Physiology lectures Flashcards
Why is there a declining CVD mortality? Consequences?
BEtter acute management, better control of RFs e.g. hypertension and cholesterol.
More people living with chronic CVD
What is CVD
Diseases affecting the heart and vascular/ circulatory system.
How many deaths is CVD reponsible for?
27% in Uk in 2004 according the BHF, 2015
Economic implications of CVD
16.1bn in 2014
19.8bn in 2020
Centre for economics and business research, 2014
Describe the process of atherosclerosis
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
Describe stages of CVD and reference
3000 autopsied bodies 10-20yrs fatty streak begins 20-30yrs - fibrous plaque 40 yrs calcification 45+ clinical symptoms McGill et al 2000
Prevalence of atherosclerosis in Korean War and source
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
Early work showing PA links to CVD mortality, references and limitations
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
Example of dose response between PA and CVD
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.
Example of change in PA and CVD risk.
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
Example of exercise intensity and link to CHD
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.
Example of dose response between fitness and CHD
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
Why is fitness possibly a better marker of PA, possibly not?
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.
General point on dose response between PA and CHD
Hardman & Stensel 2003 noted that 30 studies, 2/3 of studies support dose, more in fitness. Some show increased risk at high levels.
Example of change in fitness and change in risk of CHD
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.
Summary of evidence on PA/ fitness vs CVD. Way to strengthen?
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
Link between sitting time and CVD mortality?
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.
Evidence for the effect of non modifyable risk factors on CVS mortality
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
Explaination of why PA lowers CVD
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)
Describe the relationship between lifestyle RFs and clinical endpoints and evidence
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.
Risks of different modifiable RFs and MI in men
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
Cross sectional evidence on the effect of PA on lipid profile?
Countries
Increasing average cholesterol level causes increased total serum cholesterol and decreased HDL-cholesterol
Simons 1986
Effect of HDL on CHD mortality
Increase in 0.26mmol/l increases CHD risk by 50%
Kannel 1983
Evidence between HDL and PA
Cross sectional
LaPorte 1983
Increasing sedentary lifestyle decreases HDL.
Runners highest, then joggers, sedentary, chronic pain, Old SCI, recent SCI, New SCI
Can exercise intervention improve cholesterol levels main reference?
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
Back up reference.
Wood et al 1985 smaller study, non randomised intervention but similar results
Does the reduction in cholesterol as a result of exercise result in less CHD?
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
Describe anecdotal evidence regarding the benefits of exercise on blood flow
Clarence DeMar (Mr Marathon)
Currens & White 1961
2-3x diameter of CAs
Some artherosclerosis but no impairment of blood flow
Observational evidence regarding the BP lowering effects of exercise
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
Why is BP reduced by exercise
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.
Evidence that exercise effects BP from old stuff. - observational
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.
experimental studies that show that exercise and BP in African Americans
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)
Experimental design and exercise and SBP
Miyashita et al 2008.
Walking 10 x 3 mins or 1 x 30mins a day can lower SBP approximately 17mmHg
Meta analysis of treatment of BP
Meta analysis in 2001 average or 3.4/2.4 decrease in BP, 3x more if high BP at baseline.
Fargard 2001
How does exercise improve coronary blood flow?
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)
Cross sectional evidence that exercise helps dilating capacity?
Althetes greater dilating capacity than inactive
Haskell et al 1993
Effect of HIIT on dilation of CAs
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
Effect of acute exercise on endothelial function
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
Inflammatory mechanism by which exercise decreases CHD
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.
How may exercise effect coagulation and fibinolysis acutely
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.
How may exercise effect coag and fibrinolysis long term
Decrease PAI, INcrease t-PA, reduced platelet agg, reduced fibrinogen.
How may exercise effect insulin resistance?
Well established it enhances sensitivity and counters insulin resistnace (direct and indirect)
Ivy 1997
exercise and overweight and obesity?
May prevent.
Obesity - direct and indirect CVS also.
Why does high LDL lead to more cholesterol laden macrophages
Normally regetor down regulated but returned in macrophages hence foam cells. - higher addinity if oxidised too
Regulation of Insulin in lipids
Activate lipoprotein lipase postprandial - removes TGs when they are highest.
Describe lipoprotein lipase saturation and reults
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
Relationship between TGs and HDL
Increased TG = decreased HDL
As TGs rich lipoproteins break bown they form the shell components to HDL
Why are smaller denser LDLs worse?
More likely to leave circ and entre intima.
Break down of VLDL and low HDL associated with these
What is PA?
Howley 2001
PA - Any bodily movement produced by skeletal muscle that substantially increases energy expenditure
What is exercise?
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.
Describe primary cause of SCD in <35 yrs
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
How is Sudden CVS event linked to amount of vigorous exercise? Prospective and limitations
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
How is MI risk linked to amount of vigorous exercise? Retrospective and limitations
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
Describe incidences of cardiac arrest during long distance runners and causes
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
What does Thompson et al 2007 show? main statements
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
Types of hereditary or congentital CVS abnormalities
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
Suggested triggering mechanism in asymptomatic people of atherosclerotic disease Thompson?
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
Suggested triggering mechanism in symptomatic ppl?
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
How can time of day, activity and temp affect risk?
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
Variation in incidence of sudden cardiac events?
Massive due to population studies - heteroguity, very low incidence, random chance plays a big role.
Often lack power ad have large CIs.
Potential treatments/ preventative measures for SCD? problems with this?
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
Can screening help lower SCD?
Decrease in sudden death among athletes decreased 89% over 24 years in Italy among athletes - so many confounders
How is SCD risk linked to distance?
Harris et al 2010
Increases with increased distance swam.
Increased incidence over time
Why might running over 7.5miles per hour be for some other reason than living longer?
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
Early evidence that large amounts of PA may increase RR of death?
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
Link between daily PA and all cause mortality? Positives and negatives of study
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
Link between cardioresp fitness and CVD mortality among men with diabetes
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
Link between all cause mortality and running distance per week in a U shaped relationship
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
Why did the BBC report that ‘Training very hard is as bad as no exercise at all’
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)
Describe anecdotal evidence regarding dangers of running too much
Michah True's Death Died from heart disease Ran 25-100 miles a day Died on 12 mile training run Autopsy = unclassified cardiomyopathy
Evidence of cardiac damage in marathon runners?
Eijsvogels et al 2016
Elevated Cardiac Troponin suggesting myocardial damage and troponin
Evidence of pathological changes in rates
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
Summary of general points from Eijsvogels et al 2015
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
Definition of AF and risk of stroke
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
UK prevalence of AF?
2% of pop in UK
One in four lifetime risk
Atrial fibrillation association 2011
Incidence of AF in endurance athletes?
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
Changes and reversibility of AF and structure in endurance atheleties
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.
Case report of normal sturcture of heart with exericse
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
Does AF from long distance affect mortality?
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
Relationship between exercise capacity and AF
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
Risks of stroke, death and recurrent stroke from AF
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
Is there a sufficient amount of evidence to provide guidelines for risks of AF?
no
Arguments against screening atheletes
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.
