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SHS Phase 6 – Cornell Imaging Center Richard B. Devereux, MD Professor of Medicine SHS Phase 6 – Cornell Imaging Center Richard B. Devereux, MD Professor of Medicine Weill Cornell Medical College

Cornell Center – Cardiovascular Phenotyping in SHS Phases 2 to 5 • Phase 2 Cornell Center – Cardiovascular Phenotyping in SHS Phases 2 to 5 • Phase 2 – 3501 echocardiograms (91% LV mass) • Phase 3 – 3715 carotid ultrasounds, 3820 computerized ECGs, central BP 3560 • Phase 4 – 3629 echocardiograms (97% LV mass), 3582 carotid ultrasounds, 3645 computerized ECGs, central BP 2540 • Phase 5 – 3074 echocardiograms, 3080 carotid ultrasounds, 3038 popliteal ultrasounds, 3203 computerized ECGs • CV pheonotype of SHFS participants assessed systematically by ~31, 500 standardized ultrasounds, ECGs or central BP recordings in members of 95 families in SHS phases 3 to 5.

SHS Cardiovascular Reading Center – Peer. Reviewed Publications SHS Cardiovascular Reading Center – Peer. Reviewed Publications

SHS Phase 6 - Cornell Center Weill Cornell Medical College – Richard B. Devereux, SHS Phase 6 - Cornell Center Weill Cornell Medical College – Richard B. Devereux, M. D, P. I. MR Centers in AZ, ND/SD, OK Prior CV Exams Carotid Ultrasound Cardiac Echo Popliteal Ultrasound Computerized ECG In SHFS at 3 rd to 5 th SHS Exams MR Reading Center UCSD Claude Sirlin, MD Hepatic Triglycerides Subcutaneous Fat Intra-Abdominal Fat Abdominal Aortic Diameter Applanation Tonometry Cold Pressor Test Heart Rate Variability Mary Roman, MD Jason Umans, MD Peter Okin, MD Brachial and Central BP Reactivity of Pulse Pressure Amplification Time Domain (mean RR, PNN 50, etc) Freq Domain (LF, HR. LFHF ratio) Central Arterial Pressure Pulse Pressure Amplification Change from 4 th SHS Exam

Adiposity, Metabolic Abnormalities and Atherosclerosis • The SHS has assessed adiposity indirectly measures (BMI, Adiposity, Metabolic Abnormalities and Atherosclerosis • The SHS has assessed adiposity indirectly measures (BMI, waist circumference, bioelectric impedence). • Hepatic steatosis (trigyceride deposition): – increasing in prevalence. – instigating feature of non-alcoholic and alcoholic fatty liver disease – associated with risks of cancer, CV disease and diabetes – may contribute to emergence of diabetes • SHS Phase 6 will directly measure hepatic, intra-abdominal and subcutaneous fat in SHFS - - unique opportunity to assess relations of organ adiposity to metabolic disturbance, preclinical CV disease and CV events.

Closer Association of Hepatic than Visceral Adipose Tissue with Metabolic Abnormalities • • • Closer Association of Hepatic than Visceral Adipose Tissue with Metabolic Abnormalities • • • Visceral adipose tissue (VAT) and intrahepatic triglyceride (IHTG) content measured. Association of IHTG and VAT to metabolic function assessed by evaluating groups of obese subjects, with high vs. normal IHTG content but matched on VAT volume or had high vs. normal VAT volume matched on IHTG content. Stable isotope tracer techniques and the euglycemic-hyperinsulinemic clamp procedure were used to assess insulin sensitivity and very-lowdensity lipoprotein-triglyceride (VLDL-TG) secretion rate. Adipose tissue and muscle insulin sensitivity were 41, 13, and 36% lower (P < 0. 01), and VLDL-triglyceride secretion rate was almost double (P < 0. 001), in subjects with higher than normal IHTG content, matched on VAT. No differences in insulin sensitivity or VLDL-TG secretion were observed between subjects with different VAT volumes, matched on IHTG content. Thus IHTG, not VAT, is a better marker of the metabolic derangements associated with obesity. Fabbrini et al. : Proc Natl Acad Sci U S A. 2009; 106: 15430 -15435

MR Experimental set-up for measurements – Proof of Concept content Fig. 1. Measurement of MR Experimental set-up for measurements – Proof of Concept content Fig. 1. Measurement of Hepatic Fatof hepatic triglyceride (HTG)by MRby proton magnetic resonance spectroscopy (1 H MRS) Spectroscopy Measurement in Individual Voxels Szczepaniak, L. S. et al. Am J Physiol Endocrinol Metab 288: E 462 -E 468 2005; doi: 10. 1152/ajpendo. 00064. 2004 Copyright © 2005 American Physiological Society

Weak Relation between body mass index and Hepatic Triglyceride Content in the Dallas Heart Weak Relation between body mass index and Hepatic Triglyceride Content in the Dallas Heart Study Szczepaniak, L. S. et al. Am J Physiol Endocrinol Metab 288: E 462 -E 468 2005; doi: 10. 1152/ajpendo. 00064. 2004 Copyright © 2005 American Physiological Society

MRI Assessment of Hepatic Fat Content • Spectroscopy is most accurate method of calculating MRI Assessment of Hepatic Fat Content • Spectroscopy is most accurate method of calculating triglyceride content of individual 3 -dimensional voxels. • However, spectroscopy of large numbers of individual voxels to assess overall hepatic TG content is too complex for application in multi-center population-based studies • 20 second MRI can measure proton-density fat fraction in 2 -D pixels. By drawing multiple dispersed regions of interest can calculate whole liver fat fraction. • Images of entire liver can be stored for more labor intensive precise measurement of whole-liver and segmental fat fraction/volume.

Method to Quantify Liver Triglyceride in SHS Phase 6 MRI-based approach • Six magnitude Method to Quantify Liver Triglyceride in SHS Phase 6 MRI-based approach • Six magnitude MR images acquired at echo times of 1. 15, 2. 3, 3. 45, 4. 60, 5. 75, 6. 90 msec • Parameters are selected to avoid the errors that confound conventional MRI techniques • Entire liver imaged in 20 sec Post-processing (UCSD) • Signal intensity is modeled as a function of echo time • Corrections done for multi-speak spectral interference and exponential signal decay Yokoo T, … Sirlin C: Radiology 2009; 251: 67 -76 • Output (UCSD) • Maps of proton-density fat fraction (PDFF) • PDFF = quantitative biomarker of liver TG concentration • Abdominal aortic diameter

MRI-Determined Proton Density Fat Fraction Agrees Closely with MR Spectroscopy Fat Fraction (%) Yokoo MRI-Determined Proton Density Fat Fraction Agrees Closely with MR Spectroscopy Fat Fraction (%) Yokoo T, … Sirlin C: Radiology 2009; 251: 67 -76

MRI Protocol for SHS Phase 6 • Localizers and planning sequences – 3 minutes MRI Protocol for SHS Phase 6 • Localizers and planning sequences – 3 minutes • MRI fat quantification – 20 seconds • MRI adiposity images – 20 seconds • MRI aorta diameter – 20 seconds • Total exam time including subject set up, localization, prescribing, acquisition = 30 minutes

Blood Pressure Variation • BP varies over time – 24 -hour ambulatory BP • Blood Pressure Variation • BP varies over time – 24 -hour ambulatory BP • However, 40 -50% of variability of brachial BP remains unexplained – Genetic effects – Autonomic nervous system effects • BP highly responsive to activity – e. g. , treadmill exercise and other forms of stress • BP varies importantly between central aorta and brachial artery - due to pulse pressure amplification

Top, Difference between simultaneously recorded central aortic and radial pressure waveforms O'Rourke M F, Top, Difference between simultaneously recorded central aortic and radial pressure waveforms O'Rourke M F, Seward J B Mayo Clin Proc. 2006; 81: 1057 -1068 • Because of effect of wave reflections, systolic BP is higher in the brachial and other peripheral arteries than in the central aorta • Increase in systolic BP greatest in young individuals and in those with more compliant arteries at any age • Central arterial pressure reflects load imposed on the LV and the coronary and cerebral circulations more directly O'Rourke M F, Seward J B Mayo Clin Proc. 2006; 81: 10571068 • Therefore, central BP may be of greater prognostic significance © 2006 Mayo Foundation for Medical Education and Research

METHODS: Tonometry Applanation Tonometry: Sphygmo. Cor® METHODS: Tonometry Applanation Tonometry: Sphygmo. Cor®

METHODS: Waveforms METHODS: Waveforms

Independent Associations of Aortic and Brachial BP with CVD in the Strong Heart Study Independent Associations of Aortic and Brachial BP with CVD in the Strong Heart Study Age (p<0. 001), diabetes (p<0. 001), heart rate (p<0. 05) and creatinine (p<0. 05 to <0. 001) ± fibrinogen (p=0. 06 to 0. 008) entered all models. PARAMETER HR 95% CI p value Aortic pulse pressure* 1. 15 (1. 07 -1. 24) <0. 001 Aortic systolic pressure* 1. 07 (1. 01 -1. 14) <0. 05 Brachial pulse pressure* 1. 10 (1. 03 -1. 18) <0. 01 Brachial systolic pressure* 1. 08 (1. 02 -1. 14) <0. 05 *per 10 mm. Hg Remained significant after addition of carotid atherosclerosis and brachial pulse pressure Roman MJ et al. Hypertension 2007; 50: 197 -203.

Associations of Carotid and Brachial BP with Incident CVD in the Dicomano Study Adjusted Associations of Carotid and Brachial BP with Incident CVD in the Dicomano Study Adjusted for age (p<0. 0001) and male gender (p=0. 001) PARAMETER HR 95% CI p value Carotid PP* 1. 23 (1. 10 -1. 37) <0. 0001 Carotid SBP* 1. 19 (1. 08 -1. 31) <0. 0001 Brachial PP* 0. 063 Brachial SBP* 0. 119 *per 10 mm. Hg Pini et al. J Am Coll Cardiol 2008; 51: 2432 -2439.

Associations of Carotid and Brachial BP with Incident CVD in Taiwan 1272 healthy normotensive Associations of Carotid and Brachial BP with Incident CVD in Taiwan 1272 healthy normotensive or untreated hypertensive Taiwanese aged 30 -79, followed for 10 years; 130 all-cause deaths and 37 cardiovascular deaths Wang et al. J Hypertens 2009; 27: 461 -7.

Central Blood Pressure Measurement in SHS Phase 6 • Re-measure central systolic, pulse pressure, Central Blood Pressure Measurement in SHS Phase 6 • Re-measure central systolic, pulse pressure, waveform after ~10 years after 4 th SHS exam – largest population-based long-term follow-up • Examine effects of obesity, diabetes, dyslipidemia, renal function at baseline and intermediate 5 th SHS exam on increase of central systolic and pulse pressure • Examine associations of intra-abdominal, subcutaneous and hepatic fat with central BP and pulse pressure amplification

Cold Pressor Test • Widely used measure of brachial BP reactivity to stress, predominate Cold Pressor Test • Widely used measure of brachial BP reactivity to stress, predominate α–adrenergic mediation • Strong heritability in Heredity and Phenotype Intervention Heart Study in a population with strong founder effects: additive genetic effect 1225%. • Strong association with genes in small physiologic studies. • Impact of cold pressor BP response on central BP and association with candidate genes unknown in large population-based samples.

Familial Resemblance of SBP Response to Cold Pressor Test in the HAPI Study Familial Resemblance of SBP Response to Cold Pressor Test in the HAPI Study

Protocol for Assessment of Brachial and Central BP, Their Reactivity to Cold Pressor Test Protocol for Assessment of Brachial and Central BP, Their Reactivity to Cold Pressor Test and Heart Rate Variability in SHS Phase 6 • Brachial BP by Omron automated device, applanation tonometry to measure central BP and heart rate variability from 5 -minute ECG recording assessed at rest • Cold pressor test protocol modified from Heredity and Phenotype Intervention Heart Study to record BP by Omron at baseline and at 1, 2, 3, 4 and 5 minutes of cold pressor test • Repeat applanation tonometry between minute 2 and 3 of cold pressor test.

SHS Phase 6 – Heart Rate Variability (HRV) • 5 minute supine ECG recording SHS Phase 6 – Heart Rate Variability (HRV) • 5 minute supine ECG recording using Sphygmo. Cor HRV system • Time-Domain HRV measures – Mean and SD of mean RR interval – PNN 50 (% of consecutive RR intervals differing by >50 ms) – RMS-SDD (root mean square of successive RR intervals • Frequency-Domain HRV measures – Fast Fourier transform of RR interval data – Low Frequency (LF) power (0. 04 -0. 15 Hz, sympathetic ± vagal tone) – High Frequency (HF) power (0. 15 -0. 4 Hz, vagal tone) – LF/HF ratio (balance of vagal/sympathetic tone)

Unique Features • Relate hepatic fat fraction by MRI proton density (and intra-abdominal & Unique Features • Relate hepatic fat fraction by MRI proton density (and intra-abdominal & subcutaneous fat) to metabolic abnormalities and extensive prior CV phenotypes. • Relate abdominal aortic diameter to risk factors and prior CV phenotypes • Characterize long-term evolution of central arterial pressure and waveform • Relate heart rate variability as measure of autonomic tone to metabolic & CV phenotypes • Relate stress response of brachial & central BP & HR to above phenotypes and autonomic tone • Provide these phenotypes in members of 95 families to Genetics Component of SHS Phase 6.