in the fingertip to incident CVD events. Results: During follow-up (median, 9.2 years; range, 0.04­10.0 years), 270 participants (7%) experienced new-onset CVD events (n=270). In multivariable models adjusted for cardiovascular risk factors, baseline pulse amplitude (hazard ratio [HR] per 1 SD, 1.04 [95% CI, 0.90­1.21]; P=0.57) and PAT ratio (HR, 0.95 [95% CI, 0.84­1.08]; P=0.43) were not significantly related to incident composite CVD events, including myocardial infarction or heart failure. However, higher PAT ratio (HR, 0.76 [95% CI, 0.61­0.94]; P=0.013), but not baseline pulse amplitude (HR, 1.15 [95% CI, 0.89­1.49]; P=0.29), was related to lower risk for incident stroke. In a sensitivity analysis by stroke subtype, higher PAT ratio was related to lower risk of incident ischemic stroke events (HR, 0.68 [95% CI, 0.53­0.86]; P=0.001). Conclusions: Novel digital PAT measures may represent a marker of stroke risk in the community.

Intrinsic Frequencies of Carotid Pressure Waveforms Predict Heart Failure Events: The Framingham Heart Study.

Intrinsic frequencies (IFs) derived from arterial waveforms are associated with cardiovascular performance, aging, and prevalent cardiovascular disease (CVD). However, prognostic value of these novel measures is unknown. We hypothesized that IFs are associated with incident CVD risk. Our sample was drawn from the Framingham Heart Study Original, Offspring, and Third Generation Cohorts and included participants free of CVD at baseline (N=4700; mean age 52 years, 55% women). We extracted 2 dominant frequencies directly from a series of carotid pressure waves: the IF of the coupled heart and vascular system during systole (ω1) and the IF of the decoupled vasculature during diastole (ω2). Total frequency variation (Δω) was defined as the difference between ω1 and ω2. We used Cox proportional hazards regression models to relate IFs to incident CVD events during a mean follow-up of 10.6 years. In multivariable models adjusted for CVD risk factors, higher ω1 (hazard ratio [HR], 1.14 [95% CI], 1.03-1.26]; P=0.01) and Δω (HR, 1.16 [95% CI, 1.03-1.30]; P=0.02) but lower ω2 (HR, 0.87 [95% CI, 0.77-0.99]; P=0.03) were associated with higher risk for incident composite CVD events. In similarly adjusted models, higher ω1 (HR, 1.23 [95% CI, 1.07-1.42]; P=0.004) and Δω (HR, 1.26 [95% CI, 1.05-1.50]; P=0.01) but lower ω2 (HR, 0.81 [95% CI, 0.66-0.99]; P=0.04) were associated with higher risk for incident heart failure. IFs were not significantly associated with incident myocardial infarction or stroke. Novel IFs may represent valuable markers of heart failure risk in the community.

Clinical Associations of Vascular Stiffness, Microvascular Dysfunction, and Prevalent Cardiovascular Disease in a Black Cohort: The Jackson Heart Study.

Background Measures of vascular dysfunction are related to adverse cardiovascular disease (CVD) outcomes in non-Hispanic, White populations; however, data from Black individuals are limited. We aimed to investigate the associations between novel hemodynamic measures and prevalent CVD in a sample of Black individuals. Methods and Results Among older Black participants of the Jackson Heart Study, we assessed noninvasive vascular hemodynamic measures using arterial tonometry and Doppler ultrasound. We assessed 5 measures of aortic stiffness and wave reflection (carotid-femoral pulse wave velocity, pulse wave velocity ratio, forward pressure wave amplitude, central pulse pressure, and augmentation index), and 2 measures of microvascular function (baseline and hyperemic brachial flow velocity). Using multivariable logistic regression models, we examined the relations between vascular hemodynamic measures and prevalent CVD. In models adjusted for traditional CVD risk factors, higher carotid-femoral pulse wave velocity (odds ratio [OR],1.25; 95% CI, 1.01-1.55; P=0.04), lower augmentation index (OR, 0.84; 95% CI, 0.70-0.99; P=0.05), and lower hyperemic brachial flow velocity (OR, 0.77; 95% CI, 0.65-0.90; P=0.001) were associated with higher odds of CVD. After further adjustment for hypertension treatment, lower augmentation index (OR, 0.84; 95% CI, 0.70-0.99; P=0.04) and hyperemic brachial flow velocity (OR, 0.79; 95% CI, 0.67-0.94; P=0.006), but not carotid-femoral pulse wave velocity (OR, 1.23; 95% CI, 0.99-1.051; P=0.06), were associated with higher odds of CVD. Conclusions In a sample of older Black individuals, more severe microvascular damage and aortic stiffness were associated with prevalent CVD. Further research on hemodynamic mechanisms that contribute to cardiovascular risk among older Black individuals is merited.

Force-Induced Formation of Twisted Chiral Ribbons.

We demonstrate that an achiral stretching force transforms disk-shaped colloidal membranes composed of chiral rods into twisted ribbons with handedness opposite the preferred twist of the rods. Using an experimental technique that enforces torque-free boundary conditions we simultaneously measure the force-extension curve and the ribbon shape. An effective theory that accounts for the membrane bending energy and uses geometric properties of the edge to model the internal liquid crystalline degrees of freedom explains both the measured force-extension curve and the force-induced twisted shape.

Association between psychotropic drug use and prescription opioid use among older adults.

This study investigated the association between psychotropic drug use and prescription opioid use/high dosage opioid use among older adults. A sample of 203,750 older adults enrolled in Pennsylvania's Pharmaceutical Assistance Contract for the Elderly (PACE) program during 2017 was evaluated for prescription opioid and psychotropic drug usage. High dosage opioid use was defined as using >90 morphine milligram equivalents (MME)/day for ≥90 consecutive days. Overall, 20.7% of enrollees filled opioid prescriptions, of which 1.4% used them at high dosages. Multivariate logistic regression indicated that the odds of prescription opioid use increased with anxiolytic/sedative/hypnotic use and antidepressant use. Moreover, high dosage opioid use was significantly associated with anxiolytic/sedative/hypnotic use, antidepressant use and other factors including being younger, male, white, and married but living separately, and having multiple opioid prescribers. Clinicians should carefully evaluate opioid use among older patients using anxiolytics or antidepressants to minimize risks for adverse consequences of opioids.

Short-Long Heart Rate Variation Increases Dispersion of Action Potential Duration in Long QT Type 2 Transgenic Rabbit Model.

The initiation of polymorphic ventricular tachycardia in long QT syndrome type 2 (LQT2) has been associated with a characteristic ECG pattern of short-long RR intervals. We hypothesize that this characteristic pattern increases APD dispersion in LQT2, thereby promoting arrhythmia. We investigated APD dispersion and its dependence on two previous cycle lengths (CLs) in transgenic rabbit models of LQT2, LQT1, and their littermate controls (LMC) using random stimulation protocols. The results show that the short-long RR pattern was associated with a larger APD dispersion in LQT2 but not in LQT1 rabbits. The multivariate analyses of APD as a function of two previous CLs (APDn = C + α1CLn-1 + α2CLn-2) showed that α1 (APD restitution slope) is largest and heterogeneous in LQT2 but uniform in LQT1, enhancing APD dispersion under long CLn-1 in LQT2. The α2 (short-term memory) was negative in LQT2 while positive in LQT1, and the spatial pattern of α1 was inversely correlated to α2 in LQT2, which explains why a short-long combination causes a larger APD dispersion in LQT2 but not in LQT1 rabbits. In conclusion, short-long RR pattern increased APD dispersion only in LQT2 rabbits through heterogeneous APD restitution and the short-term memory, underscoring the genotype-specific triggering of arrhythmias in LQT syndrome.

Enhancing Autophagy Diminishes Aberrant Ca2+ Homeostasis and Arrhythmogenesis in Aging Rabbit Hearts.

AIM: Aging in humans is associated with a 10-40-fold greater incidence of sudden cardiac death from malignant tachyarrhythmia. We have reported that thiol oxidation of ryanodine receptors (RyR2s) by mitochondria-derived reactive oxygen species (mito-ROS) contributes to defective Ca2+ homeostasis in cardiomyocytes (CMs) from aging rabbit hearts. However, mechanisms responsible for the increase in mito-ROS in the aging heart remain poorly understood. Here we test the hypothesis that age-associated decrease in autophagy is a major contributor to enhanced mito-ROS production and thereby pro-arrhythmic disturbances in Ca2+ homeostasis. METHODS AND RESULTS: Ventricular tissues from aged rabbits displayed significant downregulation of proteins involved in mitochondrial autophagy compared with tissues from young controls. Blocking autophagy with chloroquine increased total ROS production in primary rabbit CMs and mito-ROS production in HL-1 CMs. Furthermore, chloroquine treatment of HL-1 cells depolarized mitochondrial membrane potential (Δψm) to 50% that of controls. Blocking autophagy significantly increased oxidation of RyR2, resulting in enhanced propensity to pro-arrhythmic spontaneous Ca2+ release under ß-adrenergic stimulation. Aberrant Ca2+ release was abolished by treatment with the mito-ROS scavenger mito-TEMPO. Importantly, the autophagy enhancer Torin1 and ATG7 overexpression reduced the rate of mito-ROS production and restored both Δψm and defective Ca2+ handling in CMs derived from aged rabbit hearts. CONCLUSION: Decreased autophagy is a major cause of increased mito-ROS production in the aging heart. Our data suggest that promoting autophagy may reduce pathologic mito-ROS during normal aging and reduce pro-arrhythmic spontaneous Ca2+ release via oxidized RyR2s.

LITAF (Lipopolysaccharide-Induced Tumor Necrosis Factor) Regulates Cardiac L-Type Calcium Channels by Modulating NEDD (Neural Precursor Cell Expressed Developmentally Downregulated Protein) 4-1 Ubiquitin Ligase.

BACKGROUND: The turnover of cardiac ion channels underlying action potential duration is regulated by ubiquitination. Genome-wide association studies of QT interval identified several single-nucleotide polymorphisms located in or near genes involved in protein ubiquitination. A genetic variant upstream of LITAF (lipopolysaccharide-induced tumor necrosis factor) gene prompted us to determine its role in modulating cardiac excitation. METHODS: Optical mapping was performed in zebrafish hearts to determine Ca2+ transients. Live-cell confocal calcium imaging was performed on adult rabbit cardiomyocytes to determine intracellular Ca2+handling. L-type calcium channel (LTCC) current (ICa,L) was measured using whole-cell recording. To study the effect of LITAF on Cav1.2 (L-type voltage-gated calcium channel 1.2) channel expression, surface biotinylation, and Westerns were performed. LITAF interactions were studied using coimmunoprecipitation and in situ proximity ligation assay. RESULTS: LITAF knockdown in zebrafish resulted in a robust increase in calcium transients. Overexpressed LITAF in 3-week-old rabbit cardiomyocytes resulted in a decrease in ICa,L and Cavα1c abundance, whereas LITAF knockdown increased ICa,L and Cavα1c protein. LITAF-overexpressing decreases calcium transients in adult rabbit cardiomyocytes, which was associated with lower Cavα1c levels. In tsA201 cells, overexpressed LITAF downregulated total and surface pools of Cavα1c via increased Cavα1c ubiquitination and its subsequent lysosomal degradation. We observed colocalization between LITAF and LTCC in tsA201 and cardiomyocytes. In tsA201, NEDD (neural precursor cell expressed developmentally downregulated protein) 4-1, but not its catalytically inactive form NEDD4-1-C867A, increased Cavα1c ubiquitination. Cavα1c ubiquitination was further increased by coexpressed LITAF and NEDD4-1 but not NEDD4-1-C867A. NEDD4-1 knockdown abolished the negative effect of LITAF on ICa,L and Cavα1c levels in 3-week-old rabbit cardiomyocytes. Computer simulations demonstrated that a decrease of ICa,L current associated with LITAF overexpression simultaneously shortened action potential duration and decreased calcium transients in rabbit cardiomyocytes. CONCLUSIONS: LITAF acts as an adaptor protein promoting NEDD4-1-mediated ubiquitination and subsequent degradation of LTCC, thereby controlling LTCC membrane levels and function and thus cardiac excitation.

Incorporation of Novel Vascular Measures into Clinical Management: Recent Insights from the Framingham Heart Study.

PURPOSE OF REVIEW: The review discusses evidence from the Framingham Heart Study that supports the assessment and utility of novel vascular and blood pressure measures to inform clinical management of blood pressure-related cardiovascular disease. RECENT FINDINGS: Recent Framingham Heart Study investigations provide new insights into the associations of novel and traditional vascular and blood pressure measures, such as measures of aortic stiffness, components of blood pressure waves, and orthostatic change in blood pressure, with cardiovascular disease events and brain structure and function. Novel vascular measures provide opportunities for additional investigation and potential development of new interventions that are more precisely targeted at underlying pathophysiology. Inclusion of novel vascular measures should be considered in clinical practice to screen for early, subclinical disease and to stratify high-risk individuals for targeted therapies.

Relations of Microvascular Function, Cardiovascular Disease Risk Factors, and Aortic Stiffness in Blacks: The Jackson Heart Study.

Background Blacks have more severe endothelial dysfunction and aortic stiffening as compared with whites. We aimed to investigate the association between aortic stiffness and microvascular function in the black community. Methods and Results We assessed the association between forearm vascular reactive hyperemia (an indicator of microvascular function) and aortic stiffness in 1458 black participants (N=965 [66% women]; mean age: 66±11 years) in the Jackson Heart Study. We evaluated 2 measures of aortic stiffness: brachial pulse pressure and carotid-femoral pulse wave velocity. Using high-resolution ultrasound and Doppler, we evaluated brachial blood flow at baseline and during reactive hyperemia after 5 minutes of forearm ischemia. Multiple cardiovascular risk factors were significantly related to baseline and hyperemic brachial flow velocity. Women had lower baseline flow across the entire age spectrum. During hyperemia, we observed a significant age-sex interaction for flow velocity ( P=0.02). Female sex was protective against microvascular dysfunction among younger participants, but older women exhibited a greater attenuation of the hyperemic flow reserve. In multivariable models that adjusted for cardiovascular disease risk factors and mean arterial pressure, higher carotid-femoral pulse wave velocity (ß=-0.106±0.033; P=0.001 was related to lower baseline flow. However, during reactive hyperemia, elevated brachial pulse pressure (ß=-0.070±0.031; P=0.03) and carotid-femoral pulse wave velocity (ß=-0.128±0.030; P<0.001) were both related to attenuated brachial flow velocity. Conclusions In a sample of blacks, higher aortic stiffness and pressure pulsatility were associated with lower flow reserve during reactive hyperemia, beyond changes attributable to traditional cardiovascular disease risk factors alone.

Left Ventricular Diastolic Dysfunction in the Community: Impact of Diagnostic Criteria on the Burden, Correlates, and Prognosis.

BACKGROUND: Left ventricular diastolic dysfunction (DD) is common, particularly in women and older individuals, and it is associated with adverse cardiovascular outcomes. We evaluated the impact of age- and sex-specific diagnostic criteria on the assessment of DD in the community-based Framingham Heart Study. METHODS AND RESULTS: We estimated age- and sex-specific reference limits for echocardiographic measures of DD in a healthy reference subsample (N=2355, mean age 44 years, 66% women). The prevalence, correlates, and association with future cardiovascular disease were compared for DD using age- and sex-specific versus single cut point reference limits in a broad sample (N=6102, mean age 50 years, 56% women). Using age- and sex-specific criteria, DD was present in ≈25% to 30% of individuals across age groups, and it was directly associated with a number of modifiable risk factors. In contrast, with single cut point criteria, age was the primary determinant of DD. During follow-up (mean 7.9±2.2 years), incident cardiovascular disease occurred in 213 of 5770 individuals. Using age- and sex-specific criteria, mild and moderate-severe DD were associated with 50% (95% confidence interval, 1.09-2.05) and 65% (95% confidence interval, 1.14-2.38) higher incidences of cardiovascular disease, respectively, in age- and sex-adjusted analyses. With single cut point criteria, moderate-severe DD (hazard ratio, 1.66; 95% confidence interval, 1.05-2.61), but not mild DD (hazard ratio, 0.94; 95% confidence interval, 0.63-1.40), was associated with incident cardiovascular disease. CONCLUSIONS: Age- and sex-specific reference limits may result in DD assessments that are less dependent on age, more robustly related to modifiable risk factors, and are more closely associated with incident cardiovascular disease.