THE AUSTRALIAN NATIONAL UNIVERSITY

1. THE AUSTRALIAN NATIONAL UNIVERSITY P-V Loops & Pathophysiological Principles of Heart Failure Christian StrickerAssociate Professor for Systems PhysiologyANUMS/JCSMR - ANUChristian.Stricker@anu.edu.auhttp://stricker.jcsmr.anu.edu.au/Heart_failure.pptx

3. Aims The students should • know how to identify critical values in a P-V loop (SV, pressure difference, diastolic filling, EF); • appreciate how a P-V loop is constructed; • be able to interpret a P-V loop (diagram); • be informed about different forms of heart failure; • be familiar with the consequences of heart failure; • understand pathophysiological principles underlying rationale therapy of heart failure; and • recognize that a failing heart is in an energy crisis.

4. Contents • P-V diagrams and cardiomyocytic properties • Example of P-V diagram • Notes on heart failure (pathophysiology) • “Forward” failure • “Backward” failure • P-V relationship in systolic heart failure • Therapeutic approaches • Cardiac metabolism and energy production • Myocardial energy crisis in heart failure

5. Different P-V Loops • Numerous important cardiac parameters can be inferred from a P-V loop.

6. Cardiomyocytic Ability • Isotonic contraction • Does not generate external work. • Maximal force production smaller than for isometric. Reason: shortening work required. • Isovolumetric contraction • Does not generate external work. • Maximal force production larger than isotonic. • Auxotonic contraction • Generates external work. • Maximal force production between isovolumetric and isotonic maxima. Modified from Schmidt & Thews, 1977

7. Maximal Myocytic Work Diagram • Passive properties: • passive volume load (filling pressure, preload). • Active properties: • isotonic maxima (smaller). • isovolumetric maxima (bigger). • orthogonal to each other. • Auxotonic maxima: • line between isovolumetricand isotonic maxima. • Determined by Pdiast and Psyst. Modified from Schmidt & Thews, 1977

8. P-V Loop/Diagram • Preload sets maxima: • Isotonic • Isovolumetric • Auxotonic • 2 values: • Pdiast • Psyst • Intersections with maxima curves set corners in loop. Modified from Schmidt & Thews, 1977

9. What Is This? Interpret! • Keep your cool! • Identify known landmarks: • “Pdiast” • “Psyst” • “Preload” • “Afterload” • Isovolumetric phases • SV* • EF* • Aortic insufficiency

10. Heart Failure

11. Heart Failure • Definition: “Heart failure (HF) is the pathophysiologic state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolising tissuesand/or allows it to do so only from an abnormally elevated diastolic volume.” E. Braunwald, in Harrison’s… • Insufficient cardiac output→output failure and/or volume retention. • Manifests itself only after most compensatory mechanisms have been exhausted (de-compensation) and typically after a precipitating cause (exacerbation).

12. Facts of Heart Failure • ~2% of population • 30 - 40% die within 1 year after diagnosis • Costs: 2% of health care costs (UK), expected to massively rise in coming years. • Annual mortality rate ~10% even with best therapies. • High mortality rate • High morbidity rate • Chronic heart failure is multifactorial. • Physiological loss of ~1 g myocardium per year on ~300 g. • Always two aspects: forward & backward failures

13. Forms of Heart Failure Defined according to underlying pathophysiological aspects

14. Pathophysiology of Acute Failure Guyton & Hall, 2001 • Acute heart failure as in heart attack. • “Backward failure”: PRA↑, activates CP reflex (pooling; HR↑). • “Forward failure” (BP↓): activates AB reflex: SY↑. • CO regained due to SY↑ at price of PRA↑ and HR↑:internal work↑ → energy efficiency↓.

15. Signs of “Backward Failure” • Increased PRA:distended central veins. • Accumulation of fluid in venous bed: expansion of plasma volume (via Na+ retention; see later kidney lecture) – weight gain; salt craving… • If PMSF↑ significantly (pooling): periph. oedema. • Lung • Respiratory rate↑ (insufficient peripheral perfusion): CPreflex and respiratory control (see later). • Oedema (left ventricular failure).

16. “Forward Failure” • Due to insufficient CO = Perfusion↓. • Fluid retention: H2O and Na+ (renal perf.↓) • Urine volume↓ • SY activation (AB): HR↑ (tachycardia)... • Shut-down what is not necessary… • Skin: low-grade fever (reduced skin perfusion). • Muscle: fatigue; cold extremities with pallor. • Viscera: anorexia and nausea associated with abdominal pain and fullness (stasis in liver). • Brain: fatigue, lack of concentration, etc. • etc.

17. P-V Diagram in HF • Systolic heart failure. • Reduced contractility. • Preload↑ (30 torr). • With Psyst↓, SV↓. • EF = 26% (50 / 190 ml). • External work significantly reduced; however, internal work massively increased (Laplace’ law); higher energy requirement than under normal conditions.

18. Decompensation in Heart Failure • Critical CO level ~ 5 L/min (renal perfusion). • If not met, Na+ actively retained (RAA system; volume↑) at price of PRA↑. • Eventually, over a few days, failure will result. • Therapy: contractility↑. • Consequence: PRA↓. Guyton & Hall, 2001

19. Therapeutic Approach • Increase SV • Increase contractility. • Decrease Pdiastand increase pressure difference. • Reduce central venous pressure (PRA). • Reduce venous return (volume due to pooling). • Decrease afterload • Reduce peripheral resistance. • Reduce end-systolic volume (increase EF). • Ensure appropriate electrical pacing • Reduce HR (where appropriate). • Convert to sinus or “like” rhythm (constant output). • Energy sparing treatments - “paradoxical” • Angiotensin-converting enzyme inhibitors, aldosterone antagonists, β-receptor blockers.

20. Myocardial Energy Production • Fuel uptake: glucose, fatty acids • High energy production: oxidative phosphory-lation • ATP transfer and its utilization: creatine-P • 6 kg ATP/d Neubauer (2007), NEJM 356:1140-51

21. Myocardial Energy Crisis in HF • Energy depletion in all 3 compartments: • Substrate utilisation↓ • Oxidative phosphorylation↓ • ATP transfer↓ • P-creatine↓ • ADP accumulation↑ • Peroxisome proliferator-activated receptor (PPARα) on nuclear membrane determines substrate utilization (switch) via gene expression. • PPARα activators could be beneficial: “fibrates” and others. • Early stages yet for pharmacological compounds. Neubauer (2007), NEJM 356:1140-51

22. Take-Home Messages • P-V diagram makes simple predictions about important parameters determining CO like SV, EF, preload, afterload and filling pressure. • Shape of the P-V loop gives interesting clues about underlying (patho-)physiology. • HF therapy is conventionally based on CO↑ by SV↑ (contractility), PRA↓, afterload↓and HR↓ (energy efficiency↑). • In HF, metabolism is challenged; in future new drug targets (PPAR) may improve function.

23. MCQ Joshua Klee, a 2 year-old male has been diagnosed with aortic valve stenosis. His blood pressure is 80/50 mm Hg, heart rate 75 bpm, stroke volume 30 ml, enddiastolic left ventricular volume and pressure 60 ml and 15 mm Hg, respectively. Which of the following P-V loops best depicts his ventricular function?

24. That’s it folks…

25. MCQ Joshua Klee, a 2 year-old male has been diagnosed with aortic valve stenosis. His blood pressure is 80/50 mm Hg, heart rate 75 bpm, stroke volume 30 ml, enddiastolic left ventricular volume and pressure 60 ml and 15 mm Hg, respectively. Which of the following P-V loops best depicts his ventricular function?