obesity: the challenge for today’s cardiologists · sheldon e. litwin, m.d. heart disease: the...

Sheldon E. Litwin, M.D.Alicia Spaulding-Paolozzi Professor of Cardiology

Medical University of South Carolina

Ralph H. Johnson VAMC

Disclosures:

None

Obesity: The challenge for today’s cardiologists

Sheldon E. Litwin, M.D.

The intersection of diseases

OBESITY HEART DISEASE


Heart Disease: The last 20 years

♦Mortality due to coronary artery disease dramatically decreased

♦Prevalence of heart failure continues to increase

♦Survival with heart failure has only marginally improved


Obesity: The Last 20 Years

♦ Obesity rates doubled over last 20 years in adults

♦ Tripled-quadrupled in children

♦ 7% of women and 3% of men are severely obese

♦ NHANES 2011-12: 34%, 2013-14: 37%

♦ Leading ““““preventable”””” cause of death (recently overtaken tobacco use), ~ 300,000/yr*

♦ Mortality most strongly associated with cardiovascular disease

♦ 10-21% of total health care costs in 2005 ($190 billion)

♦ $344 billion by 2018 (43% of Americans obese)


Obesity-related mortality♦ Reduced life expectancy in obese subjects

– Cancer prevention study (> 1 million subjects)

– NIH-AARP cohort (> 570,000 subjects)

♦ All show ““““U”””” shaped relationship between BMI and mortality

♦ 25 y.o. severely obese male has 22% ↓↓↓↓ in life expectancy (loss of 12 years of life)

Adams et al, NEJM 2006;355:763


Obesity Facts

♦ Leading ““““preventable”””” cause of death (now > tobacco use), estimated 300,000/year

♦ Cardiovascular disease, cancer, diabetes, OSA, arthritis, depression

♦ Excess mortality most strongly associated with cardiovascular disease– CAD, CHF, sudden death, stroke

♦ Cost: ~ $147 billion (2008), estimated $344 billion in 2018


56 y.o. AA woman with progressive dyspnea on exertion

♦Hx CHF, OSA, HTN, DM, arthritis, CKD

♦Highest weight 400 lbs, lowest 290 lbs

♦Dyspnea min exertion, can’t climb stairs

♦Sleeps in recliner x 2 years

♦Lower extremity edema

♦Some chest pain

♦No hx of tobacco, + DM, +HTN


HFpEF patient cont’d♦ Clonidine, carvedilol, amlodipine, doxazosin,

hydralazine

♦ Metolazone, spironolactone, bumex

♦ Weight 311 lbs, BMI 51, 158/70, hypoxic

♦ 1-2+ edema, JVP normal

♦ Impression

– Obesity, OSA, possible CHF (right heart?)

– Extensive discussion weight loss, bariatric

surgery EF 66%No ischemia

EA


HFpEF patient cont’d

♦Pulmonary evaluation

– FEV1 89% predicted

– Minimal bronchodilator response

♦Seen every few months over next 2 years

♦Minimal change in symptoms

♦ Intermittent steroids

♦Same discussion

♦Story to be continued…

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

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.

Obese

Overweight

Normal


Potential causes of CHF in obesity

♦CAD

♦HTN

♦ LVH

♦High output state

– Increased blood volume

– Increased lean and fat body mass

♦Hormonal/adipocytokine

♦OSA

♦Cardiorenal

– “Backward HF”

♦ Fat infiltration/lipotoxicity

♦ Inflammation

♦ “Pseudo” heart failure


Applicability (number of pa ents)

Cost

Lowest

Highest

Effec veness

&

Sustainability

Lowest

Highest

Lifestyle advice alone

Supervised Exercise

Meal Replacement

Bariatric Surgery

Pharmacological

Approaches to weight management

Figure 1.


Does weight loss change cardiovascular risk or survival?

Breaking news


Pharmacological Rx of ObesityDrug Class Current status

Phentermine/fenfluramine

(phen-fen)

NE reuptake blocker

Serotonin release & uptake

Fenfluramine 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

Metformin Biguanide (� gluconeogen) Approved DMII

Orlistat Lipase inhibitor

(blocks fat absorption)

OTC (small weight loss, GI

side effects)

Phentermine/Topiramate

(QsymiaTM)

NE reuptake blocker

Anticonvulsant, migraine

Approved*

Liraglutide (SandexaTM) GLP-1 agonist Approved*

Lorcascerin (BelviqTM) Serotonin agonist Approved*

Bupropion/Naltrexone

(ContraveTM)

Dopamine reuptake

inhib/Opioid receptor

antagonist

Approved*


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

TC LDL HDL TG


Lorcaserin (Belviq™)

Serotonin 5HT2c agonist

BLOOM–DMOneill et al.Obesity 2012 20: 1426-36

BLOSSOMFidler et alJ Clin Endocrinol Metab2011 96: 3067-77


Can we use weight loss for prevention or therapy of CVD

♦Efficacy (weight loss)

♦Safety

– Obesity paradox

♦Effectiveness for CVD

♦Cost effectiveness


Bariatric surgery: the only proven long-term therapy

Roux en Y GBPRestrictive/malabsorptive


Morbidity and Mortality Related to Gastric Bypass Surgery (2001-2015 DK-55006)

♦ 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/m2 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, 6 years and 12 years

Single center, prospective registry, University of Utah


Baseline characteristics

Surgery cases(n=420)

Denied controls(n=415)

Age 42 42

Gender (% female) 84 85

Weight (lbs) 295 285

BMI (kg/m2) 47 46

Systolic BP 126 126

Diastolic BP 71 72

Heart Rate 73 71

Apnea-hypopnea index

(hr-1)

22 21


Echocardiographic dataNonobese (n=59)

Obese (n=455)

P value

BMI (kg/m2) 24 45 <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

Concentric remodeling or hypertrophy despite nl BPNormal LV EFReduced MWFS (equivalent to strain)


The Impact of Obesity on the Left Ventricle: MESA

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

Obesity associated with concentric LVH with normal ejection fraction.Conventional wisdom about obesity incorrect!

LV

Ma

ss

(g

)

Eje

cti

on

Fra

cti

on

(%

)


LVH: Interaction between BMI,HTN and OSA

Avelar et al, Hypertension 2007;49:34


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


Unadjusted changes from baseline

Surgery Denied Control

Weight (lbs) -100* -14

BMI -15.9 * -2.4

Systolic BP -11 * -2

Diastolic BP -1.7 +0.3

Resting HR -13 * -6

Apnea-HypopneaIndex

-20 * -5.5

Avg nightime SpO2 +2.9 * -2.5

Changes in hemodynamic factors associated with LVH


LV mass after GBS

50

75

100

125

150

175

200

Baseline 2 Year F/U

LV

mass (

g)

Nonsurg

GBS

NS p < 0.0001

r = 0.49

p < 0.0001

Weight (lbs)

LV

ma

ss

(g

)

25 g decrease in LV mass after surgery> than the effect seen by instituting BP medications in pt’s w HTN


Mid wall fractional shortening(similar for systolic strain)

*

T statistic P value

Age -3.18 0.0018

Δ LV mass index -2.35 0.0197

Δ in E/e’ 1.47 0.1439

Ch

an

ge i

n M

WF

S *


Atrial Fibrillation and Obesity

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

Wang TJ, Parise H, Levy D, et al. Obesity and the risk

of new-onset atrial fibrillation. JAMA 2004;292:2471–7


Decreased Left Atrial Volume after GBS

54

55

56

57

58

59

60

61

62

63

64

Baseline 2 Year

GBS

Nonsurg

*


Adaptations to weight loss include:-Increased appetite-Susceptibility to food cues and reward eating-Disproportionately reduced total energy expenditure


SOS 10 year data: Banding vs. GBS


Weight regain after GBS

Weight recidivism does not cause recurrence of metabolic syndrome, but does reverse the drop in LV mass

Implication: LV mass governed by hemodynamics, not metabolic state


Persistent Obesity(n=253 nonsurgical patients)

Baseline Visit 4 (12 years)

LV mass (g) 188 208

LV EDV (ml) 96 111

RWT 0.51 0.45

LV Ejection Fraction (%) 65 68

LA dimension (cm) 3.87 3.99

LA volume (ml) 51 60

E/A 1.2 0.9

E/e’ 9.18 9.4

Is there a “cardiomyopathy of obesity”?


Can weight loss slow or reverse the progression of CAD?


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


Baseline Coronary Risk FactorsSurgery (n=420)

Denied Controls(n=421)

Glucose (mg/dl) 102 106

Hb A1C (%) 5.8 5.9

Insulin (IU/ml) 20 17*

HOMA-IR 5.1 4.6

LDL (mg/dl) 107 107

HDL (mg/dl) 46 44

Triglycerides (mg/dl) 185 185


Unadjusted changes from baseline

Surgery Denied Controls

Cholesterol (mg/dl) -21 * -4

Triglyceride (mg/dl) -79 * -19

HDL (mg/dl) +9.8 * -1.2

LDL (mg/dl) -14.7 * +1.8

Insulin (IU/ml) -21.0 * -6.6

HOMA- IR -6.2 * -1.4

Hb A1c (%) -0.25 * -0.03

Change in metabolic coronary risk factors


Percent of patients with resolved or new onset

Surgery Denied Controls

Diabetes resolved 81% 21%

Diabetes new onset 1% 4%

Hypertension resolved 45% 8%

Hypertension new onset 1% 6%

CAD new 1 0

Stroke new 0 0

Cancer new 1 1

Cured diseases


Predicted change in CV risk

♦Obesity associated with unfavorable CV risk factors

♦Beneficial 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


Can GBS slow progression of CAD?

• Subjects returning for 6 year follow up offered coronary calcium scanning

• Enrolled 136 consecutive subjects

• CAC score

• Single abdominal slice at L4 to determine visceral adipose tissue volume


Coronary Calcium Scores


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?

• Relatively few “hard” end-points so far

• Don’t know if lower CAC scores translates into lower CV events


Survival

♦2 years: 2 deaths GBS (0.4%), 3 denied controls

♦Perioperative mortality low

♦6 years: 12 deaths in GBS subjects (3%), 14 in control group 1 (3%) and three in control group 2 (1%)

♦Mortality after GBS previously reported much higher in older men in 1 VA study


Effects of bariatric surgery on mortality in Swedish Obese Subjects. Sjostrom et al NEJM 2007; 357:741


Summary of Utah Obesity Study

♦Reduced diabetes, HTN, OSA

♦Decreased LV mass

♦ Improved midwall fractional shortening

♦Decreased LA size

♦Reduced coronary calcium

♦Weight regain -> persistent metabolic improvement, but return of LV mass

♦ Persistent obesity -> gradual increase LV mass

♦ Treatment for CHF?


Heart Failure with Preserved Ejection Fraction (HFpEF)

Normal HF reduced EF

HF preserved EF

• 50% of HF cases

• No effective treatment


♦Obesity

♦Hypertension

♦Atrial Fibrillation

♦Kidney Dysfunction

♦Diabetes

♦Sleep apnea

Heart Failure with Preserved Ejection Fraction (HFpEF)


WTLSSCHF-1

♦ Intensive lifestyle modification

– Meal replacement

♦13 of planned 50 patients enrolled

♦4 patients completed 15 week program

Sheldon E. Litwin, M.D.J Am Coll Cardiol 2016;67:895–903

-524 HF pt’s who had bariatric surgery (administrative data)-HF hospitalization rate before and after surgery


LV EF after bariatric surgeryVest et al. Circ Heart Fail. 2016;9:e002260

• Retrospective review• Bariatric patients w EF < 50%

and 2 echoes (n=38), mean 698 days

• Obese controls (n=38)• Weight loss 22% in LVSD

group vs. 28% in nl EF group• 12 month mortality 0/41w

LVSD vs. 27/2559 (1%)

Surgery + 5.1%Control +3.4%


Our patient♦F/U visit, 1 month s/p gastric bypass

surgery♦Lost 40 lbs♦No edema♦DC’d amlodipine, hydralazine, ♦DC’d DM medications♦Breathing much better

♦8 month’s, lost 100 lbs♦Off diuretics♦“New person”


Conclusions♦Resurrection of drugs for obesity?

♦Should we offer GBS more liberally?

– Less severe obesity

– Younger ages

– Known CV disease

♦ Is GBS cost-effective?

♦Proof that surgically-induced weight loss reduces cardiovascular events

– MI/ACS

– Atrial fibrillation, other arrythmias

– CHF

obesity: the challenge for today’s cardiologists · sheldon e. litwin, m.d. heart disease: the...

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