Showing papers by "Edward G. Lakatta published in 2018"

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.

Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future

Characteristics of healthy vascular ageing in pooled population-based cohort studies: the global Metabolic syndrome and Artery REsearch Consortium.

Abstract: OBJECTIVE: Arterial ageing is characterized by increasing arterial stiffness as measured by pulse wave velocity (PWV). This process is enhanced in participants with early vascular ageing (EVA), but slowed in participants with healthy vascular ageing (HVA). We aimed to describe characteristics of EVA and HVA in a transcontinental study including 11 cohorts.METHODS: In all, 18 490 participants from the global MARE Consortium, free of cardiovascular disease, participated with data on PWV and cardiometabolic risk factors. We defined HVA as the lowest 10% and EVA as the highest 10% of the standardized PWV distribution, adjusted for age intervals. HVA individuals were compared with the 90% of non-HVA individuals with ANCOVA, adjusted for age, sex and hypertension.RESULTS: The 1723 HVA participants were at the same age as the rest of the population, more likely women (59.4 vs 57.0%), and with significantly lower levels of established cardiovascular risk factors (blood pressure, lipids, glucose). Similarly, the prevalence rate of obesity, diabetes mellitus, hypertension and the metabolic syndrome was lower in the HVA participants. In the presence of similar levels of cardiovascular risk factors, HVA participants in the 50-64 years of age group presented lower PWV 5.8 (SD 0.5) vs. 7.4 (1.4) m/s (P < 0.0001) than control individuals in the 35-49 years of age group, corresponding to an estimated difference in chronological age of 14 years.CONCLUSION: Participants with healthy vascular ageing (HVA), belonging to the lowest end of the PWV distribution, are in general characterized by an up to 14 years estimated younger biological (vascular) age than those with higher PWV values, and have lower levels of risk factors.

A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells

Abstract: The spontaneous rhythmic action potentials generated by the sinoatrial node (SAN), the primary pacemaker in the heart, dictate the regular and optimal cardiac contractions that pump blood around the body. Although the heart rate of humans is substantially slower than that of smaller experimental animals, current perspectives on the biophysical mechanisms underlying the automaticity of sinoatrial nodal pacemaker cells (SANCs) have been gleaned largely from studies of animal hearts. Using human SANCs, we demonstrated that spontaneous rhythmic local Ca2+ releases generated by a Ca2+ clock were coupled to electrogenic surface membrane molecules (the M clock) to trigger rhythmic action potentials, and that Ca2+-cAMP-protein kinase A (PKA) signaling regulated clock coupling. When these clocks became uncoupled, SANCs failed to generate spontaneous action potentials, showing a depolarized membrane potential and disorganized local Ca2+ releases that failed to activate the M clock. β-Adrenergic receptor (β-AR) stimulation, which increases cAMP concentrations and clock coupling in other species, restored spontaneous, rhythmic action potentials in some nonbeating "arrested" human SANCs by increasing intracellular Ca2+ concentrations and synchronizing diastolic local Ca2+ releases. When β-AR stimulation was withdrawn, the clocks again became uncoupled, and SANCs reverted to a nonbeating arrested state. Thus, automaticity of human pacemaker cells is driven by a coupled-clock system driven by Ca2+-cAMP-PKA signaling. Extreme clock uncoupling led to failure of spontaneous action potential generation, which was restored by recoupling of the clocks. Clock coupling and action potential firing in some of these arrested cells can be restored by β-AR stimulation-induced augmentation of Ca2+-cAMP-PKA signaling.

PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity.

Abstract: Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

Segment-specific associations between local haemodynamic and imaging markers of early atherosclerosis at the carotid artery: an in vivo human study

Abstract: Low and oscillatory wall shear stress (WSS) has long been hypothesized as a risk factor for atherosclerosis; however, evidence has been inferred primarily from model and post-mortem studies, or clinical studies of patients with already-developed plaques. This study aimed to identify associations between local haemodynamic and imaging markers of early atherosclerosis. Comprehensive magnetic resonance imaging allowed quantification of contrast enhancement (CE) (a marker of endothelial dysfunction) and vessel wall thickness at two distinct segments: the internal carotid artery bulb and the common carotid artery (CCA). Strict criteria were applied to a large dataset to exclude inward remodelling, resulting in 41 cases for which personalized computational fluid dynamic simulations were performed. After controlling for cardiovascular risk factors, bulb wall thickening was found to be weakly, but not significantly, associated with oscillatory WSS. CE at the bulb was significantly associated with low WSS (p < 0.001) and low flow helicity (p < 0.05). No significant associations were found for the CCA segment. Local haemodynamics at the bulb were significantly correlated with blood flow rates and heart rates, but not carotid bifurcation geometry (flare and curvature). Therefore low, but not oscillatory, WSS is an early independent marker of atherosclerotic changes preceding intimal thickening at the carotid bulb.

Electrophysiological heterogeneity of pacemaker cells in the rabbit intercaval region, including the SA node: insights from recording multiple ion currents in each cell

Abstract: In the present study, a hitherto unrecognized range of heterogeneity of ion currents in pacemaker cells from the intercaval region is demonstrated. Relationships between basal beating rate and L-ty...

TGFβ1 reinforces arterial aging in the vascular smooth muscle cell through a long-range regulation of the cytoskeletal stiffness.

Abstract: Here we report exquisitely distinct material properties of primary vascular smooth muscle (VSM) cells isolated from the thoracic aorta of adult (8 months) vs. aged (30 months) F344XBN rats. Individual VSM cells derived from the aged animals showed a tense internal network of the actin cytoskeleton (CSK), exhibiting increased stiffness (elastic) and frictional (loss) moduli than those derived from the adult animals over a wide frequency range of the imposed oscillatory deformation. This discrete mechanical response was long-lived in culture and persistent across a physiological range of matrix rigidity. Strikingly, the pro-fibrotic transforming growth factor β1 (TGFβ1) emerged as a specific modifier of age-associated VSM stiffening in vitro. TGFβ1 reinforced the mechanical phenotype of arterial aging in VSM cells on multiple time and length scales through clustering of mechanosensitive α5β1 and αvβ3 integrins. Taken together, these studies identify a novel nodal point for the long-range regulation of VSM stiffness and serve as a proof-of-concept that the broad-based inhibition of TGFβ1 expression, or TGFβ1 signal transduction in VSM, may be a useful therapeutic approach to mitigate the pathologic progression of central arterial wall stiffening associated with aging.

Dietary Sodium Restriction Reduces Arterial Stiffness, Vascular TGF-β-Dependent Fibrosis and Marinobufagenin in Young Normotensive Rats

Abstract: High salt (HS) intake stimulates the production of marinobufagenin (MBG), an endogenous steroidal Na/K-ATPase ligand, which activates profibrotic signaling. HS is accompanied by a blood pressure (BP) increase in salt-sensitive hypertension, but not in normotensive animals. Here, we investigated whether HS stimulates MBG production and activates transforming growth factor-beta (TGF-β) profibrotic signaling in young normotensive rats, and whether these changes can be reversed by reducing salt to a normal salt (NS) level. Three-month old male Sprague–Dawley rats received NS for 4 and 8 weeks (0.5% NaCl; NS4 and NS8), or HS for 4 and 8 weeks (4% NaCl; HS4 and HS8), or HS for 4 weeks followed by NS for 4 weeks (HS4/NS4), n = 8/group. Systolic BP (SBP), pulse wave velocity (PWV), MBG excretion, aortic collagen 1α2, collagen 4α1 and TGF-β, Smad2, Smad3, Fli-1 mRNA, and total collagen abundance were measured at baseline (BL), and on weeks 4 and 8. Statistical analysis was performed using one-way ANOVA. SBP was not affected by HS (125 ± 5 and 126 ± 6 vs. 128 ± 7 mmHg, HS4 and HS8 vs. BL, p > 0.05). HS increased MBG (164 ± 19 vs. 103 ± 19 pmol/24 h/kg, HS4 vs. BL, p < 0.05) and PWV (3.7 ± 0.2 vs. 2.7 ± 0.2 m/s, HS4 vs. NS4, p < 0.05). HS8 was associated with a further increase in MBG and PWV, with an increase in aortic Col1a2 80%), Col4a1 (50%), Tgfb1 (30%), Smad2 (30%) and Smad3 (45%) mRNAs, and aortic wall collagen (180%) vs. NS8 (all p < 0.05). NS following HS downregulated HS-induced factors: in HS4/NS4, the MBG level was 91 ± 12 pmol/24 h/kg (twofold lower than HS8, p < 0.01), PWV was 3.7 ± 0.3 vs. 4.7 ± 0.2 m/s (HS4/NS4 vs. HS8, p < 0.05), aortic wall Tgfb1, Col1a2, Col4a1, Smad2, Smad3 mRNAs, and collagen abundance were reversed by salt reduction to the BL levels (p < 0.05). HS was associated with an activation of TGF-β signaling, aortic fibrosis and aortic stiffness accompanied by an MBG increase in the absence of SBP changes in young normotensive rats. The reduction of dietary salt following HS decreased MBG, PWV, aortic wall collagen and TGF-β. Thus, HS-induced aortic stiffness in normotensive animals occurred in the context of elevated MBG, which may activate SMAD-dependent TGF-β pro-fibrotic signaling. This data suggests that a decrease in salt consumption could help to restore aortic elasticity and diminish the risk of cardiovascular disease by reducing the production of the pro-fibrotic factor MBG.

The reality of getting old.

Abstract: Life expectancy around the world has increased steadily for nearly 200 years. This Focus Issue of Nature Reviews Cardiology features five insightful Review articles that describe numerous facets of the latest research on cardiovascular ageing.

Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype.

Abstract: Background Aging exponentially increases the incidence of morbidity and mortality of quintessential cardiovascular disease mainly due to arterial proinflammatory shifts at the molecular, cellular, ...

Basal Spontaneous Firing of Rabbit Sinoatrial Node Cells Is Regulated by Dual Activation of PDEs (Phosphodiesterases) 3 and 4

Abstract: Background: Spontaneous firing of sinoatrial node cells (SANCs) is regulated by cAMP-mediated, PKA (protein kinase A)-dependent (cAMP/PKA) local subsarcolemmal Ca 2+ releases (LCRs) from RyRs (ryanodine receptors). LCRs occur during diastolic depolarization and activate an inward Na + /Ca 2+ exchange current that accelerates diastolic depolarization rate prompting the next action potential. PDEs (phosphodiesterases) regulate cAMP-mediated signaling; PDE3/PDE4 represent major PDE activities in SANC, but how they modulate LCRs and basal spontaneous SANC firing remains unknown. Methods: Real-time polymerase chain reaction, Western blot, immunostaining, cellular perforated patch clamping, and confocal microscopy were used to elucidate mechanisms of PDE-dependent regulation of cardiac pacemaking. RESULTS: PDE3A, PDE4B, and PDE4D were the major PDE subtypes expressed in rabbit SANC, and PDE3A was colocalized with α-actinin, PDE4D, SERCA (sarcoplasmic reticulum Ca 2+ ATP-ase), and PLB (phospholamban) in Z-lines. Inhibition of PDE3 (cilostamide) or PDE4 (rolipram) alone increased spontaneous SANC firing by ≈20% ( P P >0.05), respectively, but concurrent PDE3+PDE4 inhibition increased spontaneous firing by ≈45% ( P 2+ current (I Ca,L ) by ≈60% ( P P >0.05), respectively, and PLB phosphorylation by ≈20% ( P >0.05) each, but dual PDE3+PDE4 inhibition increased I Ca,L by ≈100% ( P P P 2+ refilling time ( P 2+ transient to subsequent LCR; P P Conclusions: Basal cardiac pacemaker function is regulated by concurrent PDE3+PDE4 activation which operates in a synergistic manner via decrease in cAMP/PKA phosphorylation, suppression of LCR parameters, and prolongation of the LCR period and spontaneous SANC cycle length.

Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.

Abstract: In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Erratum to: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits : (Nature Genetics, (2018), 50, 10, (1412-1425), 10.1038/s41588-018-0205-x)

Abstract: markdownIn the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

Aldosterone, inactive matrix gla-protein, and large artery stiffness in hypertension.

Abstract: Vascular calcification leads to increased large artery stiffness. Matrix gla-protein (MGP) is a vitamin K–dependent protein that inhibits arterial calcification. Aldosterone promotes vascular calcification and stiffness, but the relationships between aldosterone, MGP, and arterial stiffness are unknown. We studied 199 adults (predominantly older men) with hypertension. We assessed the relationship between levels of dephospho-uncarboxylated MGP (dp-ucMGP), aldosterone, and carotid-femoral pulse wave velocity (CF-PWV) using standard regression and mediation analyses. Plasma aldosterone was measured in a subgroup of subjects (n = 106). Aldosterone was strongly associated with dp-ucMGP (standardized β = 0.50, P

Antibody to Marinobufagenin Reverses Placenta-Induced Fibrosis of Umbilical Arteries in Preeclampsia.

Abstract: Background: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Immunoneutralization of heightened MBG by Digibind, a digoxin antibody, reduces blood pressure (BP) in patients with PE, and anti-MBG monoclonal antibody lessens BP in a rat model of PE. Recently, we demonstrated that MBG induces fibrosis in cardiovascular tissues via a mechanism involving inhibition of Fli-1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. Objectives and Methods: We hypothesized that in PE, elevated placental MBG levels are associated with development of fibrosis in umbilical arteries. Eleven patients with PE (mean BP 124 ± 4 mmHg; age 29 ± 2 years; 39 weeks gest. age) and 10 gestational age-matched normal pregnant subjects (mean BP 92 ± 2 mmHg; controls) were enrolled in the clinical study. Results: PE was associated with a higher placental (0.04 ± 0.01 vs. 0.49 ± 0.11 pmol/g; p < 0.01) and plasma MBG (0.5 ± 0.1 vs. 1.6 ± 0.5 nmol/L; p < 0.01), lower Na/K-ATPase activity in erythrocytes (2.7 ± 0.2 vs. 1.5 ± 0.2 µmol Pi/mL/hr; p < 0.01), 9-fold decrease of Fli-1 level and 2.5-fold increase of collagen-1 in placentae (p < 0.01) vs. control. Incubation of umbilical arteries from control patients with 1 nmol/L MBG was associated with four-fold decrease in Fli-1 level and two-fold increase in collagen-1 level vs. those incubated with placebo (p < 0.01), i.e., physiological concentration of MBG mimicked effect of PE in vitro. Collagen-1 abundance in umbilical arteries from PE patients was 4-fold higher than in control arteries, and this PE-associated fibrosis was reversed by monoclonal anti-MBG antibody ex vivo. Conclusion: These results demonstrate that elevated placental MBG level is implicated in the development of fibrosis of the placenta and umbilical arteries in PE.

Reduced vasorin enhances angiotensin II signaling within the aging arterial wall.

Abstract: The glycosylated protein vasorin physically interacts with the transforming growth factor-beta1 (TGF-β1) and functionally attenuates its fibrogenic signaling in the vascular smooth muscle cells (VSMCs) of the arterial wall. Angiotensin II (Ang II) amplifies TGF-β1 activation in the VSMCs of the arterial wall with aging. In this study, we hypothesized that a reduced expression of the protein vasorin plays a contributory role in magnifying Ang II-associated fibrogenic signaling in the VSMCs of the arterial wall with aging. The current study shows that vasorin mRNA and protein expression were significantly decreased both in aortic wall and VSMCs from old (30 mo) vs. young (8 mo) FXBN rats. Exposing young VSMCs to Ang II reduced vasorin protein expression to the levels of old untreated cells while treating old VSMCs with the Ang II type AT1 receptor antagonist Losartan upregulated vasorin protein expression up to the levels of young. The physical interaction between vasorin and TGF-β1 was significantly decreased in old vs. young VSMCs. Further, exposing young VSMCs to Ang II increased the levels of matrix metalloproteinase type II (MMP-2) activation and TGF-β1 downstream molecules p-SMAD-2/3 and collagen type I production up to the levels of old untreated VSMCs, and these effects were substantially inhibited by overexpressing vasorin. Administration of Ang II to young rats (8 mo) for 28 days via an osmotic minipump markedly reduced the expression of vasorin. Importantly, vasorin protein was effectively cleaved by activated MMP-2 both in vitro and in vivo. Administration of the MMP inhibitor, PD 166793, for 6 mo to young adult (18 mo) via a daily gavage markedly increased levels of vasorin in the aortic wall. Thus, reduced vasorin amplifies Ang II profibrotic signaling via an activation of MMP-2 in VSMCs within the aging arterial wall.

Unique Ca2+-cycling protein abundance and regulation sustains local Ca2+ releases and spontaneous firing of rabbit sinoatrial node cells

Abstract: Spontaneous beating of the heart pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) and caused by gradual change of the membrane potential called diastolic depolarization (DD). Submembrane local Ca2+ releases (LCR) from sarcoplasmic reticulum (SR) occur during late DD and activate an inward Na+/Ca2+ exchange current, which accelerates the DD rate leading to earlier occurrence of an action potential. A comparison of intrinsic SR Ca2+ cycling revealed that, at similar physiological Ca2+ concentrations, LCRs are large and rhythmic in permeabilized SANC, but small and random in permeabilized ventricular myocytes (VM). Permeabilized SANC spontaneously released more Ca2+ from SR than VM, despite comparable SR Ca2+ content in both cell types. In this review we discuss specific patterns of expression and distribution of SR Ca2+ cycling proteins (SR Ca2+ ATPase (SERCA2), phospholamban (PLB) and ryanodine receptors (RyR)) in SANC and ventricular myocytes. We link ability of SANC to generate larger and rhythmic LCRs with increased abundance of SERCA2, reduced abundance of the SERCA inhibitor PLB. In addition, an increase in intracellular [Ca2+] increases phosphorylation of both PLB and RyR exclusively in SANC. The differences in SR Ca2+ cycling protein expression between SANC and VM provide insights into diverse regulation of intrinsic SR Ca2+ cycling that drives automaticity of SANC.

Dual Activation of Phosphodiesterases 3 and 4 Regulates Basal Spontaneous Beating Rate of Cardiac Pacemaker Cells: Role of Compartmentalization?

Abstract: Spontaneous firing of sinoatrial (SA) node cells (SANC) is regulated by cAMP-mediated, PKA-dependent (cAMP/PKA) local subsarcolemmal Ca2+releases (LCRs) from ryanodine receptors (RyR). LCRs occur during diastolic depolarization (DD) and activate an inward Na+/Ca2+ exchange current that accelerates DD rate prompting the next action potential (AP). Basal phosphodiesterases (PDEs) activation degrades cAMP, reduces basal cAMP/PKA-dependent phosphorylation and suppresses normal spontaneous firing of SANC. cAMP-degrading PDE1, PDE3 and PDE4 represent major PDE activities in rabbit SANC, and PDE inhibition by IBMX increases spontaneous firing of SANC by ~50%. Though inhibition of single PDE1-PDE4 only moderately increases spontaneous SANC firing, dual PDE3+PDE4 inhibition produces synergistic effect hastening spontaneous SANC beating rate by ~50%. Here we describe expression and distribution of different PDE subtypes within rabbit SANC, several specific targets (L-type Ca2+channels and phospholamban) regulated by basal concurrent PDE3+PDE4 activation and critical importance of RyR Ca2+releases for PDE-dependent regulation of spontaneous SANC firing. Colocalization of PDE3 and PDE4 beneath sarcolemma or in straited patterns inside SANC strongly suggests that PDE-dependent regulation of cAMP/PKA signaling might be executed at the local level; this idea, however, requires further verification.

Association of arginine vasopressin with low atrial natriuretic peptide levels, left ventricular remodelling, and outcomes in adults with and without heart failure.

Abstract: Aims The arginine vasopressin (AVP) pathway has been extensively studied in heart failure (HF) with reduced ejection fraction (HFrEF), but less is known about AVP in HF with preserved EF (HFpEF). Furthermore, the association between AVP and atrial natriuretic peptide (ANP, a well-known inhibitor of AVP secretion) in HF is unknown. Methods and results We studied subjects with HFpEF (n = 28) and HFrEF (n = 25) and without HF (n = 71). Left ventricular (LV) mass and left atrial (LA) volumes were measured with cardiac magnetic resonance imaging. Arginine vasopressin and ANP were measured with enzyme-linked immunosorbent assay. Arginine vasopressin levels were significantly greater in HFpEF [0.96 pg/mL; 95% confidence interval (CI) = 0.83-1.1 pg/mL] compared with subjects without HF (0.69 pg/mL; 95% CI = 0.6-0.77 pg/mL; P = 0.0002). Heart failure with preserved ejection fraction (but not HFrEF) was a significant predictor of higher AVP after adjustment for potential confounders. Arginine vasopressin levels were independently associated with a greater LA volume and also paradoxically, with lower ANP levels. Key independent correlates of higher AVP were the presence of HFpEF (standardized β = 0.32; 95% CI = 0.09-0.56; P = 0.0073) and the ANP/LA volume ratio (standardized β = -0.23; 95% CI = -0.42 to -0.04; P = 0.0196). Arginine vasopressin levels were independently associated with LV mass (β = 0.26; 95% CI = 0.09-0.43; P = 0.003) and with an increased risk of death or HF admissions during follow-up (hazard ratio = 1.61; 95% CI = 1.13-2.29; P = 0.008). Conclusions Arginine vasopressin is increased in HFpEF and is associated with LV hypertrophy and poor outcomes. Higher AVP is associated with the combination of LA enlargement and paradoxically low ANP levels. These findings may indicate that a relative deficiency of ANP (an inhibitor of AVP secretion) in the setting of chronically increased LA pressure may contribute to AVP excess.

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.Association analyses in over 1 million individuals identify 535 new loci influencing blood pressure traits. The results provide new insights into blood pressure regulation and highlight shared genetic architecture between blood pressure and lifestyle exposures.

Discovering patterns of pleiotropy in genome-wide association studies

Abstract: Genome-wide association studies have had great success in identifying human genetic variants associated with disease, disease risk factors, and other biomedical phenotypes. Many variants are associated with multiple traits, even after correction for trait-trait correlation. Discovering subsets of variants associated with a shared subset of phenotypes could help reveal disease mechanisms, suggest new therapeutic options, and increase the power to detect additional variants with similar pattern of associations. Here we introduce two methods based on a Bayesian framework, SNP And Pleiotropic PHenotype Organization (SAPPHO), one modeling independent phenotypes (SAPPHO-I) and the other incorporating a full phenotype covariance structure (SAPPHO-C). These two methods learn patterns of pleiotropy from genotype and phenotype data, using identified associations to discover additional associations with shared patterns. The SAPPHO methods, along with other recent approaches for pleiotropic association tests, were assessed using data from the Atherosclerotic Risk in Communities (ARIC) study of 8,000 individuals, whose gold-standard associations were provided by meta-analysis of 40,000 to 100,000 individuals from the CHARGE consortium. Using power to detect gold-standard associations at genome-wide significance (0.05 family-wise error rate) as a metric, SAPPHO performed best. The SAPPHO methods were also uniquely able to select the most significant variants in a parsimonious model, excluding other less likely variants within a linkage disequilibrium block. For meta-analysis, the SAPPHO methods implement summary modes that use sufficient statistics rather than full phenotype and genotype data. Meta-analysis applied to CHARGE detected 16 additional associations to the gold-standard loci, as well as 124 novel loci, at 0.05 false discovery rate. Reasons for the superior performance were explored by performing simulations over a range of scenarios describing different genetic architectures. With SAPPHO we were able to learn genetic structures that were hidden using the traditional univariate tests.

Age-dependent hypertension and vascular remodeling in dahl-s rats are associated with elevated levels of marinobufagenin and cognitive decline

Abstract: Objective: Age-associated hypertension and central arterial stiffening contribute to cognitive impairment. Increase in blood pressure (BP) and aortic remodeling occur in Dahl salt-sensitive rats (Dahl-S) with an advancing age even on a normal salt intake. Marinobufagenin (MBG), a novel pro-hypertensive factor, is implicated in Dahl-S hypertension. Here we determined whether age-associated arterial remodeling and hypertension implicate in cognitive decline in Dahl-S and whether these changes are accompanied by an increase in pro-hypertensive and pro-fibrotic factor MBG. Design and method: Male Sprague-Dawley rats (S-D) and Dahl-S were kept on a normal 0.5% NaCl intake (n = 8/14 per group) for the duration of the study. Systolic BP (SBP), pulse wave velocity (PWV), MBG, aortic collagen, and behavioral tests (open field test (OFT); novel object test; redundant place-cue version of the Morris water maze test (MWM); rotarod test) were assessed in 3-mo and 12-mo animals. Results: At 3-mo Dahl-S had higher SBP, PWV and aortic wall remodeling vs. 3-mo S-D. Between 3 and 12-mo both S-D and Dahl-S exhibited an increase in SBP, PWV, MBG and aortic wall collagen deposition. These parameters were significantly higher in 12-mo Dahl-S than in age-matched S-D (Table). MBG correlated with SBP in Dahl-S only (Pearson R = 0.52, p = 0.04), and with PWV in both S-D (Pearson R = 0.37, p = 0.01) and Dahl-S (Pearson R = 0.54, p = 0.04). Behaviorally, in an MWM, 12-mo DSS demonstrated impaired spatial hippocampal memory vs. 12-mo S-D. Compared to 3-mo, both 12-mo S-D and Dahl-S demonstrated an age-dependent decline in OFT activity, but 12-mo Dahl-S were more active in OFT, had more endurance during the rotarod test indicating non-impaired motor coordination, and showed increased object exploration vs. age-matched S-D (Table). Performance in behavioral tests by 12-mo hypertensive Dahl-S may suggest the development of age-associated anxiety and change in emotional status, and a decline in their spatial hippocampal memory. Conclusions: Cognitive deficit in aged hypertensive Dahl-S is limited to hippocampal-dependent spatial memory. In Dahl-S, development of age-dependent hypertension and aortic wall remodeling, occurred in context with an increase in MBG, may contribute to hippocampal spatial memory impairment, and suggested a possible implication of MBG in these declines. Figure. No caption available.

ARA290, A Small Non-Hematopoietic Peptide Derived From Erythropoietin, Prolongs Healthspan And Attenuates Age-Associated Declines In The Heart's Structure And Function

Abstract: Background Chronic inflammation is linked to age-associated declines in heart structure and function that contribute to increased risks for cardiovascular mortality and frailty, a state of high vul...

Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

Abstract: Electrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel) Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci The majority of associations discovered in European-descent populations were also present in African-American populations Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci These additional analyses identified another 13 novel loci Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes