sheldon litwin md presentation-6-5-2011 - oregon acc · 2 sheldon e. litwin, m.d. obesity-related...

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Sheldon E. Litwin, M.D.Chief, Cardiology Division, Georgia Health Sciences

University

Disclosures:

None

Obesity and the Heart: Can Weight Loss Reverse Remodeling and Slow

Atherosclerosis?

Sheldon E. Litwin, M.D.

The problem…

♦Prevalence of overweight and obesity are increasing (~70% of people in the USA)♦5% severely obese (2.8% Male, 6.9% Female)

In the last quarter we saw remarkable gains.

10%…15%…even 20%!

With minimal losses, all signs point to

unprecedented growth in the future. In other

words…

Net worth is up!!

Net WEIGHT is up.


Obesity Facts

♦ Leading “preventable” cause of death (now > tobacco use), estimated 300,000/year*♦ Cardiovascular disease, cancer, diabetes, OSA,

arthritis, depression♦ Mortality most strongly associated with cardiovascu lar

disease– CAD, CHF, sudden death, stroke

♦ Cost (in 1995 dollars) ~ $99.2 billion$51.6 billion direct / $47.6 billion indirect

♦ 5.7% of total health care costs in 1995

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Obesity-related morbidity and mortality

♦Nearly all studies show reduced life expectancy in obese subjects– Cancer prevention study (> 1 million subjects)– Large Chinese study (> 150,000 subjects)– 2 recent papers in NEJM (2006)♦ “U” shaped relationship between BMI and

mortality♦ 25 y.o. severely obese male has 22% ↓ in life

expectancy (loss of 12 years of life)

Obesity and the risk of heart failure. Kenechiah et al, NEJM 2002;347:305

Obese

Overweight

Normal

Based on BMI at time of enrollment.

Mean age at enrollment was 53 years.

Of the patients who had an echo near the time of CHF dx, most had a reduced EF.


Obesity and CAD Risk Factors

♦Hypertension♦Dyslipidemia

– Particularly low HDL, high TG

♦Diabetes/glucose intolerance♦Sleep disordered breathing♦Inflammatory state♦Physical inactivity

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Obesity and age of first MI. Madala et al. JACC 2008

CRUSADE registry, 189,000 patients, 2001-2007

Most obese subgroup (BMI > 40) were 15 years younger than leanest subgroup at time of first MI


Other potential causes of CHF in obesity

♦HTN♦LVH♦High output state

– Increased blood volume– Increased lean and fat body mass

♦Fat infiltration/lipotoxicity


What physicians do about obesity…

� Our advice is not useful, not followed or ineffective

�Weight loss achieved by lifestyle modification is not maintained

� Long term use of diet drugs is unsafe or unstudied; however, obesity is clearly chronic

�Severe obesity is refractory to drug and diet therapy

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Pharmacological Rx of ObesityDrug Class Current status

Phentermine/fenfluramine (phen-fen)

NE reuptake blockerSerotonin release & uptake

Withdrawn due to valve damage & PHTN

Sibutramine NE & serotonin reuptake blocker

Withdrawn due to adverse CV effects

Rimonabant cannabinoid receptor inhibitor

Withdrawn due to depression/suicide

Orlistat Lipase inhibitor OTC (small weight loss, GI side effects)

Phentermine/Topiramate NE reuptake blockerAnticonvulsant, migraine

Investigational*

Metformin Biguanide (� glucogeogen) Approved DMII

Exenatide, Liraglutide GLP-1 agonists Approved DMII

Fluoxetine, Sertraline SSRI’s Rx of depression

Bupropion Dopamine reuptake inhib investigational

Zonisamide anticonvulsantSerotonin/dopamine agonist

investigational


Effects of low dose, controlled release, phentermin e plus topiramate combination on weight and associated com orbities in overweight and obese adults (CONQUER): A randomized , placebo-controlled phase 3 trialGadde KM, et al Lancet 2011; 377:1341-52


Bariatric surgery: the only therapy that really works

Roux en Y GBPRestrictive/malabsorptive

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Gaps in bariatric surgical research

♦Generalizability♦Safety♦Longitudinal Outcomes/durability

– Adequate control group

♦Differences between procedures– restrictive vs. malabsorptive

Courcalis AP, Flum DR. JAMA 2005; 254:1957-1960


Morbidity and Mortality Related to Gastric Bypass Surgery (2001-2015)

♦ Body weight and composition♦ Lipid profile♦ Fasting glucose, insulin,

HgbA1C♦ Echocardiography♦ Limited polysomnography♦ PFT’s♦ Blood pressure♦ Exercise Testing♦ Physical activity/diet♦ Quality of life assessment♦ CAC scoring

� 1156 severely obese subjects (BMI > 40 kg/m 2 or > 35 with complications)

� 423 GBS, 412 seeking surgery but denied by insurance, 321 controls not seeking surgery

� ~850 subjects had overnight admission to GCRC with extensive testing

� Return visit at 2 years, 5 years and 10 years

Single center, prospective registry, University of Utah


Baseline demographics and Cardiovascular risk factors

Sugery cases Denied controls

Age 42 42

BMI 47 46

Systolic BP 126 126

Diastolic BP 71 72

Heart Rate 73 71

Glucose 102 106

Hb A1C 5.8 5.9

Insulin 20 17*

HOMA-IR 5.1 4.6

LDL 107 107

HDL 46 44

Triglycerides 185 185

Apnea-hypopnea index

22 21

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Echocardiographic dataNonobese (n=59)

Obese (n=455)

P value

BMI (kg/m2) 24 45 <0.001

Systolic BP (mmHg) 113 123 0.001

Diastolic BP (mmHg) 69 70 NS

Heart Rate (bpm) 67 73 <0.001

Septal thickness (cm) 0.9 1.1 <0.001

PW thickness (cm) 0.8 1.0 <0.001

LVIDd (cm) 4.4 4.7 0.001

Relative wall thickness 0.40 0.46 <0.001

LV mass index (g/ht2.7) 40 58 <0.001

Fractional Shortening (%) 35 35 NS

Mid wall FS (%) 17 15 <0.001


Interaction between BMI,HTN and OSA

Avelar et al, Hypertension 2007;49:34


The Impact of Obesity on the Left Ventricle: MESA

Turkbey et al, JACC imaging. 2010;3:266-274

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Picture brought in by a proud and happy participant in our study at the time of his 2 year follow up visit

Average weight loss in GBS subjects at 2 years = -100 lbs

Average change in BMI at 2 years = -15 units


Abdominal CT ScansNonsurgery Subjects Surgery Subjects


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Cured Diseases

Table 8. Percent of Subjects with New Onset or Resolved DiseaseDisease Surgery

CasesDeniedControls

RandomControls

DiabetesResolved 81 21 9Incidence since baseline 1 4 8HypertensionResolved 45 8 5Incidence since baseline 1 6 10

CAD incidence 1 0 0Stroke incidence 0 0 1Cancer incidence 1 1 2


Survival

♦5 deaths at 2 year time point (2 cases, 3 denied, 95% complete follow up)♦Perioperative mortality low and

comparable to published data♦Compare to older medicare patients

undergoing GBS with much higher 6-12 month mortality– Worse in males– Worse with surgeons performing lower

numbers of procedures


LV mass after GBS

50

75

100

125

150

175

200

Baseline 2 Year F/U

LV m

ass (

g)

NonsurgGBS

NS p < 0.0001

r = 0.49t = 13.46p < 0.0001

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Mid wall fractional shortening


Tissue Doppler Imaging

• Tissue Doppler Images of septal mitralannulus were measured in early diastole(E’), late diastole (A’) and systole (S’).

S’

E’ A’


TDI in GBS patients

♦TDI not part of routine echo at the beginning of the study♦Did not begin acquiring this data until

more than half way through the baseline studies♦Subsequent slides, will show

comparison of 2 year data in ~ 250 subjects/group (GBS vs. Nonsurgery)

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Tissue Doppler (2 year data)

*1.06 ± .36

0.87 ± .29

E’ /A’

GastricBypass

Non-Surgical

*8.3 ± 1.6*10.1 ± 2.1*10.2 ± 2.6

8.8 ± 2.011.1 ± 2.69.2 ± 2.3

S’ (cm/s)A’ (cm/s)E’ (cm/s)

Significantly higher in Gastric Bypass group

Significantly lower in Gastric Bypass group

* p < 0.05 vs. Nonsurg


Clinical Correlates of TDI

.121 .081 - .239 .203A’

.092 .023 - .122 .133S’

- .241* - .296* .298* - .251*E’/A’

- .232 - .302* .185 - .152E’

Fasting Glucose(mg/dL)

SystolicBloodPressure(mmHg)

ExerciseDuration(sec)

BMI(kg/m2)

Inversely related variables with statistical signif icancePositively related variables with statistical signi ficance


Importance of Left Atrial Size

♦Multiple studies show left atrial size to be a very powerful predictor of survival♦Atrial size is thought to be an indicator of

the average filling pressures over time (the “hemoglobin A1C of the heart”)

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Atrial Fibrillation and Obesity

The association between atrial fibrillation and BMI disappeared when LA dimension was put into the multivariate analysis


Decreased Left Atrial Volume after GBS

5455565758596061626364

Baseline 2 Year

GBSNonsurg

*


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Change in weight vs. LV mass: Effects of weight regainde las Fuentes, et al. JACC 2009;54:2376-81

Dietary interventionAverage weight loss 9.9 kg

Diet vs. Surgery?Rider, et al. JACC 2009;54:718-26

Weight loss in diet group = 12 kgWeight loss in surgery group = 33 kg


SOS 10 year data: Banding vs. GBS


Predicted change in CV risk♦Obesity associated with unfavorable CV risk

factors♦ Favorable changes in BP, lipids, glucose

homeostasis after surgery♦Meta-analysis of 6 studies reporting changes

in CV risk factors after bariatric surgery♦ 10 year Framingham or PROCAM risk

calculated from 7% to 3.5% and 4.1% to 2%, respectively (RR reduction 18-79%)– Batsis et al, Am J Cardiol 2008;102:930-937

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Can weight loss slow or reverse the progression of CAD?


Coronary CalciumCACS = 285 CACS > 4000


Obesity and the presence or progression of coronary calcification

♦Dallas Heart Study (JACC 2007;50:752)

♦ CAC prevalence significantly greater in 5th vs. 1st quintile of BMI, but increased stepwise across quintiles of waist circumference and waist/hip♦ WHR independ predictor

after adjustment for standard risk factors

♦MESA (Circ 2007;115:2722)

♦ Risk factors for progression of CAC♦ Newly detectable CAC

6% per yr♦ With existing CAC,

median annual change 14-21 Agatston units♦ BMI mild, but signif

predictor of progression♦ Diabetes strongest

predictor of progression

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CAC Progression and risk of MI

Raggi, ATVB, 2007;24:1272


Can GBS slow progression of CAD?

• Subjects returning for 5 year follow up offered coronary calcium scanning

• IRB approved, signed consent form• Enrolled 136 consecutive subjects

• CAC score• Single abdominal slice at L4 to determine visceral

adipose tissue volume


Results of CAC Substudy

GBS group No surgery

P value

N=61 N=72

Weight change (pounds) -93 +0.3 <0.01

Visceral adipose tissue (mL): mean ± SD

55 ± 39 143± 63 <0.01

Systolic BP change (mmHg) -4.6 -6.6 NS

LDL cholesterol change (mg/dL) -7.8 4.0 0.04

Glucose change -18 -11 NS

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Results of CAC SubstudyGBS No surgery P

value

n=61 n=72

CAC score: mean ± SD (range)

33 ± 114 (0-645)

107 ± 340 (0-2517) <0.01

CAC score: zero 67% (n=41) 43% (n=31)

<0.01CAC score: 1-10 16% (n=10) 22% (n=16)

CAC score: 11-100 10% (n=7) 18% (n=13)

CAC score: >100 7% (n=4) 17% (n=12)

•GBS patients more likely to have zero CAC; OR = 2.3, p=0.04•Independent of gender, age, smoking, systolic BP, a nd LDL cholesterol


Limitations

• No baseline CAC score• Risk factors for cardiovascular disease similar at

baseline

• Non surgical patients had no weight loss• Would diet induced weight loss be the same or

better?

• Few “hard end-points” so far• Don’t know if lower CAC scores translates into lowe r

CV events


Conclusions

• Severely obese with GBS surgery• Lower CAC than obese without surgery• More likely to have zero CAC

• GBS may slow progression of coronary atherosclerosis, at least partially independent of traditional risk factors

• Long follow up in our study (5 years) and Women’s Health Initiative (7 years) may explain the ability to detect slowing of CAC progression

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Conclusions

♦Should we offer GBS more liberally?– Less severe obesity– Younger ages

♦Is GBS cost-effective?♦Proof that surgically-induced weight loss

reduces cardiovascular events– MI/ACS– Atrial fibrillation, other arrythmias– CHF

Does Obesity Affect Response to Treatment in Acute Decompensated Heart

Failure?: A Diuretic Optimization Strategies Evaluation (DOSE) Trial Substudy

Achal Gupta, Josef Stehlik, Steven McNulty, Kerry M . Lee, Edward M. Gilbert, Feras M. Bader, Kevin Anstrom, Deborah Budge, Abdallah G. Kfoury, Rami Alharethi, David A. Bull, Margaret M. Redield, G. Michael Felk er, Divya R. Verma, Stavros G. Drakos, Theophilus E. Ow an, Christopher M. O’Connor and Sheldon E. Litwin

• Obesity might affect diuretic responsiveness:- pharmacokinetics- risk of chronic kidney disease- � intra-abdominal pressure �� renal perfusion

• Diuretic Optimization Strategies Evaluation (DOSE) study- randomized 308 pts with acute HF to low (1.0 x dail y oral dose) vs. high (2.5 x daily oral dose) intensi fication intravenous diuretic therapy - mean BMI = 33.6.

Post Hoc analysis splitting patients by enrollment BMI < 30 or ≥ 30 kg/m 2

Background

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Results: Patient Characteristics♦ Obese and non-obese patients had similar gender

distribution, etiology of HF, qualifying furosemide dosage, number of HF hospitalizations in the past 12 months, history of atrial fibrillation and basel ine serum creatinine.

BMI≤30 (N=119) BMI>30 (N=173) P-Value

Age 69.7±13.1 64.3±13.5 <0.001

LVEF (%) 32.5±16.7 36.6±17.9 0.029

Diabetes Mellitus 38% 61% <0.001

Systolic BP (mm Hg) 114±17 121±21 0.004

NT Pro-BNP (pg/mL) 10,135±7898 5,630±6479 <0.001

Results: Primary & Secondary Endpoints

BMI≤30 (N=119)

BMI>30 (N=173)

P-Value

Global assessment of symptoms Visual analog scale(VAS) area under the curve ( AUC) (72 hrs)

4180±1452 4329±1417 0.666

Free from congestion at 72 hrs (%) 14.0±16 14.2±24 0.969

Fluid loss at 72 hrs (mL) 3654±3036 4631±3184 0.019

NT Pro-BNP, change at 72hrs (pg/mL)

-2165±4665 -1153±3731 0.825

Serum creatinine (mg/dL)- change at at 72 hrs- change at 60 days

-0.00±0.280.05±0.41

0.09±0.310.11±0.45

0.0060.368

Worsening Renal Function (Cr � > 0.3 mg/dl)

- at 72 hrs- 60 days

13%22%

22%22%

0.0640.934


Fluid Loss

Low Intensification Strategy

High Intensification Strategy

P-Value

BMI≤30(N=61) (N=58)

0.018Fluid loss (ml, 72 hrs) 2945±2268 4409±3555

BMI>30(N=83) (N=90)

0.014Fluid loss (ml, 72 hrs) 3962±2726 5272±3467

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Worsening Renal Function

024681012141618

24 48 72

Worse

ning r

enal

functi

on (%

)

Hours from randomization

High intensification strategy

024681012141618

24 48 72

Worse

ning r

enal

functi

on (%

)

Hours from randomization

Low intensification strategy

Non obese (BMI <=30)Obese (BMI > 30)


Time to First Event: Death, Re-hospitalization, ER Visit


Conclusions

♦High intensification intravenous diuretic treatment in obese patients produces greater volume loss without additional detrimental effect on renal function. This strategy may be preferable as initial approach in the growing population of obese patients with heart failure.

♦ Additional study specifically targeted to treatment of obese subjects with HF is warranted

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Obesity and the heart

♦Increased CV morbidity and mortality– CHF, AF, CAD, stroke, sudden death

♦Weight loss reverses risk factors– LVH, LAE, CV risk factors (BP, glucose,

lipids)

♦Possible slowing of atherosclerosis♦First data suggesting treatment

strategies based on adiposity


Thank YouSteve HuntTed AdamsSara Frogley

Russel VinickNathan WannerMike StrongRobert Pendleton

Theophilus OwanTravis AultTiffany PriesterRonny Jiji Nathaniel HallZachary Williams Kimberly Morley

Tom ClowardTom NuttallJim WalkerFrank Yanowitz

Sonographers & Staff at Univ of Utah Echo lab

Erick AvelarNate SegersonBrigham SmithKevin PreeceLillian KhorDivya KapoorJames Gallagher

Josef StehlikAchal GuptaDOSE investigators


Abdominal CT Scans:Adipose tissue quantification

Noncontrast scan

Nonsurgery Subjects

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Noncontrast Heart CTNonsurgery Subject Surgery Subject

4 Ch

SAX

4 Ch

SAX


Epicardial Fat: New risk factor?

♦ Visceral fat believed to contribute directly to met abolic syndrome (insulin resistance)♦ Epicardial fat suggested to behave similarly and th us increase

risk of CAD (produces inflammatory cytokines)♦ At 5 year f/u, epicardial fat was lower in GBS vs. Nonsurg subjects

(89 cc vs. 150 cc, p < 0.05).♦ Correlation between visceral and epicardial fat (ov erall r = 0.8, p <

0.001; GBS r = 0.71, Nonsurg r = 0.72)♦ Epicardial fat correlates w BMI (r = 0.63) & waist circumference (r

= 0.69)♦ Epicardial fat volume not different in those with z ero CAC vs.

those with > zero CACS (113 cc vs. 155 cc Nonsurg) ♦ Conclusions: Visceral fat declines more than epicar dial fat after

GBS. Epicardial fat volume is related to BMI, waist circumference and visceral fat. However, no clear link between ep icardial fat and coronary calcification was found.


Subclinical LV dysfunction in obesity

♦ Several studies showing normal ejection fraction, but decreased midwall fractional shortening, strain and strain rate♦Mechanism is probably increased radial

excursion due to concentric hypertrophy, but reduced longitudinal shortening due to myocyte dysfunction♦Unclear if these abnormalities improve with

weight loss

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Diastole

Myocyte shortening

Systole

Overestimation of Myocardial Function in LVH

Diastole

Nor

mal

LVH

70%

Systole EF

55%


Pseudonormal systolic function


What is strain?

♦ Regional deformation (shortening or lengthening)– Like fractional shortening of a piece of myocardium

♦ How is it measured?– MRI tissue tagging– Tissue Doppler– Speckle tracking

♦ Regional myocardial function in systole or diastole– Speckle tracking not sensitive to transducer positi on or

angulation– Not affected by translation, tethering or function of adjacent

segments

♦ Can assess longitudinal, radial or circumferential deformation, movement and velocity

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Speckle Tracking

Unique patterns (“fingerprints”) in the myocardium created by myofibers and backscatter


Velocity Vector Imaging™


Normal Strain

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Strain: Abnormal


Strain analysis♦ 62 subjects studied at baseline and 2 years after G BS♦ Longitudinal strain and strain rate in 4 chamber vi ew♦ Global strain (average of 6 sements)♦ Strain increased from BL to 2 year visit

– -18.7±3.8 to -21.7±4.1 (p < 0.001)

♦ Strain rate tended to increase– -1.15±0.3 to -1.25±0.3 (p = 0.07)

♦ Positive correlation between change in BMI and change in strain between visit 1 and visit 2– Independent of LV mass, systolic BP and age

♦ Conclusions: GBS associated with long term improvement in myocardial function. Associated with amount of weight loss, but not explained by traditi onal hemodynamic or metabolic parameters.

sheldon litwin md presentation-6-5-2011 - oregon acc · 2 sheldon e. litwin, m.d. obesity-related...

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