Showing papers by "Edward G. Lakatta published in 2019"

To help aging populations, classify organismal senescence.

Abstract: Comprehensive disease classification and staging is required to address unmet needs of aging populations Globally, citizens exist for sustained periods in states of aging-related disease and multimorbidity. Given the urgent and unmet clinical, health care, workforce, and economic needs of aging populations, we need interventions and programs that regenerate tissues and organs and prevent and reverse aging-related damage, disease, and frailty (1). In response to these challenges, the World Health Organization (WHO) has called for a comprehensive public-health response within an international legal framework based on human rights law (1). Yet for a clinical trial to be conducted, a disease to be diagnosed, intervention prescribed, and treatment administered; a corresponding disease classification code is needed, adopted nationally from the WHO International Classification of Diseases (ICD). Such classifications and staging are fundamental for health care governance among governments and intergovernmental bodies. We describe a systematic and comprehensive approach to the classification and staging of organismal senescence and aging-related diseases at the organ and tissue levels in order to guide policy and practice and enable appropriate interventions and clinical guidance, systems, resources, and infrastructure.

Overexpression of a Neuronal Type Adenylyl Cyclase (Type 8) in Sinoatrial Node Markedly Impacts Heart Rate and Rhythm.

Abstract: Heart rate (HR) and HR variability (HRV), predictors of over-all organism health, are widely believed to be driven by autonomic input to the sinoatrial node (SAN), with sympathetic input increasing HR and reducing HRV. However, variability in spontaneous beating intervals in isolated SAN tissue and single SAN cells, devoid of autonomic neural input, suggests that clocks intrinsic to SAN cells may also contribute to HR and HRV in vivo. We assessed contributions of both intrinsic and autonomic neuronal input mechanisms of SAN cell function on HR and HRV via in vivo, telemetric EKG recordings. This was done in both wild type (WT) mice, and those in which adenylyl cyclase type 8 (ADCY8), a main driver of intrinsic cAMP-PKA-Ca2+ mediated pacemaker function, was overexpressed exclusively in the heart (TGAC8). We hypothesized that TGAC8 mice would: (1) manifest a more coherent pattern of HRV in vivo, i.e., a reduced HRV driven by mechanisms intrinsic to SAN cells, and less so to modulation by autonomic input and (2) utilize unique adaptations to limit sympathetic input to a heart with high levels of intrinsic cAMP-Ca2+ signaling. Increased adenylyl cyclase (AC) activity in TGAC8 SAN tissue was accompanied by a marked increase in HR and a concurrent marked reduction in HRV, both in the absence or presence of dual autonomic blockade. The marked increase in intrinsic HR and coherence of HRV in TGAC8 mice occurred in the context of: (1) reduced HR and HRV responses to β-adrenergic receptor (β-AR) stimulation; (2) increased transcription of genes and expression of proteins [β-Arrestin, G Protein-Coupled Receptor Kinase 5 (GRK5) and Clathrin Adaptor Protein (Dab2)] that desensitize β-AR signaling within SAN tissue, (3) reduced transcripts or protein levels of enzymes [dopamine beta-hydorxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT)] required for catecholamine production in intrinsic cardiac adrenergic cells, and (4) substantially reduced plasma catecholamine levels. Thus, mechanisms driven by cAMP-PKA-Ca2+ signaling intrinsic to SAN cells underlie the marked coherence of TGAC8 mice HRV. Adaptations to limit additional activation of AC signaling, via decreased neuronal sympathetic input, are utilized to ensure the hearts survival and prevent Ca2+ overload.

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

Abstract: The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Age-related changes of the retinal microvasculature

Abstract: PURPOSE: Blood vessels of the retina provide an easily-accessible, representative window into the condition of microvasculature. We investigated how retinal vessel structure captured in fundus photographs changes with age, and how this may reflect features related to patient health, including blood pressure. RESULTS: We used two approaches. In the first approach, we segmented the retinal vasculature from fundus photographs and then we correlated 25 parameterized aspects ("traits")-comprising 15 measures of tortuosity, 7 fractal ranges of self-similarity, and 3 measures of junction numbers-with participant age and blood pressure. In the second approach, we examined entire fundus photographs with a set of algorithmic CHARM features. We studied 2,280 Sardinians, ages 20-28, and an U.S. based population from the AREDS study in 1,178 participants, ages 59-84. Three traits (relating to tortuosity, vessel bifurcation number, and vessel endpoint number) showed significant changes with age in both cohorts, and one additional trait (relating to fractal number) showed a correlation in the Sardinian cohort only. When using second approach, we found significant correlations of particular CHARM features with age and blood pressure, which were stronger than those detected when using parameterized traits, reflecting a greater signal from the entire photographs than was captured in the segmented microvasculature. CONCLUSIONS: These findings demonstrate that automated quantitative image analysis of fundus images can reveal general measures of patient health status.

Complexities in cardiovascular rhythmicity: Perspectives on circadian normality, ageing and disease

Abstract: Biological rhythms exist in organisms at all levels of complexity, in most organs and at myriad time scales. Our own biological rhythms are driven by energy emitted by the sun, interacting via our retinas with brain stem centres, which then send out complex messages designed to synchronize the behaviour of peripheral non-light sensing organs, to ensure optimal physiological responsiveness and performance of the organism based on the time of day. Peripheral organs themselves have autonomous rhythmic behaviours that can act independently from central nervous system control but is entrainable. Dysregulation of biological rhythms either through environment or disease has far-reaching consequences on health that we are only now beginning to appreciate. In this review, we focus on cardiovascular rhythms in health, with ageing and under disease conditions.

Role of Adipokines in the Association between Thyroid Hormone and Components of the Metabolic Syndrome.

Abstract: Metabolic syndrome (MS) increases cardiovascular risk. The role of thyroid hormone on components of MS is unclear. We analyzed a sample of 4733 euthyroid subjects from SardiNIA study. In female thyrotropin (TSH) was significantly and positively associated with triglycerides (Standardized regression coefficients (β) = 0.081, p < 0.001). Free thyroxine (FT4) was positively associated with HDL (β = 0.056, p < 0.01), systolic blood pressure (SBP) (β = 0.059, p < 0.001), diastolic blood pressure (DBP) (β = 0.044, p < 0.01), and fasting glucose (β = 0.046, p < 0.01). Conversely, FT4 showed a negative association with waist circumference (β = -0.052, p < 0.001). In TSH was positively associated with triglycerides (β = 0.111, p = <0.001) and FT4 showed a positive association with DBP (β = 0.51, p < 0.01). The addition of leptin and adiponectin to the regression models did not substantially change the impact of thyroid hormones on components of MS. Our data suggest that, even within the euthyroid range, excess of truncal adipose tissue is associated with variations in FT4. Leptin and adiponectin exert an additive effect rather than a causal effect. Additional studies should be performed to determine the clinical significance of this finding.

Monoclonal Antibody to Marinobufagenin Downregulates TGFβ Profibrotic Signaling in Left Ventricle and Kidney and Reduces Tissue Remodeling in Salt-Sensitive Hypertension.

Abstract: Background Elevated levels of an endogenous Na/K‐ATPase inhibitor marinobufagenin accompany salt‐sensitive hypertension and are implicated in cardiac fibrosis. Immunoneutralization of marinobufagen...

Discoidin domain Receptor 2: A determinant of metabolic syndrome-associated arterial fibrosis in non-human primates.

Abstract: Collagen accumulation and remodeling in the vascular wall is a cardinal feature of vascular fibrosis that exacerbates the complications of hypertension, aging, diabetes and atherosclerosis. With no specific therapy available to date, identification of mechanisms underlying vascular fibrogenesis is an important clinical goal. Here, we tested the hypothesis that Discoidin Domain Receptor 2 (DDR2), a collagen-specific receptor tyrosine kinase, is a determinant of arterial fibrosis. We report a significant increase in collagen type 1 levels along with collagen and ECM remodeling, degradation of elastic laminae, enhanced fat deposition and calcification in the abdominal aorta in a non-human primate model of high-fat, high-sucrose diet (HFS)-induced metabolic syndrome. These changes were associated with a marked increase in DDR2. Resveratrol attenuated collagen type I deposition and remodeling induced by the HFS diet, with a concomintant reduction in DDR2. Further, in isolated rat vascular adventitial fibroblasts and VSMCs, hyperglycemia increased DDR2 and collagen type I expression via TGF-β1/SMAD2/3, which was attenuated by resveratrol. Notably, gene knockdown and overexpression approaches demonstrated an obligate role for DDR2 in hyperglycemia-induced increase in collagen type I expression in these cells. Together, our observations point to DDR2 as a hitherto unrecognized molecular link between metabolic syndrome and arterial fibrosis, and hence a therapeutic target.

Cardiotonic Steroids Induce Vascular Fibrosis Via Pressure-Independent Mechanism in NaCl-Loaded Diabetic Rats.

Abstract: Endogenous cardiotonic steroid, marinobufagenin (MBG), induces Fli1-dependent tissue fibrosis. We hypothesized that an increase in MBG initiates the development of aortic fibrosis in salt-loaded rats with type 2 diabetes mellitus (DM2) via pressure-independent mechanism. DM2 was induced by a single intraperitoneal administration of 65 mg/kg streptozotocin to neonatal (4-5 days) male Wistar rats. Eight-week-old DM2 rats received water or 1.8% NaCl (DM-NaCl) solution for 4 weeks (n = 16); half of DM-NaCl rats were treated with anti-MBG monoclonal antibody (mAb) (DM-NaCl-AB) during week 4 of salt loading; control intact rats received water (n = 8/group). Blood pressure, MBG, erythrocyte Na/K-ATPase activity, aortic weights, levels of fibrosis markers (Fli1, protein kinase Cδ, transforming growth factor-β1, receptors of the transforming growth factor beta5, fibronectin, collagen-1), and sensitivity of the aortic explants to the vasorelaxant effect of sodium nitroprusside were assessed. No changes in systolic blood pressure were observed while erythrocyte Na/K-ATPase was inhibited by 30%, plasma MBG was doubled, and aortic markers of fibrosis became elevated in DM-NaCl rats versus control. Treatment of DM-NaCl rats with anti-MBG mAb activated Na/K-ATPase, prevented increases in aortic weights, and the levels of fibrosis markers returned to the control levels. The responsiveness of the aortic rings from DM-NaCl rats to the relaxant effect of sodium nitroprusside was reduced (half maximal effective concentration (EC50) = 29 nmol/L) versus control rings (EC50 = 7 nmol/L) and was restored by anti-MBG mAb (EC50 = 9 nmol/L). Our results suggest that in salt-loaded diabetic rats, MBG stimulates aortic collagen synthesis in a pressure-independent fashion and that 2 profibrotic mechanisms, Fli1 dependent and transforming growth factor-β dependent, underlie its effects.

Subclinical Longitudinal Change in Ankle-Brachial Index With Aging in a Community-Dwelling Population Is Associated With Central Arterial Stiffening.

Abstract: Background Aging is associated with a modest decline in ankle‐brachial index (ABI); however, the underpinnings of this decline are not fully understood. The greater systolic ankle than brachial blo...

Acute salt loading and cardiotonic steroids in resistant hypertension.

Abstract: The study addresses the association of marinobufagenin (MBG), a natriuretic and vasoconstrictor steroid, and Na/K-ATPase (NKA) activity with pressor response to salt-loading and arterial stiffness in resistant hypertension (RH). Thirty-four patients (18 males and 16 females; 56±8 years) with RH on a combined (lisnopril/amlodipine/hydrochlorothiazide) therapy and 11 healthy age-matched normotensive subjects (7 males and 4 females; 54±2 years) were enrolled in this study. Salt-loading was performed via intravenous infusion of 1000mL saline (0.9% NaCl) for 1h. Arterial stiffness was measured by Sphygmocor Px device with a calculation of pulse-wave velocity (PWV). Activity of NKA was measured in erythrocytes. We demonstrated that plasma levels of MBG and magnitude of NaCl-induced MBG-dependent NKA inhibition are associated with PWV, and that this association has gender- and age-specific fashion in RH patients.