Characteristics of the cardiovascular system , abnormalities and diseases PART 1

1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Miklós Székely and Márta Balaskó Molecular and Clinical Basics of Gerontology – Lecture 8 Characteristics of thecardiovascularsystem, abnormalities and diseasesPART 1

3. Mortality data • In 1995 the leading causes of death were: 1 Cardiovascular 50.7% 2 Malignancies 22.9% 3 Diseases of the GI tract 8.1% 4 Injuries, poisons, violence 7.8%

4. Prevalence • Leading cause of death in both gender was cardiovascular (even preceding malignancies) • 65-74 years 50-52% • above 75 years 60%

5. Age-related physiological changesin the heart1 • Each ventricle pumps 200,000 m3 blood in 60 years through 40,000 km long capillary system with 1,000 m2 surface • The aging of the cardiovascular system determines survival and longevity (100-120 years).

6. Age-related physiological changesin the heart2 Growth factors (AII, NE, ET, TGFβ) Autonomic modulation Autonomic modulation Cardiac factors: Contractility Stretch (systolic, diastolic) Vascular factors: Pulsatileelastance reflected waves Nonpulsatile PVR

7. Age-related physiological changesin the heart3 • In normotensive individuals a moderate, age-related thickening of the ventricular wall may be physiological • The size of theleft atrium and the internal diameter of ventricle also increaseswith age (not always statistically significant) • On a chest X-ray an increase of heart contours is observed • Hypertrophy of the myocytesis mostly behind the thickening of the ventricular wall, but increase in the connective tissue(fibrosis) also contributes • Fibrosis and calcification may be observed everywhere within the heart (aortic valve, annulus fibrosus), ventricular compliance decreases

8. Age-related physiological changesin the heart4 • Early diastolic filling of the heart decreases (at the age of 80 years ca. 50%, in the young 2× as much blood flows into the ventricle than in later phases) • The mitral valve closes more slowly • The late diastolic filling is quicker/more effective (due to the contraction of the heart) (filling in the elderly early:late=1:1) • EDV mostlyincreasesparticularlyinmales

9. Age-related physiological changesin the heart5 At rest During Exercise Young heart At the start of heart beat, at rest At the end of heart beat, at rest Size at the start of heart beat is the same as at rest Size at the end of heart beat is smaller than at rest Old heart At the start of heart beat, at rest At the end of heart beat, at rest Size at the start of heart beat is larger than at rest Size at the end of heart beat is the same as at rest

10. Age-related physiological changesin the heart6 • The number of the atrial pace-maker cells decreases 50-75% by the age of 50 – pulse decreases • The cell count of the AV node is maintained, but the speed of conduction is slower • His cell count decreases –fibrosis • The heart rate at rest remains normal, but exercise induced maximum decreases by 30% (by the age of 80) the maximal possible heart rate and cardiac output decreases to the same extent • The responsiveness to b-adrenergic effects decreases (changes in the membrane G-proteins)

11. Cardiac output measured at rest and at exhausting exercise (upright position) vs. ageinathletes and sedentaryindividuals 20 r=.14, p>.26 D 16 r=.47, p<.001 12 Cardiac output (L/min) C 8 r=.16, p>.23 B r=.70, p<.001 4 A 20 40 60 80 Age (years)

12. Age-related physiological changesin the circulation1 • The arterial wall becomes more rigid, the aorta shows distension: due to the quantitative and qualitative changes in elastin and collagen fibers. • Calcium deposition and collagen cross-links make the vessels even more rigid. • Glycoprotein disappears from the elastic fibers, they become fragile/brittle, the mineral content of the elastin increases, the polar aminoacid content also rises. • The elasticity of the aorta is diminished, during diastole the pressure falls steeply!(It decreases coronary circulation!)

13. Age-related physiological changesin the circulation2 • Remodelling of the small vessels, the functional capillary number decreases – the oxygen supply of the tissues decreases! • The thickness of the tunica intima and media increases, e.g. in the a. carotiscommunis the normal mean of 0.35 mm – may increase to 2-3-times higher (higher levels of growth factors, smooth muscle proliferation, transformation) • The tone of the vessels changesNO decreases, ROS, TxA2 PGH2 increase Ca-dependent vasoconstriction is Ca-activated or voltage-dependent K+-channel a-subunit density decreases in the vascular smooth muscle membranes • Besides all these, atherosclerosis further increases the rigidity of the vessels (depending on severity)

14. Age-related physiological changesin the coronary circulation • The myocardial contractility decreases • The duration of both thesystole, and the diastole increases (slower)(ionflux of the L type Ca++ channels increases, their activity becomes longer) • Due to the fall of the diastolic pressure the coronary circulation decreases

15. Changes in the cardiovascular function1 • Ventricular filling, preload • The early filling becomes progressively slower after the age of 20, by 80-y it is only half of the original • despite this, the EDV does not decrease inhealthy old people, because the major part of thefilling takes place in the second phase • The enlargement of the atria and their strongercontraction is responsible for the late filling (at 20-y 20%, 80-y 40%)

16. Comparison between theearly diastolic and atrial contribution toleft ventricular filling in persons of a broad age range men women 50 90 40 80 Late diastolic filling due to atrial contraction (% of total filling volume) Early diastolic filling volume (% of total filling volume) 30 70 20 60 10 50 0 20 40 60 80 100 100 0 20 40 60 80 Age (years) Age (years)

17. Changes in the cardiovascular function2 • Ventricular filling , preload • In auscultation 4th (atrial) sound appears – gallop rhythm • In acute atrial fibrillation the loss of coordinated atrial contraction leads to a loss of this function. In people with chronicleft ventricular failure it leads to an acute heart failure

18. Changes in the cardiovascular function3 • Afterload • the vessels are more rigid • the speed of the pulse wave is up – with a quick reflection ofthe pulse wave, already within the systole, interferenceof waves may decrease the coronary circulation • the sensitivity of the baroreceptor reflex decreases • the systolic blood pressure increases • the ventricular emptying is impaired • dilatation of the left ventricle • the thickening of the ventricular wall may havebenefits according to the LaPlace law),normalizing the systolic function and the ejectionfraction In case of an abnormal blood pressure, treatment is necessary – isolatedsystolic hypertension

19. Myocardial contractility • The myocardial performance, i.e. the cardiac output depends (besides the pre- and afterload) on the contractility of the heart

20. The interplay of vascular and adaptive cardiac changes during aging  early diastolic filling  aorticroot size prolonged contraction  pulse wave velocityandearly reflected waves  systolic blood pressure with late peak normalend-systolic volume and ejection fraction Normali-sation ofLV wall tension  LVwall tension  LVhyper-trophy arterial stiffening Normalend-diastolic volume atrialsize atrialfilling and contraction