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 – 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

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2007-2009

SHS Phase 6 - Cornell Center

Weill Cornell Medical College – Richard B. Devereux, M.D, P.I.

MR Centers in

AZ, ND/SD,

OK

MR Reading CenterUCSD

Claude Sirlin, MD

Hepatic Triglycerides

Subcutaneous FatIntra-Abdominal Fat

Abdominal Aortic Diameter

Applanation Tonometry

Mary Roman, MD

Cold Pressor Test

Jason Umans, MD

Heart Rate Variability

Peter Okin, MD

Central Arterial

Pressure Pulse

Pressure Amplification Change from 4th SHS Exam

Prior CV ExamsCarotid Ultrasound

Cardiac EchoPopliteal UltrasoundComputerized ECGIn SHFS at 3rd to 5th

SHS Exams

Brachial and Central

BP Reactivity

Reactivity of Pulse

Pressure Amplification

Time Domain(mean RR,

PNN50, etc)Freq Domain

(LF, HR. LFHF ratio)

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

• 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-low-density 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

Copyright ©2005 American Physiological Society

Szczepaniak, L. S. et al. Am J Physiol Endocrinol Metab 288: E462-E468 2005;doi:10.1152/ajpendo.00064.2004

Fig. 1. Experimental set-up for measurements of hepatic triglyceride (HTG) content by proton magnetic resonance spectroscopy (1H MRS)

MR Measurement of Hepatic Fat – Proof of Concept by MR Spectroscopy Measurement in Individual Voxels

Copyright ©2005 American Physiological Society

Szczepaniak, L. S. et al. Am J Physiol Endocrinol Metab 288: E462-E468 2005;doi:10.1152/ajpendo.00064.2004

Weak Relation between body mass index and Hepatic Triglyceride Content in the Dallas Heart Study

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.

Yokoo T, … Sirlin C: Radiology 2009; 251:67-76

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

•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

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Yokoo T, … Sirlin C: Radiology 2009; 251:67-76

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• 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, Seward J B Mayo Clin Proc. 2006;81:1057-1068

© 2006 Mayo Foundation for Medical Education and Research

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

• Therefore, central BP may be of greater prognostic significance

METHODS: Tonometry

Applanation Tonometry: SphygmoCor®

METHODS: Waveforms

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 mmHg

Roman MJ et al. Hypertension 2007;50:197-203.

Remained significant after addition of carotid atherosclerosis and brachial pulse pressure

Associations of Carotid and Brachial BP with Incident CVD in the Dicomano Study

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 mmHg

Pini et al. J Am Coll Cardiol 2008;51:2432-2439.

Adjusted for age (p<0.0001) and male gender (p=0.001)

Associations of Carotid and Brachial BP with Incident CVD in Taiwan

Wang et al. J Hypertens 2009;27:461-7.

1272 healthy normotensive or untreated hypertensive Taiwanese aged 30-79, followed for 10 years; 130 all-cause deaths and 37 cardiovascular deaths

Central Blood Pressure Measurement in SHS Phase 6

• Re-measure central systolic, pulse pressure, waveform after ~10 years after 4th SHS exam – largest population-based long-term follow-up

• Examine effects of obesity, diabetes, dyslipidemia, renal function at baseline and intermediate 5th 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 α–adrenergic mediation

• Strong heritability in Heredity and Phenotype Intervention Heart Study in a population with strong founder effects: additive genetic effect 12-25%.

• 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

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 using SphygmoCor HRV system

• Time-Domain HRV measures– Mean and SD of mean RR interval

– PNN50 (% 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 & 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.