Physiology lectures

Question 1

Why is there a declining CVD mortality? Consequences?

Answer 1

BEtter acute management, better control of RFs e.g. hypertension and cholesterol.
More people living with chronic CVD

Question 2

What is CVD

Answer 2

Diseases affecting the heart and vascular/ circulatory system.

Question 3

How many deaths is CVD reponsible for?

Answer 3

27% in Uk in 2004 according the BHF, 2015

Question 4

Economic implications of CVD

Answer 4

16.1bn in 2014
19.8bn in 2020
Centre for economics and business research, 2014

Question 5

Describe the process of atherosclerosis

Answer 5

Response to injury hypothesis
Endothelial damage
Lipid accumulation in intima
Migration and proliferation of SM
Oxidation of lipid.
Immune cell migration and proliferation/ immune response - T cell activation (enhance platelet aggregation and adherence).
Uptake of lipid by macrophage (from recruitment of monocytes monocyte) to form foam cell.
Forms plaque
Proliferation of smooth muscle cells and further uptake of lipid.
Forms fibrous plaque and may become calcified (reducing elasticity).
May haemorrage, thrombosis, embolise, total occlusion
Symptoms at 45% stenosis - clinical horizon

Question 6

Describe stages of CVD and reference

Answer 6

3000 autopsied bodies
10-20yrs fatty streak begins
20-30yrs - fibrous plaque
40 yrs calcification
45+ clinical symptoms
McGill et al 2000

Question 7

Prevalence of atherosclerosis in Korean War and source

Answer 7

77% of yound men (22.1yrs) autopsied after Korean war. Varied from fibrous thickening to complete occlusion of one or more of the main branches
Enos et al 1953

Question 8

Early work showing PA links to CVD mortality, references and limitations

Answer 8

Professor Jeremy Morris and the London Bus studies.
Conductors vs drivers
Conductors had half the number of heart attacks than drivers, occured later and were less severe.
Cross sectional - self selection bias

Question 9

Example of dose response between PA and CVD

Answer 9

Morris et al 1990
Whitehall studies
9k civil servants followed for an average of 9 years.
Those that do vig activity >6 MET or considerable amountsof cycline or walking pace >4mph had less than half non fatal or fatal CHD than those that do not.
Also showed a dose response between number of bouts of vig sport and age adjusted rate of CHD. Accounted for confounders including fx, stature, health attitude, smoking, BMI, history of disease. Relationship not found for non-vig PA.

Question 10

Example of change in PA and CVD risk.

Answer 10

Paffenbarger et al 1993
Harvard alumini health study.
Asked activity in 1963/66, asked again 12 yrs later in 1977. Recorded activity ‘yes’ or ‘no’ - very arbitary.
Those tha did MV sports ‘no’ ‘yes’ decreased RR by 43%. vs no no.
PA index >2000kcal/week no-yes decrease by 17%. vs no no
Lowest overall risk in yes-yes.
Adjusted for smoking hypertension, BMI

Question 11

Example of exercise intensity and link to CHD

Answer 11

Lee et al 2003
Harvard Alumini
Intensity of exercise has a strong relationship with risk of CHD independent of total energy expenditure.
Limited as not objective but VAS.

Question 12

Example of dose response between fitness and CHD

Answer 12

Barlow et al 2012 - Dallas Texas
Fitness determined on maximal treadmill test.
+11,000 individuals ages 30-50 followed up 27 yrs.
.29HR between fittest quintile and unfittest.
1MET increase in baseline cardioresp fitness associated with 18% reduction in CVD deaths after adjusting for confounders

Framingham “low risk” people only

Question 13

Why is fitness possibly a better marker of PA, possibly not?

Answer 13

Objective measure.
Collerates well with PA
Influence of genetics.
More correct categorisation.
INcreases precision of measurement.
Increases chances that true findings will not be missed.
Supported by fitness being better predictor that PA.

Question 14

General point on dose response between PA and CHD

Answer 14

Hardman & Stensel 2003 noted that 30 studies, 2/3 of studies support dose, more in fitness. Some show increased risk at high levels.

Question 15

Example of change in fitness and change in risk of CHD

Answer 15

Blair et al 1995
Physically active should remain active
Physically inactive should become active
5yr between maximal treadmill testing and 5 yr follow up.
Reduction in mortality of 44% if became fit.
Reduction in CVS risk of 52% if become fit.
Arbitatory - fit or unfit?
However also seen between quintile 2/3 but less strong.
Dose response - Each increase in minute between treadmill times resulted in a decrease of 7.9% risk of mortality.

Question 16

Summary of evidence on PA/ fitness vs CVD. Way to strengthen?

Answer 16

All cohort/ prospective.
Strengthens association but proving? Self selection and subclinical disease causing sedentariness?
Randomised needed but unethical with disease endpoints. Affect on other RFs - direct and indirectly show improvement to help ‘prove’ increase in activity reduces CVS. Also provide evidence for biological plausibility

Question 17

Link between sitting time and CVD mortality?

Answer 17

Katzmarzyk et al 2009
54% increase in CVS mortality between no sitting and sitting all day
17000 canadian men 12 yrs independent of other factors.

Question 18

Evidence for the effect of non modifyable risk factors on CVS mortality

Answer 18

Genetics
Khera et al 2016.
50 polymorphisms associated with CHD.
Low, mod or high depending on which ones were present.
Lifestyle also low mod or hig.
Genetics has an independent association - 75% higher risk than low risk.
Regardless of genetic risk PA can decrease risk by approx 50% - no obesity, regula PA, healthy diet and smoking status

Question 19

Explaination of why PA lowers CVD

Answer 19

Genes evolved in a active/ hunter gatherer way of life. genes that decreased mortality with PA became favorable, only recently that genes that cause decreaes in mort with sendentary lifestyle have become unfavorable.
PA through direct or indirect (other RFs)

Question 20

Describe the relationship between lifestyle RFs and clinical endpoints and evidence

Answer 20

Lifestyle risk factors (PA, smoking and diet) effect both novel risk factors and established e.g. endothelial function, inflammatory pathways, thrombosis/ coagulaton, arrhythmia and blood pressure, lipids and adiposity. These then cause subclinical vasc disease, onto symptoms and diability (clinical endpoints)
Mozaffarian et al 2008.

Question 21

Risks of different modifiable RFs and MI in men

Answer 21

Pa similar to BP, high cholesterol and smokng risk of MI in men
Hypertension 2.1
high cholesterol 2.4
Smoking 2.5
Powell et al 1987

Question 22

Cross sectional evidence on the effect of PA on lipid profile?

Answer 22

Countries
Increasing average cholesterol level causes increased total serum cholesterol and decreased HDL-cholesterol
Simons 1986

Question 23

Effect of HDL on CHD mortality

Answer 23

Increase in 0.26mmol/l increases CHD risk by 50%

Kannel 1983

Question 24

Evidence between HDL and PA

Answer 24

Cross sectional
LaPorte 1983
Increasing sedentary lifestyle decreases HDL.
Runners highest, then joggers, sedentary, chronic pain, Old SCI, recent SCI, New SCI

Question 25

Can exercise intervention improve cholesterol levels main reference?

Answer 25

Slentz et al 2007 240 sedentary overweight ppl randomised to 6 months to control or exercise intervention. Vig intensity better than mod intensity at decreasing HDL (increase in 3mg/dl) and small LDL. Mod is better at decreasing VLDL-TAG

Question 26

Back up reference.

Answer 26

Wood et al 1985 smaller study, non randomised intervention but similar results

Question 27

Does the reduction in cholesterol as a result of exercise result in less CHD?

Answer 27

Kramsch et al 1981 - diet and exercise on cholesterol and CHD in monkeys. HDL lower in exercise LDL + VLDL - only slighly improved with exercise. However 35% to 10% coronary artery narrowing in both left and right coronary arteries

Question 28

Describe anecdotal evidence regarding the benefits of exercise on blood flow

Answer 28

Clarence DeMar (Mr Marathon) Currens & White 1961 2-3x diameter of CAs Some artherosclerosis but no impairment of blood flow

Question 29

Observational evidence regarding the BP lowering effects of exercise

Answer 29

Kuung Bushmen in Botswana Truswell et al 1972 Maintain in SBP and DBP in bushmen with age in mena nd women - BP does not invariably increase with age

Question 30

Why is BP reduced by exercise

Answer 30

After exercise Co falls but arterial vasodilation takes longer BP = CO x TPR longer life with lower BP Also reduces symp tone at rest due to catecholamine release in response to exercise May modify baroreceptor effect.

Question 31

Evidence that exercise effects BP from old stuff. - observational

Answer 31

Harvard - Paffenbargar 1983 - vig exercise decrease in 35% hypertension in 6-10yr follow up. (only men) Aerobic centre Blair et al 1984 52% more likely in least fit quintile compared with most fit to develop hypertension.

Question 32

experimental studies that show that exercise and BP in African Americans

Answer 32

Kokkinos et al 1996 46 men with severe hypertension. stationary cycling 3x a week Sig decrease in DBP and IV septum thickness and LV mass at 16 weeks (better function)

Question 33

Experimental design and exercise and SBP

Answer 33

Miyashita et al 2008. | Walking 10 x 3 mins or 1 x 30mins a day can lower SBP approximately 17mmHg

Question 34

Meta analysis of treatment of BP

Answer 34

Meta analysis in 2001 average or 3.4/2.4 decrease in BP, 3x more if high BP at baseline. Fargard 2001

Question 35

How does exercise improve coronary blood flow?

Answer 35

Less lipid so less atherosclerosis, recruitment of coronary collaterals, endothelial function - No in response to exercise/ shear stress force exerted by blood from and SM dilatin - flow induced arterial vasdilation. Endothelial dysfunction occurs in early atherosclerosis and can trigger myocardial ischaemia (gielen et al 2001)

Question 36

Cross sectional evidence that exercise helps dilating capacity?

Answer 36

Althetes greater dilating capacity than inactive | Haskell et al 1993

Question 37

Effect of HIIT on dilation of CAs

Answer 37

Hambrecht et al 2000 Exercise vs control Vessel diameter with angiography 6 sesh/ week, 10min/session, 80% HR max 4 weeks Sig imporvement with dilation in response to ach

Question 38

Effect of acute exercise on endothelial function

Answer 38

``` Gill et al 2004 Improved endothelial function by approximately 15% - fasting and post prandial. 20 middle aged men 90 min walking at 50% VO2max Doppler ```

Question 39

Inflammatory mechanism by which exercise decreases CHD

Answer 39

Via CRP decreases and other inflam markers. Ford 2002. INcrease CRP may decrease NO bioavailability in endothelial cells, increase PAI and independently related to insulin sensitivity.

Question 40

How may exercise effect coagulation and fibinolysis acutely

Answer 40

Pro coagulant state Increased fibrinogen, thrombin, platelet activation, haemoconc. Explain Cardiac events. Followed by rapid increase in fibrinolytic activity. Imhof and Koenig 2001 Rauramaa et al 2001.

Question 41

How may exercise effect coag and fibrinolysis long term

Answer 41

Decrease PAI, INcrease t-PA, reduced platelet agg, reduced fibrinogen.

Question 42

How may exercise effect insulin resistance?

Answer 42

Well established it enhances sensitivity and counters insulin resistnace (direct and indirect) Ivy 1997

Question 43

exercise and overweight and obesity?

Answer 43

May prevent. | Obesity - direct and indirect CVS also.

Question 44

Why does high LDL lead to more cholesterol laden macrophages

Answer 44

Normally regetor down regulated but returned in macrophages hence foam cells. - higher addinity if oxidised too

Question 45

Regulation of Insulin in lipids

Answer 45

Activate lipoprotein lipase postprandial - removes TGs when they are highest.

Question 46

Describe lipoprotein lipase saturation and reults

Answer 46

Does both chylo and VLDLs. More affinity for chylomicros. IF low VLDL then faster clearence of chylo. Insulin supresses VLDL output, resistance causes increases VLDL (even if broken down shell becomes LDL too) and atherosclerosis, incrased chylomicrons/ TG. so more in intima/ exposed to endothelial cells

Question 47

Relationship between TGs and HDL

Answer 47

Increased TG = decreased HDL | As TGs rich lipoproteins break bown they form the shell components to HDL

Question 48

Why are smaller denser LDLs worse?

Answer 48

More likely to leave circ and entre intima. | Break down of VLDL and low HDL associated with these

Question 49

What is PA?

Answer 49

Howley 2001 PA - Any bodily movement produced by skeletal muscle that substantially increases energy expenditure

Question 50

What is exercise?

Answer 50

Exercise - A sub category of leisure time PA in which planned, structured and repetitve movements are performed to improve or maintain one or more components of physical fitness.

Question 51

Describe primary cause of SCD in <35 yrs

Answer 51

``` HCM - hyperobstructive cardiomyopathy Inherited disease of the heart muscle Left and right ventricle muscle wall is thickened Compromise cardiac function Lead to dangerous arrythmias 1 in 500 British Heart FOundation ```

Question 52

How is Sudden CVS event linked to amount of vigorous exercise? Prospective and limitations

Answer 52

Albert et al 2000 21,000 physicians 12 years 122 sudden deaths Absolute risk is very low 1 per 1.5 mil episodes. Inreased in vig exercise and up to 30 mins after RR = 16.9. Higher the number of Vig exercise per week, the lower the risk <1/wk = 74.1 and >5 = 10.9. Limit: - Only men - Only physicians - Fewer cases than other Positives - Long follow up, large study

Question 53

How is MI risk linked to amount of vigorous exercise? Retrospective and limitations

Answer 53

Mittleman 1993 Case control style Contacted people for interview 4 days average after MI. Ask about frequency of vig exercise. Compared with simialr controls. Risk raised in vig activity. Lower risk if more frequence. +100RR if av frequency of 0. Vig exerertion transiently increase risk of AMI/ SCD particularly among habitually sedentary persons with occult or known CAD performing unaccustomed, vig PA. Positives: -more cases than albert, didnt do 0 frequency in his Limitations: - Recall bias - although only 4 days - C

Question 54

Describe incidences of cardiac arrest during long distance runners and causes

Answer 54

``` Kim et al 2012 More in marathon than half More in older More in men .54 per 100,000 participant-hours As much as 50% due to HCM ```

Question 55

What does Thompson et al 2007 show? main statements

Answer 55

Consensus statements Overall risk of SCD/ ACM is very low Both highest in inactive performing unaccustomed exercise. Athero in older SCD in young HCM and anomolous Cas are not improved by vig exerices unlike CHD

Question 56

Types of hereditary or congentital CVS abnormalities

Answer 56

HCM, CA abnormalities, arrhythmias/ conductio disorders e.g. long QT syndrome, AS, Aortic dissection and ruture from CT disroder e.g. Marfans, mitral prolapse. Arrhythmia is COD

Question 57

Suggested triggering mechanism in asymptomatic people of atherosclerotic disease Thompson?

Answer 57

Exercise induced CA spasm Increased wall stress from increased HR and BP Flexing of atherosclerotic epicardial CAs Plaques disruption or erosion Deepening of Coronary fissures in plaques Catecholamine induced platelet aggregation

Question 58

Suggested triggering mechanism in symptomatic ppl?

Answer 58

Iscaemia-induced VF from plaque 1 - decreased perfusion due to shortened diastole 2 - increased demand to to increased HR and CO - catecholamine repsonse 3 - decrease perfusion after exercise due to lower venous return/ BO as lower TPR

Question 59

How can time of day, activity and temp affect risk?

Answer 59

Most common in the early morning hours Young mostly in afternoon but varies on cause. Cold increases angina. Increased higher rate-pressure products with activity such as snow shovelling vs treadmill

Question 60

Variation in incidence of sudden cardiac events?

Answer 60

Massive due to population studies - heteroguity, very low incidence, random chance plays a big role. Often lack power ad have large CIs.

Question 61

Potential treatments/ preventative measures for SCD? problems with this?

Answer 61

Preparticipation screening, teaching of athletic staff to deal e.g. defibrillation, recognition of prodromal symptoms (fairly common and ignored), graded exercise programs, warm up and cool down periods, exclusion of high risk participants from certain activities. No systemic evaluation of any of this

Question 62

Can screening help lower SCD?

Answer 62

Decrease in sudden death among athletes decreased 89% over 24 years in Italy among athletes - so many confounders

Question 63

How is SCD risk linked to distance?

Answer 63

Harris et al 2010 Increases with increased distance swam. Increased incidence over time

Question 64

Why might running over 7.5miles per hour be for some other reason than living longer?

Answer 64

O'Keefe et al. 2012 Long term excessive endurance exercise may induce pathological structural remodeling of the heart and large arteries. Elevation of biomarkers in extreme endurance events Fibrosis - particularly in atria and IV septum and RV Can get A or V arrhythmias

Question 65

Early evidence that large amounts of PA may increase RR of death?

Answer 65

Paffenbarger 1986 Increase in age adjusted RR of death over 3499kcal/week Pa expenditure from 3000-3499. Stil lower than <500. Only Harvard peeps and males

Question 66

Link between daily PA and all cause mortality? Positives and negatives of study

Answer 66

``` Wen et al 2011 Vig exercise more beneficial for ACM than mod or total PA. Peak benefit at 40-50min/day of vig at 45% MOderate at 90mins with 30% reduction Largest improvement form 0 Limitations -Taiwanese -Questionnaire ``` Postiive - 400,000ppl - 8 years follow up - 5 cateories

Question 67

Link between cardioresp fitness and CVD mortality among men with diabetes

Answer 67

``` Church et al 2005. Benefit in ACM (lower death vate) with fitness at baseline up to >13 MET when death rate increases from 12-12.9 METs 2,300 men 15.9 yrs Aerobic Centre Limitations -obese/ overweight DM patients only - Men only ```

Question 68

Link between all cause mortality and running distance per week in a U shaped relationship

Answer 68

Cited in O'Keefe and Lavie 2012 U shaped relationshup between fitness and morality and morbidity, Fintess levels above 12METS do not seem to translate into additional gains in CV health and longevity. Increase in morality after 20miles/week

Question 69

Why did the BBC report that 'Training very hard is as bad as no exercise at all'

Answer 69

Schnohr et al 2015 Dose of jogging and long-term mortality underpowered, only 2 deaths in strenuous group. Classified into light moderate or strenuous based on self reported pace and frequencey. Adjusted for age, sex, smokig, alcohol, education and DM status there was not a signficicant result (>5% due to chance)

Question 70

Describe anecdotal evidence regarding dangers of running too much

Answer 70

``` Michah True's Death Died from heart disease Ran 25-100 miles a day Died on 12 mile training run Autopsy = unclassified cardiomyopathy ```

Question 71

Evidence of cardiac damage in marathon runners?

Answer 71

Eijsvogels et al 2016 | Elevated Cardiac Troponin suggesting myocardial damage and troponin

Question 72

Evidence of pathological changes in rates

Answer 72

Rats ran 60 mins a day for 16 weeks Fibrosis thickening and scarring, particularly in RV free wall, IVS and LVFW. LEads to arrhythmias Benito et al 2011

Question 73

Summary of general points from Eijsvogels et al 2015

Answer 73

A safe upper-dose limit of exercise potentially exists Chronic intense sustained exercise can cause patchy myocardial fibrosis particularly in atria, IVS and RV leading to arrythmias Chronic can also lead to artery calcification, diastolic dysfunction adn large-artery wall stiffening. Veteran endurance athletes have a 5 fold increase in the prevalence of AF Excessive show markers of myocardial injury e.g. troponin and BNP correlated with transient reductions in RV ejection fraction Eijsvogels et al 2015

Question 74

Definition of AF and risk of stroke

Answer 74

Chaotic electrical activity that replaces normal sinus rhythm and eliminates the contribution of atrial contraction to LV filling Eijsvogels et al 2016 Af lead to 5x increase in risk of stroke

Question 75

UK prevalence of AF?

Answer 75

2% of pop in UK One in four lifetime risk Atrial fibrillation association 2011

Question 76

Incidence of AF in endurance athletes?

Answer 76

Animal models show long term intensive exercise training induces fibrosis in both atria and susceptibility to AF. There is a variable but high prevalence in different elite athlete populations compared with control RR 5.5 to 14.4 Wilhelm et al 2012

Question 77

Changes and reversibility of AF and structure in endurance atheleties

Answer 77

Guasch et al 2013 Programme in rats after 8-16 weeks on treadmill Time matched controls AF inducibility increased after 16 weeks and rapidly returned to baseline with detraining. Atrial dilation and fibrosis after 16 weeks of training and failed to fully recover following 4-8 week cessation Autonomic changes, atrial dilation and fibrosis and potential mechanisms. Vagal promotion - augmented baroreflex responsiveness.

Question 78

Case report of normal sturcture of heart with exericse

Answer 78

``` De arujo et al 2014 Case report on a six time ultraman winner and a normal heart 47 yr old 50,000h of training and competition 35yr career. Normal ECG, Echocardiogram and MRI ```

Question 79

Does AF from long distance affect mortality?

Answer 79

Moderate levels of exercise reduce AF risk and even though risk is increased in very high, there is no effect on mortality. No firm threshold or guideline from existing literature Bosomworth 2015

Question 80

Relationship between exercise capacity and AF

Answer 80

Andersen et al 2015 U shaped relationship between exercise capcity and muscle strength and risk of arrhythmia driven by a direct association with risk of AF and U shaped association with bradyarrhythmia

Question 81

Risks of stroke, death and recurrent stroke from AF

Answer 81

Despite higher AF and potential strok risk. Death and recurrent stroke is similar to nonskiers. HIgh incidence of AF but lower risk of recurring stroke 700,000 people 600 incidences of stroke Hallmarker et al 2015

Question 82

Is there a sufficient amount of evidence to provide guidelines for risks of AF?

Answer 82

no

Question 83

Arguments against screening atheletes

Answer 83

Small proportion of yong athletes at risk of SCD Poor sensitivity of health questionnaires and physical examination but ore elaborate are costly ECGs can detect (not CAD) but some causes however vary on activity, age, race, sex and skilled docotrs are needed to avoid large num of false positive test results - implementation hampered by lack of resources and infrastructure and connot be regarded as cost effective in most countries.