Arterial function and longevity Focus on the aorta

Arterial function and longevity Focus on the aorta Panagiota Pietri, MD, PhD, FESC Director of Hypertension Unit Athens Medical Center Athens, Greece

Secrets of longevity

Secrets of longevity Unveiling the secrets of longevity: the Ikaria Study. C. Stefanadis. Hell J Cardiol 2011;52:479-480 IKARIA Study Exposure to low environmental radiation and longevity. Insights from the Ikaria Study Chrysohoou C, et al. Int J Cardiol 2013;169:e97-98 Consumption of boiled Greek type of coffee is associated with improved endothelial function: the Ikaria Study. Siasos G, et al. Vasc Med 2013;18:55-62 The natural history of multifocal atrial rhythms in elderly outpatients: Insights from the Ikaria Study. Lazaros G, et al. Ann Noninvasive Electrocardiol 2014;19:483-489.

Secrets of longevity: The role of aorta

Aortic function AORTIC ELASTIC PROPERTIES Aorta (and the large, elastic type arteries) serve predominately as a cushioning reservoir that stores blood during systole and expels it to the tissues during diastole. The predominant elastic materials of the vessel wall is elastin and collagen fibers. Pulsatile pump Steady flow McDonald s Blood Flow in Arteries, 6 th ed.

Non-invasive assessment of aortic function Pulse Wave Velocity (PWV)

Aortic stiffness and wave reflections Elastic Arteries: normal PWV P during diastole coronary perfusion Stiff arteries: increased PWV LV afterload MVΟ2 Coronary perfusion

Aortic stiffness: Predisposing factors Age Arterial hypertension Hyperlipidaemia Smoking Abnormal glucose metabolism Inflammation Genetic background..

Aortic stiffness: Predisposing factors Age Arterial hypertension Hyperlipidaemia Smoking Abnormal glucose metabolism Inflammation Genetic background

Aortic stiffness: Predisposing factors 77 studies association of PWV with risk factors. Age and blood pressure were consistently independently associated with PWV in most of the studies (91% and 90% of studies, respectively). The contribution of risk factors other than age and blood pressure was small or insignificant. Cecelja M et al. Hypertension 2009;54:1328-1336

Aortic stiffness, BP pattern and age Franklin S, et al. Circulation 1997;96:308-315

Aortic distensibility and age A significant decrease in aortic distensibility before the 5 th decade of life 111 asymptomatic patients Aortic distensibility and aortic arch PWV (MRI) Red dots: age<50 Blue dots: age>50 Redheuil A, et al. Hypertension 2010;55:319-326

Aortic stiffness: Reference Values according to age and BP level 11092 subjects 8 European countries Free from CVD non diabetic The Reference Values for Arterial Stiffness Collaboration. Eur Heart J 2010;31:2338-2350

Aortic stiffness: Prognostic role Prospective studies demonstrating the independent prognostic role of aortic stiffness on cardiovascular events and mortality. Assessment First author Events FU (years) Population Αortic PWV Blacher (1999, Fr) CV mortality 6.0 ESRD Laurent (2001, Fr) CV mortality 9.3 Hypertension Meaume (2001,Fr) CV mortality 2.5 Elderly Shoji (2001, Jp) CV mortality 5.2 ESRD Boutouyrie (2002, Fr) CHD events 5.7 Hypertension Cruickshank (2002, GB) All-cause mortality 10.7 IGT Laurent (2003, Fr) Fatal strokes 7.9 Hypertension Sutton-Tyrrell (2005,USA) CV mortality 4.6 Elderly Ascending aorta (invasive) Stefanadis (2000, Gr) Reccurent acute CHD 3.0 Acute CHD Carotid Distensibility Blacher (1998, Fr) All cause mortality 2.1 ESRD Barenbrock (2001, Ge) CV events 7.9 ESRD

Aortic stiffness: Prognostic role 141 subjects Mean age=87 years FU: 30 months PWV was the most powerful predictor of cardiovascular mortality (1 m/s increase in PWV increased CV mortality 19%), whereas SBP and PP had no additive role. Arterioscl Thromb Vasc Biol 2001;21:2046-2050

Aortic stiffness: Prognostic role PWV = 2 times increased risk of CV events and mortality 15,877 ασθενείς mean FU 7.7 yrs JACC, March 30, 2010 Vlachopoulos C, et al. JACC 2010;55:1318-1327

Aortic function and longevity IKARIA Study.

Aortic distensibility and cognitive function Increased aortic distensibility, as evaluated by echocardiography, was associated with increased likelihood of having good mental function, in advanced age, and in both genders, after various adjustment for several cardiovascular risk factors. Furthermore having PP levels in the upper tertile (>70 mmhg), increases by 55% the likelihood of having MMSE < 24 (OR for above 70 mmhg = 0.45, 95%CI 0.22, 0.92) Chrysohoou C, et al. Maturitas 2013;74:241-245

Aortic distensibility and cognitive function Arterial aging mediates the effect of TNF-α and ACE polymorphisms on mental health in elderly individuals: insights from IKARIA study 178 participants>75 years Gene polymorphisms of ACE (Insertion/Deletion) and TNF (G/A transition) Calculation of a combined genetic index (GI) for both genes GI was independently associated with Aortic Distensibility Subjects being double homozygous (DD for ACE, GG for TNF) had significantly decreased mental score (MMSE) Vascular aging may modulate the genetic substrate of elderly subjects on the risk for developing dementia Georgiopoulos G, et al. QJM 2017;Epub ahead of print

Aortic stiffness and longevity Pietri P, et al. J Am Coll Cardiol 2015;66:1842-3

Purpose Given first, the prognostic significance of aortic stiffness (PWV) for total and cardiovascular mortality and second, the absence of data on aortic stiffness in populations with high longevity rates, the aim of the present study was: 1. To assess aortic stiffness in several age groups in Ikaria inhabitants. 2. To compare the measured values of PWV with the reference values according to age and BP levels.

Methods We studied 138 Ikaria inhabitants who were divided in 4 age groups (per decade): 1. 40-49 years 2. 50-59 years 3. 60-69 years 4. 70 years Exclusion criteria: Established cardiovascular disease Diabetes mellitus Use of statins or antihypertensive drugs

Assessment of aortic stiffness

Estimation of reference values Eur Heart J 2010;31:2338-2350

Results Baseline characteristics of the study population 40-49 years (Group 1) 50-59 years (Group 2) 60-69 years (Group 3) 70 years (Group 4) Males (%) 38 54 51 38 Smokers (%) 55 43 23 18 BMI (Kg/m 2 ) 28.5±5.4 30.3±4.0 28.3±4.3 29.5±4.9 Systolic BP (mmhg) Diastolic BP (mmhg) Mean BP (mmhg) Pulse pressure (mmhg) Heart rate (beats/min) 131.1±11.7 136.7±14.1 142.9±17.1 152.1±21.8 81.7±6.5 83.9±10.1 80.8±7.7 81.7±11.6 98.2±7.5 101.5±11.0 101.5±9.7 105.1±13.4 48.9±7.9 52.8±7.9 62.1±13.8 70.4±17.6 69.5±9.0 66.6±10.2 61.4±9.5 65.9±11.5

Results Baseline characteristics of the study population 40-49 y (Group 1) 50-59 y (Group 2) 60-69 y (Group 3) 70 y (Group 4) Ολική χοληστερόλη (mg/dl) 221.2±44 207.8±39.6 208.7±48.6 191.7±36.8 HDL (mg/dl) 46.6±10.4 47.1±9.7 48.6±8.8 44.6±11.3 LDL (mg/dl) 145.9±35 136.9±35.4 133.9±42.5 120.6±35.5 Τριγλυκερίδια (mg/dl Σάκχαρο (mg/dl) Κρεατινίνη ορού (mg/dl) hscrp (mg/l) Ουρικό οξύ (mg/dl) 120.7±68 119.2±39.5 131.5±66.5 145.1±119.2 98.3±38.8 96.8±16.7 103.1±19.6 97.9±10.8 0.82±0.12 0.82±0.12 0.84±0.13 0.89±0.26 3.22±4.85 4.50±4.81 2.65±2.21 2.75±1.87 4.7±1.3 5.2±1.2 5.2±1.3 5.1±1.6

Results PWV across the age groups There was a gradual increase in PWV as age decade was increased PWV (m/s) 14 13 12 11.53±2.22 11 10 9 8 7.98±0.96 8.71±1.22 9.87±1.17 7 40-49 50-59 60-69 70 Age decade (years) Pietri P, et al. J Am Coll Cardiol 2015;66:1842-3

Results Determinants of PWV Factors that were independently associated with PWV: Age (b=0.61, p<0.001) Mean arterial pressure (b=0.29, p=0.001) Heart rate (b=0.23, p=0.006) Creatinine (b=0.19, p=0.01) Pietri P, et al. J Am Coll Cardiol 2015;66:1842-3

Results Difference between measured PWV and reference PWV After the age of 50 years, the measured PWV (PWV M) was consistently and significantly decreased compared to the reference values (PWV R). PWV (m/s) 15 13 p<0.001 p<0.01 11.53 vs 13.17 11 9 p<0.01 p=ns 8.71 vs 9.22 7.98 vs 7.92 9.87 vs 10.78 PWV M PWV R 7 5 40-49 50-59 60-69 >=70 Age (years) Pietri P, et al. J Am Coll Cardiol 2015;66:1842-3

Results Difference between measured PWV and reference PWV After the age of 50 years, the measured PWV (PWV M) was consistently and significantly decreased compared to the reference values (PWV R). Pietri P, et al. J Am Coll Cardiol 2015;66:1842-3

Conclusions In Ikaria inhabitants, aortic stiffness increases with age. However, after the age of 50 years, PWV is significantly and consistently reduced compared to reference values of PWV (estimated according to age and BP levels). This finding may imply a slower progression of vascular aging in the Ikaria population. Given the high prognostic significance of aortic stiffness, it might be suggested, although extrapolation, that part of the longevity privilege in Ikaria population may be due to the slowing of vascular aging.

Chronological or vascular age? A man is as old as his arteries Thomas Sydenham (1624-1689)

The most commendable thing of this island is their air and water, both so healthful that the people are very long lived, it being an ordinary thing to see persons in it of 100 years of age, which is a great wonder, considering how hardily they live Pietri P, Papaioannou T, Stefanadis C. Nature 2017;544:416 ACKNOWLEDGEMENTS Mary Kay Pietris, Library of Congress Washington D.C, USA