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

2. CHARACTERISTICS OF THE CARDIOVASCULAR SYSTEM, ABNORMALITIES AND DISEASES PART 1 Miklós Székely and Márta Balaskó Molecular and Clinical Basics of Gerontology – Lecture 8 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

3. TÁMOP-4.1.2-08/1/A-2009-0011 Mortality data In 1995 the leading causes of death were: 1 1Cardiovascular 50.7% 2 2Malignancies 22.9% 3 3Diseases of the GI tract 8.1% 4 4Injuries, poisons, violence 7.8%

4. TÁMOP-4.1.2-08/1/A-2009-0011 Prevalence Leading cause of death in both gender was cardiovascular (even preceding malignancies) 65-74 years 50-52% above 75 years 60%

5. TÁMOP-4.1.2-08/1/A-2009-0011 1 Age-related physiological changes in the heart 1 Each ventricle pumps 200,000 m 3 blood in 60 years through 40,000 km long capillary system with 1,000 m 2 surface The aging of the cardiovascular system determines survival and longevity (100-120 years).

6. TÁMOP-4.1.2-08/1/A-2009-0011AutonomicmodulationAutonomicmodulation Growth factors (AII, NE, ET, TGF β ) Cardiac factors: Contractilit y Stretch (systolic, diastolic) Vascular factors: Pulsatile elastance reflected waves Nonpulsatile PVR 2 Age-related physiological changes in the heart 2

7. TÁMOP-4.1.2-08/1/A-2009-0011 thickening of the ventricular wallIn normotensive individuals a moderate, age-related thickening of the ventricular wall may be physiological left atrium internal diameter of ventricle also increasesThe size of the left atrium and the internal diameter of ventricle also increases with age (not always statistically significant) On a chest X-ray an increase of heart contours is observed Hypertrophy of the myocytes increase in the connective tissueHypertrophy of the myocytes is mostly behind the thickening of the ventricular wall, but increase in the connective tissue (fibrosis) also contributes Fibrosis and calcificationFibrosis and calcification may be observed everywhere within the heart (aortic valve, annulus fibrosus), ventricular compliance decreases 3 Age-related physiological changes in the heart 3

8. TÁMOP-4.1.2-08/1/A-2009-0011 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) mitral valve closes more slowlyThe mitral valve closes more slowly diastolic filling is quicker/more effectiveThe late diastolic filling is quicker/more effective (due to the contraction of the heart) (filling in the elderly early:late=1:1) EDV mostly increasesEDV mostly increases particularly in males 4 Age-related physiological changes in the heart 4

9. TÁMOP-4.1.2-08/1/A-2009-0011 During Exercise At rest Youngheart Oldheart Size at the end of heart beat is smaller than at rest Size at the start of heart beat is the same as 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 At the end of heart beat, at rest At the start of heart beat, at rest At the start of heart beat, at rest At the end of heart beat, at rest 5 Age-related physiological changes in the heart 5

10. TÁMOP-4.1.2-08/1/A-2009-0011 atrial pace-maker cells decreases 50-75% by the age of 50The 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 slowerThe cell count of the AV node is maintained, but the speed of conduction is slower His cell count decreasesHis 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  -adrenergic effects decreases (changes in the membrane G-proteins) 6 Age-related physiological changes in the heart 6

11. TÁMOP-4.1.2-08/1/A-2009-0011 Cardiac output measured at rest and at exhausting exercise (upright position) vs. age in athletes and sedentary individuals D A B C 20 16 12 8 4 20406080 Age (years) Cardiac output (L/min) r=.14, p>.26 r=.47, p<.001 r=.16, p>.23 r=.70, p<.001

12. TÁMOP-4.1.2-08/1/A-2009-0011 1 Age-related physiological changes in the circulation 1 arterial wall becomes more rigidThe 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- linksCalcium 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 amino acid content also rises. The elasticity of the aorta is diminished, during diastole the pressure falls steeply! (It decreases coronary circulation!)

13. TÁMOP-4.1.2-08/1/A-2009-0011 Remodelling capillary number decreasesRemodelling of the small vessels, the functional capillary number decreases – the oxygen supply of the tissues decreases! thickness of the tunica intima and media increasesThe thickness of the tunica intima and media increases, e.g. in the a. carotis communis 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 changesThe tone of the vessels changes NO decreases, ROS, TxA 2 PGH 2 increase Ca-dependent vasoconstriction is Ca-activated or voltage-dependent K+-channel  -subunit density decreases in the vascular smooth muscle membranes atherosclerosisBesides all these, atherosclerosis further increases the rigidity of the vessels (depending on severity) 2 Age-related physiological changes in the circulation 2

14. TÁMOP-4.1.2-08/1/A-2009-0011 contractility decreasesThe myocardial contractility decreases systole, and the diastole increases (slower)The duration of both the systole, and the diastole increases (slower) (ionflux of the L type Ca++ channels increases, their activity becomes longer) fall of the diastolic pressureDue to the fall of the diastolic pressure the coronary circulation decreases Age-related physiological changes in the coronary circulation

15. TÁMOP-4.1.2-08/1/A-2009-0011 1 Changes in the cardiovascular function 1 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 in healthy old people, because the major part of the filling takes place in the second phase The enlargement of the atria and their stronger contraction is responsible for the late filling (at 20-y 20%, 80- y 40%)

16. TÁMOP-4.1.2-08/1/A-2009-0011 Comparison between the early diastolic and atrial contribution to left ventricular filling in persons of a broad age range 90 80 70 60 50 020406080 100 Age (years) Early diastolic filling volume (% of total filling volume) 50 40 30 20 10 020406080100 Age (years) Late diastolic filling due to atrial contraction (% of total filling volume) menwomen

17. TÁMOP-4.1.2-08/1/A-2009-0011 2 Changes in the cardiovascular function 2 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 chronic left ventricular failure it leads to an acute heart failure

18. TÁMOP-4.1.2-08/1/A-2009-0011 3 Changes in the cardiovascular function 3Afterload the vessels are more rigid the speed of the pulse wave is up – with a quick reflection of the pulse wave, already within the systole, interference of 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 have benefits according to the LaPlace law), normalizing the systolic function and the ejection fraction isolated systolic hypertension In case of an abnormal blood pressure, treatment is necessary – isolated systolic hypertension

19. TÁMOP-4.1.2-08/1/A-2009-0011 Myocardial contractility The myocardial performance, i.e. the cardiac output depends (besides the pre- and afterload) on the contractility of the heart

20. TÁMOP-4.1.2-08/1/A-2009-0011 The interplay of vascular and adaptive cardiac changes during aging arteria l stiffen ing  pulse wave velocit y and early reflect ed waves  systoli c blood pressur e with late peak  LV wall tension  LV hyper- trophy Normali- sation of LV wall tension normal end- systolic volume and ejection fraction  aortic root size prolonged contracti on  early diastolic filling  atrial size  atrial filling and contracti on Normal end- diastolic volume