Physical Activity and Cardiovascular Disease ANDREAS PITTARAS MD

Survival of the Fittest “…in the last 15 years, many epidemiological studies have shown an unequivocal and robust relationship of fitness, physical activity, and exercise to reduce overall and CVD mortality.” Balady JG, New Engl J Med 2002;346 (11):852-53

Coronary Heart Disease and Physical Activity of Work Morris JN, et al Coronary Heart Disease and Physical Activity of Work Morris JN, et al. Lancet 1953:2:1053-1120 Approximately 50% lower risk of CHD in those with physically demanding (i.e. mail carriers) vs those with sedentary occupations (i.e. desk clerks).

Physical Activity and the Incidence of Coronary Heart Disease Powell KE, et al. Annu Rev Public Health 1987; 8:253-87 121 studies reviewed; 43 were included. The relationship between sedentary lifestyle and increase risk of CHD is likely to be causal.

Ann Review Public Health 1987; 8:253-87 Relative Risk for CAD Ann Review Public Health 1987; 8:253-87 RR Physical Inactivity SBP>150 mm Hg TC>268 mg/dL Smoking >1 pack

Population Attributable Risk by Risk Factor

It is Estimated that 250,000 Deaths/Year in the USA are Attributable to Lack of Regular Physical Activity Siegel PZ, at al., Weekly Reports 1991

Physical Activity Status in US Population 20% - 22% - Exercise Regularly 40% - 54% - Some Activity 24% - 40% - Sedentary 34% of pts are being counseled by physicians to begin or continue exercise.

AHA Position Statement Circulation 1991:86(1):340-44 Physical inactivity an as independent risk factor for the development of CHD equal in status to the traditional risk factors of HTN, DM, Dyslipidemia and smoking.

Exercise Type ? Most information is derived from aerobic exercise studies. Some evidence from occupational studies support that repeated busts of high energy output may offer protection against premature coronary mortality.

Dynamic/Isotonic Exercise Low Intensity Aerobic FFA as Fuel High Intensity Anaerobic CHO as Fuel -Walking -Jogging -Cycling Strength Training

Physiologic Adaptations to Exercise Training Chronic exercise of proper intensity, duration and frequency imposes a demand on the body. Consequently, the body makes appropriate and specific changes to accommodate the imposed demand.

Cardiovascular Adaptations with Aerobic Exercise Decrease Rest HR & BP Rest & Exercise RPP Exercise HR & BP (abs. WL) ESV Increase LV Chamber EDV SV CO VO2 max

Cardiovascular Adaptations with Anaerobic Exercise No Change Rest HR & BP Rest & Exercise RPP Exercise HR & BP (abs. WL) ESV No Change LV Chamber ? EDV ? SV CO VO2 max

LVH with Aerobic and Anaerobic Exercise Volume Load Diastolic Stress New Fibers in Series Chamber size Eccentric LVH Anaerobic Pressure Load Systolic Stress New fibers in parallel Wall Thickness Concentric LVH

CHD Death in Norwegian Men 40-59 years of Age (N=2,014) Lie et al. Eur Heart J ’85; 147-57 P<0.001 CHD Daeth in 7 yr/100 Fitness Quartiles

CVD Death /10,000 person-years CVD Death in Men (N=10,224) Blair et al. JAMA1989; 262:2395-2401 CVD Death /10,000 person-years METs

A Prospective Study of Walking as Compared with Vigorous Exercise in the Prevention of CHD in Women Manson JE, et al., NEJM 1999;341:650-8 N = 72,488 Female Nurses Age : 40 to 65 yrs old in 1986 Free of CVD or Cancer Follow-up: 8 yrs Incidence of Coronary Events: 645 Fatal or Non-Fatal MI

Physical Activity & RR Adjusted for Confounding Factors (N=72,488) Mason JE, et al. NEJM:’99;341:650-8 P<0.001 Physical Activity Quintiles

Relative Risk for Coronary Events and Walking Pace (n=72,488) Mason JE, et al. NEJM:’99;341:650-8 Relative Risk Walking Pace (min/mile)

Relative Risk for Coronary Events and Walking Time Mason JE, et al. NEJM:’99;341:650-8 RR Minutes Walking/Wk

Relative Risk for Coronary Events and Walking Time in Women (n=72,488) Mason JE, et al. NEJM:’99;341:650-8 RR Minutes Walking/Wk

F I N D I N G S Brisk Walking for 100-200 min/week at a Pace of <20 min/mile or <13 min/km. Reduces the Risk for Coronary Events in Women by 30 to 40 Percent. Similar Caloric Expenditure Yields Similar Reductions in Risk for Coronary Events.

Are Exercise Health Benefits Long-Lasting? The Harvard Alumni study (n=16,936) has shown that Ex-Varsity athletes retained lower risk for CHD only if they maintained a physically active lifestyle throughout life. Paffenberger et al., Am J Epidemiol 1978 108(3):161-175

Relative Risk of CHD & Aerobic Activity in Men (N=51,529) RR Tanasescu M, et al. JAMA:’02;288:1994-2000 P<0.001

Survival for Fit & Unfit Men (n=9,777) Blair et al, JAMA 1995;273:1093-97 Survival Probability Unfit to Fit 44% Reduction in Risk Unfit to Unfit

How Much Physical Activity?

How Much Exercise? Not an easy Question Exercise Intensity, Duration and Frequency must be considered, as well as the interaction. Caloric expenditure is one approach. Intensity still may play an independent role.

Physical Activity and All –Cause and CVD Mortality in Women >65 yrs Gregg EW, et al. JAMA’03;289:2379--86 Relative Risk CVD Kcal/wk

Weekly Energy Expanded and Relative Risk of CHD in Men (n=7,337) Lee, I-Min et al. Circulation 2003;107:1110-16 Relative Risk * Kcal/Week

Age-adjusted First MI Rates by Physical Activity (n=16,963) Paffenbarger et al., Am J Epidem. 1978;108(3):161-75 MI/10,000 person-yrs Total Non-Fatal Fatal

Exercise Intensity and Relative Risk of CHD in Men (n=7,337) Lee I-Min, et al. Circulation 2003;107:1110-16 Relative Risk Kcal/Week

Exercise Intensity and Relative Risk of CHD in Men (n=7,337) Lee I-Min, et al. Circulation 2003;107:1110-16 Relative Risk

Relative Risk of All-Cause Death and Exercise Capacity Myers J et al. NEJM 2002;346:793-801 RR of Death <6 METS 6-7.9 METS 8-9.9 METS 10-12.9 METS >13 METS Quintiles of Exercise Capacity

Survival Curves for Normal and CVD Patients According to Exercise Capacity Myers J et al. NEJM 2002;346:793-801

Conclusions Myers J et al. NEJM 2002;346:793-801 Exercise Capacity is a more powerful predictor of mortality for CVD than other established risk factors. A linear reduction in mortality. For each 1 MET increase in exercise capacity, a 12%, decrease in mortality was observed.

Exercise Capacity and Risk of Death in Women Gulati M, et al. Circulation 2003;108:1554-59 Hazard Ratio of Death 3.1 1.9

Exercise Capacity and Risk of Death in Women

Gulati M, et al. Circulation 2003;108:1554-59 Conclusions Gulati M, et al. Circulation 2003;108:1554-59 Exercise capacity is a strong and independent predictor of all-cause mortality in asymptomatic women, even after adjusting for traditional cardiac risk factors. For each 1 MET increase in exercise capacity, a 17%, decrease in mortality was observed.

Exercise Threshold for Health Benefits METs < 4 – 5 7 10 ? Threshold Intensity Fast walk Running 6 km/hr 10 km/hr Kcal/wk 500 - 1000 3,000 120 min/wk 750 - 1050 1,500 240 min/wk 1500-2100 3,000

Exercise in Patients with Risk factors and/or Chronic Disease

Age-Adjusted CVD Death Rates &CHD Risk Factors (n=26,980) Blair, et al. JAMA 1996 51 Death Rate Death Rate 27.5 46 12.6 Cardiorespiratory Fitness

Relative Risk of All-Cause Death and Exercise Capacity Myers J et al. 2002;346:793-801 RR of Death >8 Mets 5-8 Mets <5 Mets

CV Events and Physical Activity in Diabetic Women (n=5125) Hu F, et al. Ann Intern Med :’01;134;96-105 Relative Risk * Hours/Wk

Body Weight/ Obesity

Relative Risk for Physical Activity & BMI, Adjusted For Risk Factors Mason JE, et al. NEJM:’99;341:650-8 RR >29 N=72,488 <29 Physical Activity Quintiles

F I N D I N G S Brisk Walking for 100-200 min/week at a Pace of <20 min/mile or <13 min/km. Reduces the Risk for Coronary Events in Women by 30 to 40 Percent. Similar Caloric Expenditure Yields Similar Reductions in Risk for Coronary Events.

Relative Risk of All-Cause Death and Exercise Capacity Myers J et al. 2002;346:793-801 RR of Death Normal CVD <6 METS 6-7.9 METS 8-9.9 METS 10-12.9 METS >13 METS Quintiles of Exercise Capacity

Conclusions Myers J et al. 2002;346:793-801 Exercise Capacity is a more powerful predictor of mortality for CVD than other established risk factors. A linear reduction in mortality. For each 1 MET increase in exercise capacity, a 12%, decrease in mortality was observed.

S T R O K E

The NIH Consensus Development Panel on Physical Activity and CVD JAMA ‘96;276:241-46 Data are inadequate to determine whether stroke incidence is affected by physical activity or exercise training.

Follow-up: 8 years (560,087 person-years) 407 Strokes Physical Activity and Risk of Stroke in Women Hu FB, et al , JAMA 2000;283:2961-67 N=72,488 Female Nurses with no CVD or Cancer at Baseline Age: 40-65 years Follow-up: 8 years (560,087 person-years) 407 Strokes 258 Ischemic 67 Subarachnoid Hemorrhages 42 Intracerebral & 40 of Unknown type

Multivariate Relative Risk of Total Strokes P=0.005 MET Quintiles

Multivariate RR for Ischemic Strokes Relative Risk P=0.003 MET Quintiles

Multivariate Relative Risk of Total Strokes by Walking Activity P=0.01 METS

Multivariate Relative Risk of Ischemic Strokes by Walking Activity p=0.02 METS

RR of Total Strokes by Walking Pace Relative Risk Age-Adjusted Multivariate P<0.001

Relative Risk of Hemorrhagic Strokes by Walking Pace Age-Adjusted P<0.06 Multivariate

Findings and Conclusions Sedentary women who became active in middle to late adulthood had significantly lower risk for: Total Strokes : 27% - Age-adjusted 20% - Multivariate Ischemic Strokes: 38% - Age-adjusted 30% - Multivariate

Findings and Conclusions Walking pace is strongly associated with risk of stroke, Independent of the number of hours spent walking. Comparable magnitudes of risk reduction with equivalent energy expenditures from walking and vigorous activity.

Physical Activity ?? Cardiac Function HTN Dyslipidemia Body Fat Endothelial Function DM Type II

Hypertension

Kokkinos P., et al. Cardiology Clinics 2001;19(3):507-516 Average Reduction in BP: Active: 10.5/7.6 mm Hg Controls: 3.8/1.3 mm Hg

BP Changes with Exercise Kokkinos ,Pittaraset al. NEJM 1995;333:1462-7 mm Hg SBP DBP P<0.05 16 weeks 32 weeks

BP Changes with Exercise mm Hg 2 Wks 2 Wks 16 Wks 16 Wks DBP SBP

Relative Risk of All-Cause Death and Exercise Capacity in Hypertensive Patients Myers J et al. 2002;346:793-801 RR of Death

LVMI at Baseline and 16 Weeks Kokkinos, Pittaras et al. NEJM 1995;333:1462-7 * p<0.05 * Baseline 16 weeks

Wall Thickness at Baseline and 16 wks Kokkinos, Pittaras et al. NEJM 1995;333:1462-7 mm * p<0.05 * *

Left ventricular hypertrophy is a powerful and independent predictor of cardiovascular events in patients with and without obstructive coronary disease. Ghali JK et al., 1992; Ann Intern Med 1992;117:831-36 Koren MJ et al., 1991; Ann Intern Med 1991;114:345-52 Casale PN, et al., Ann Intern Med 1986;105:173-78

Rodriguez et al., JACC 2002;39(2):1482-8 LV Mass and Stroke Odds Ratio Unadjusted Adjusted Quartiles of LV Mass

LVH, Physical Activity and Risk of Stroke Rodriguez et al., JACC 2002;39(2):1482-8 LVH, Physical Activity and Risk of Stroke Adjusted Odds Ratio Active 4.79 3.92 3.53 3.29 2.9

LVH, Physical Activity & Risk of Stroke Rodriguez et al., JACC 2002;39(2):1482-8 LVH, Physical Activity & Risk of Stroke Odds Ratio Sedentary Active

SBP Following Aerobic Training Kokkinos et al, AJC 1997 p<0.01 * * * *

May mitigate the hemodynamic load during daily physical activities. Attenuate the development and/or progression of LVH.

Patient Adapts Sedentary Lifestyle Heart Failure Skeletal Muscle Atrophy Patient Adapts Sedentary Lifestyle Diminished Aerobic Capacity Muscular Changes Cardiorespiratory Changes Neurohormonal Changes Kokkinos et al.. AHJ:140(1): 2000

All Cardiac Event Survival for HF Patients Belardinelli et al, Circulation ‘ 99;99:1173-82 Trained Untrained

Hospitalization for Heart Failure Belardinelli et al, Circulation ‘ 99;99:1173-82 Trained Untrained

Cardiac Deaths for HF Patients Belardinelli et al, Circulation ‘ 99;99:1173-82 Trained Untrained

Lipid & Lipoprotein Metabolism

Changes in Lipids & Lipoproteins with Exercise and Diet in Men Wood et al., NEJM 1991;325:461-6 % Change Control Diet Diet+Ex HDL-C TG LDL-C

Changes in Lipids & Lipoproteins with Exercise and Diet in Women Wood et al., NEJM 1991;325:461-6 % Change Control Diet Diet+Ex TG HDL-C LDL-C

Is There A Dose-Response Relationship? A dose-response relationship between HDL-C Levels and weekly distance run or weekly caloric expenditure is supported by most studies.

HDL-C and Km Run/Week: A dose-Response Relationship Kokkinos P., et al. Arch Intern Med ‘95;155:415-20 mg/dL N=2,906 * p<0.001 * Km/Week

Is There An Exercise Threshold? The exercise-induced changes in lipid metabolism are likely the result of the interaction among exercise: Intensity, Duration, Frequency and Length of Training. It is also likely that an exercise threshold exists for each of these exercise components.

HDL-C and Weekly Distance Kokkinos P., et al. Arch Intern Med ‘95;155:415-20 mg/dL N=2,906 * p<0.001 * Km/Week

Carbohydrate Metabolism

The Association between Cardiorespiratory Fitness and Impaired Fasting Glucose and Type II DM Wei M, et al., Ann Intern Med 1999;130:89-96 N = 8,633 Non-Diabetic Men Age : 30 to 79 yrs old 7,511 Had Normal Fasting Blood Glucose Follow-up: 6 yrs 149 Developed DM and 593 Developed Impaired Fasting Glucose

Cardiorespiratory Fitness & Relative Risk for Type II Diabetes Wei M, et al. Ann Intern Med:1999;130:89-96 Relative Risk p<0.001 Fitness Levels

Cardiorespiratory Fitness & Relative Risk for Impaired Fasting Glucose Wei M, et al. Ann Intern Med:’99;130:89-96 Relative Risk p<0.001 Fitness Levels

Cardiorespiratory Fitness & RR for Impaired Fasting Glucose & Type II Diabetes in Women (n=338) Relative Risk p<0.001 Fitness Levels

Cumulative Incidence of Diabetes Diabetes Prevention Program Research Group NEJM 346 (6) 393-403 Cumulative Incidence of DM (%) Placebo Metformin Lifestyle

Plasma Fasting Glucose Diabetes Prevention Program Research Group NEJM 346 (6) 393-403 Plasma Glucose (mg/dl Placebo Metformin Lifestyle

Glycosylated Hemoglobin Diabetes Prevention Program Research Group NEJM 346 (6) 393-403 Glycosylated Hemoglobin (%) Placebo Metformin Lifestyle

Conclusions Lifestyle changes and treatment with metformin both reduced the incidence of DM in persons at high risk. Lifestyle intervention was more effective than metformin. Number of pts need to be treated for 3 yrs to prevent 1 case of DM is 6.9 for the lifestyle intervention and 13.9 for metformin.

Plasma Glucose Levels Before & After Aerobic Training Smutok et al. Metabolism ‘93 Plasma Glucose (mg/dl) Pre-Training * * Post-Training Minutes After Glucose Ingestion

Plasma Glucose Levels Before & After Strength Training Smutok et al. Metabolism ‘93 ‘ Plasma Glucose (mg/dl) Pre-Training * * * Post-Training Minutes After Glucose Ingestion

Plasma Insulin Levels Before & After Aerobic Training Smutok et al. Metabolism ‘93 Plasma Insulin (U/ml) Pre-Training * * Post-Training Minutes After Glucose Ingestion

Plasma Insulin Levels Before & After Strength Training Plasma Insulin (U/ml) Smutok et al. Metabolism ‘93 Pre-Training * * Post-Training Minutes After Glucose Ingestion

Body Weight/ Obesity

Relative Risk for Physical Activity & BMI, Adjusted For Risk Factors Mason JE, et al. NEJM:’99;341:650-8 RR N=72,488 >29 <29 Physical Activity Quintiles

Cardiorespiratory Fitness & CVD Mortality in Men (N=25,714) Wei M, et al.JAMA:’99;282(16);1547-53 Relative Risk Fit Unfit (Normal) (Obese) (Over WT)

CVD Mortality Predictors in Normal WT Men (BMI 18.5-24.9) Wei M, et al.JAMA:’99;282(16);1547-53 Relative Risk

CVD Mortality Predictors in Overweight Men (BMI 25-29.9) Wei M, et al.JAMA:’99;282(16);1547-53 Relative Risk

CVD Mortality Predictors in Obese Men (BMI >30) Wei M, et al.JAMA:’99;282(16);1547-53 Relative Risk

These findings suggest that it is as important for a clinician to assess the fitness status of patients, (especially obese) as it is to assess blood glucose, TC, HTN and smoking habits.

Exercise Recommendations Aerobic Activity 3-5 times/wk Brisk Walk to Slow Jog 60% to 80% of PMHR 100 to 200 minutes/week 1200 to 2400 Kcal/Wk

LVMI at Baseline and 16 Weeks in Patients with LVH g/m2 Kokkinos, Pittaras et al. New Engl J Med 1995;333:1462-7 * p<0.05 * Baseline 16 weeks

Wall Thickness at Baseline and 16 wks Kokkinos, Pittaras et al. New Engl J Med 1995;333:1462-7 mm * p<0.05 * *

How Much Physical Activity ? Do something Choose something you enjoy Start Low & Progress Slowly Increase duration by 1-2 min/wk Be Consistent (2-5 times/week) Goal: 100-200 minutes/week

Exercise Training is Governed By Three Principles Specificity Overload Reversibility

The Specificity Principle Biological Systems will Make Specific Adaptations to Accommodate an Imposed Demand !

SPECIFICITY Aerobic Anaerobic Long Duration (>10 min) Low Intensity (<85% of PMHR) ATP via TCA Cycle FFA as Fuel Anaerobic Short Duration (<5 min) High Intensity ( >90% of PMHR) ATP via Glycolysis CHO as Fuel

The Overload Principle The performance of a Biological System will Improve Only If the Demand Imposed upon it is Greater than the System is Currently Accustomed.

and/or Intensity Must be Increased Periodically. Overload Principle Frequency, Duration and/or Intensity Must be Increased Periodically.

Reversibility Principle Training adaptations diminish if stimulation (training) is discontinued for a length of time (12 -90 days).

Exercise Components Frequency - Times/Wk Duration - Min/Session Intensity - How Hard Length - How many Wks

Frequency 2- 5 Times per Week Exercise Every Other Day Multiple Short Daily Sessions (5-10 min) for Those with Functional Capacity < 3 METS

Duration 20-60 Minutes/Session of Continuous Aerobic Activity Multiple Daily Sessions (~ 10 min) for Those with Functional Capacity < 3 METs. Slow, Progressive Increase

Length of Training Most Exercise Benefits Are Evident Within 12 Weeks of Consistent Training.

ACSM Exercise Intensity Classifications METS %PMHR Low <4 35-59 Moderate 4-6 60-79 High > 6 > 80

Exercise For Overweight & Obese Patients Exercise Modality that does not Impose Excessive Orthopedic Stress (walking, stationary bike, aquatic exercises).

Exercise Intensity for Patients on Chronotropic Medications Base Exercise intensity on 50% to 80% of Peak HR achieved during ETT.

METs & Kcal for 30 Minutes of Select Physical Activities (80-kg person) Activity METs Kcal Fast Walk 5 200 Jog (12 min/mile) 8 320 Bike (Stationary) 7 280 Health Club 7 280 Dancing 5 200 Stair Climbing 5 200

Contraindications & Recommendations for Exercise Complete Physical Resting BP< 190/105 mm Hg Exercise BP <240/120 mm Hg Exercise SBP drop >10 mm Hg (baseline) Unable to complete 5 METs (ETT) or climb a flight of stairs without severe SOB or symptoms. Gill et al. JAMA 2000

Relative Risk of Onset of MI with Physical Activity

Relative Risk of Onset of MI with Physical Activity

The relative MI Risk for a 50-yr-old Non-smoking, Non-diabetic Man during a given hour is 1 in 1 million. If this man were sedentary and engaged in heavy physical exertion during that hour, his risk would increase 100 times or 1 in 10,000. Framingham Heart Study