Heart failure Assessment of cardiac performance: P-V diagram Compensatory mechanisms to maintain CO Systolic and diastolic (dys)function Heart remodeling patterns Etiopathogenesis of HF HF as a syndrome Assessment of cardiac performance: pressure-volume loop Mechanical work of the heart • Ventricular filling occurs along the end-diastolic pressure-volume relationship (EDPVR), or passive filling curve for the ventricle. The slope of the EDPVR is the reciprocal of ventricular compliance • The area within the loop is the ventricular stroke work • The maximal pressure that can be developed by the ventricle at any given left ventricular volume is defined by the end-systolic pressure-volume relationship (ESPVR), which represents the inotropic state of the ventricle Heart needs a lot of energy to continually perform as a pump CO (4–6 L/min) = SV (usually 1mL/kg, i.e. approx. 60–100mL)  f sympathetic n. system parasympathetic n. system venous return Changes in ventricular function in response to changes of preload, afterload and inotropy • If effects considered separately • These ventricular changes can be complex because preload, afterload and inotropy are interdependent variables • when one variable is changed (by disease), the other variables change in response • interactions between preload and afterload at constant inotropy • secondary changes of preload by changes in afterload • change in inotropy affects both preload and afterload Interdependent Changes in Preload, Afterload and Inotropy during Exercise For heart to perform as a pump both systolic and diastolic function has to be preserved • Pathophysiological spectrum heart failure (HF) • from asymptomatic cardiac dysfunction as a preceding stage in the progression to clinically overt HF • Myocardial dysfunction is a state when CO is potentially affected • types of myocardial dysfunction • systolic and/or diastolic • acute or chronic • compensated or uncompensated • uni- or biventricular • Systolic (dys)function • (impaired) ventricular contraction and ejection • Diastolic (dys)function • (impaired) relaxation and ventricular filling • Left ventricular dysfunction or heart failure (LHF) is the dominant picture of heart failure syndrome • approx. 70% HF patients has SdF • however often with component of DdF • approx. 30% HF patients has DdF • But the right heart can develop isolated failure as well • Biventricular failure is mostly an end-stage clinical situation of the heart failure syndrome From cardiac dysfunction to heart failure • Distinction between systolic or diastolic LV dysfunction depends on the ejection fraction (EF) • portion/percentage of blood volume (i.e. LVEDV) pumped from the ventricle in one heartbeat • EF <40% = systolic dysfunction • clinically HF with reduced EF (HFrEF) • EF >40% = diastolic dysfunction • clinically HF with preserved EF (HFpEF) • Consequence of LV dysfunction • note! they are the same for systolic or diastolic dysfunction Heart failure syndrome (HFS) • a systemic illness affecting several organs, creating high morbidity and mortality rates due to • the heart’s inability to deliver adequate oxygenated blood and metabolites to the body to meet end-organ metabolic needs and oxygenation at rest or during exercise • and to accommodate venous return • typically due to the left ventricular pump dysfunction and related clinical symptoms (dyspnea, fatigue, exercise intolerance, metabolic dysturbances etc.) including signs of volume overload (pulmonary crackles, peripheral edema, etc.) • HFS develops due to any structural and/or functional cardiac abnormalities • the pathophysiologic state perpetuates the progression of the failure, regardless of the precipitating event via several compensatory mechanisms (circulus vicious) • classification of LHF is dependent on whether the left ventricular ejection fraction (LVEF) is reduced or preserved • acute event or acute refractory form of chronic HF can be fatal, whereas chronic prognosis is characterized by terminal congestive heart failure symptoms Functional classification of HF instead of CO NYHA classification Class Symptoms Class I No symptoms with ordinary activity Class II Slight limitation of physical activity Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, dyspnea or angina Class III Marked limitation of physical activity Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnea, or angina Class IV Unable to carry out any physical activity without discomfort Symptoms of cardiac insufficiency may be present even at rest ACC/AHA classifications Stage Disease Stage A Patient at high risk for developing HF with no structural disorder of the heart Stage B Patient with structural disorder of the heart without symptoms of HF Stage C Patient with past or current symptoms of HF associated with underlying structural heart disease Stage D Patient with end-stage disease who requires specialized treatment strategies hypertension HF results from injury to the myocardium from a variety of causes • multiple etiologies can lead to final common clinical pathway • aetiology = any disease causing a loss of a critical quantity of functional myocardial cells • some are common, some are rare • ¾ of all HF patients have pre-existing systemic arterial hypertension • this risk factor alone doubles the risk of developing HF compared to normotensive patients – can lead to HF on its own • accelerates progression of any other aetiology heartfailure coronary artery disease valvular disease cardio- myopathy myo- carditis cardio- toxic various diseases / aetiologies gradually slowly rarely acutely/chronically quickly progression toHF SYNDROME of variable severity decompensation death ILLNESS clinical manifestation of disease & compensatory mechanisms SYMPTOMS & SIGNS differential DIAGNOSIS Left heart failure (LHF) Left ventricular pressure-volume relationships: • In systolic LHF, an adequate stroke volume cannot be sustained due to reduced ventricular systolic contractile function, which shifts the whole pressure-volume relationships to the right • In diastolic LHF, an adequate filling cannot be realized due to diastolic stiffness (poor ventricular compliance, impaired relaxation, worsened end-diastolic pressure), which shifts the diastolic pressurevolume curve upward; however, the systolic pressure-volume curve does not change COMPENSATORY MECHANISMS TO MAINTAIN CARDIAC OUTPUT Compensatory mechanisms to maintain CO • Mean arterial pressure (MAP) is closely regulated and is defined as the product of CO and total peripheral resistance (TPR) • The failing heart strives to balance “preload” and “afterload” for compensation of impaired contractility and to deter the development of congestion using a myriad of mechanisms • CO sensing mechanisms • low-pressure volume receptors • present mainly in the cardiac atria • release of natriuretic peptides • high-pressure mechanoreceptors • located in the left ventricle, aortic arch, carotid sinus and renal juxtaglomerular apparatus • From asymptomatic to symptomatic stages, several mechanisms are activated: • (1) the Frank–Starling mechanism • (2) neuro-hormonal activation • (3) ventricular remodelling Compensatory mechanisms to maintain CO • (1) the Frank–Starling mechanism • SV as a function of LVEDP • increases myocardial contraction power, but this positive effect reverses after the sarcomere length reaches the upper limit of 2.2 μm • efficient under various contractility Low contractility Compensatory mechanisms to maintain CO • (3) neuro-hormonal activation to augment MAP • (3a) sympathetic nervous system activation • mediated through β1, β2, and α1 receptors • chronotropic effect  increasing heart rate frequency • this positive effect is reversed after tachycardia reaches a threshold of 140–150 beats/min • inotropic effect  increasing contractility • increasing TPR • by peripheral vasculature (vasoconstriction) • activation of the renin–angiotensin–aldosterone system (RAAS) β1 and α1 receptors causing • peripheral vasoconstriction • sodium and water retention • (3b) activation of RAAS by kidney hypoperfusion • (3c) activation of vasopressin • release from hypothalamus and posterior pituitary facilitated by angiotensin II and central baroreceptors • (3d) natriuretic peptide release Natriuretic peptides – potentially beneficial • play a significant role in water and salt homeostasis • counter-regulatory balance to the harmful neurohumoral pathways already discussed (3a – 3c) • beneficial effects include • vasculature: direct vasodilatation = lowering of blood pressure • kidney: natriuresis and diuresis, lowering the release of renin from the kidneys, increasing renal blood flow • heart: decreasing cardiac hypertrophy and fibrosis • natriuretic peptide system consists of three main peptides: • atrial natriuretic peptide (ANP) • B-type natriuretic peptide (BNP) • ANP and BNP released from myocytes in response to cardiac stretch • C-type natriuretic peptide (CNP) • released from endothelial cells • biomarkers: elevated circulating levels of NP found in patients with chronic heart failure • assessment of BNP (or its inactive N-terminal fragment, NTproBNP) is now a key component of the diagnostic pathway for patients with suspected heart failure • therapeutic potential: inhibition of the breakdown of natriuretic peptides (ANP, BNP, CNP and urodilatin) by a membrane bound endopeptidase neprilysin • caution since it breaks down also bradykinin and angiotensin II • has to be used together with ARBs Compensatory mechanisms to maintain CO • (4) ventricular remodelling as a response to • volume or pressure overload • increases in LV wall thickness decrease LV wall stress following Laplace’s law, thereby maintaining cardiac efficiency • increased oxygen demand • wall tension + any degree of ischemia • background conditions Factors influencing myocardial O2 consumption (MVO2) • (1) wall tension • that’s why O2 demand is  in pressure or volume overload • (2) contractility • (3) heart rate • that’s why (i.e. 2 & 3) O2 demand is  during sympathetic activation • (4) myocardial mass • that’s why O2 demand is  in cardiac hypertrophy (esp. maladaptive) • rough estimate of energetic demands of heart: tension-time index (TTI) • SBP x heart rate Wall tension x pressure or volume overload x MVO2 • wall tension () = tension generated by myocytes that results in a given intraventricular pressure at a particular ventricular radius • pressure and volume overload have very various effects on MVO2 • afterload = pressure • preload = volume (filling ~ end-diastolic pressure) • V = 4/3 × r3 • r = 3 V •  = P × 3 V / d • 100% increase in ventricular volume (V) increases wall tension () by only 26% • in contrast, increasing intraventricular pressure (P) by 100% increases wall tension () by 100%! for detail see previous slide Why hypertrophy does not  O2 consumption at the end • the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload • hypertrophy ( d) normalizes wall tension () per gram of myocardium in case of pressure or volume overload •  = P × r / d • initially, it does reduces MVO2 when wall tension increases and heart has to generate higher pressure to overcome V or P overload • however, as the total mass of myocardium increases, consumption of O2 increases as well • myocardial hypertrophy is not paralleled by similar growth of coronary bed Cardiac hypertrophy - physiological • individual cardiomyocytes often undergo enlargement • cardiac hypertrophy increases contractility, at least initially, through the addition of sarcomere units • two types of hypertrophy (each form regulated by distinct cellular signalling pathways): • physiological • occur during normal postnatal growth, pregnancy and repetitive endurance training, and is mainly identified by a mild (10–20%) increase in ventricular volume with a coordinated increase in wall thickness (eccentric hypertrophy) and individual cardiomyocyte growth in both length and width • after relief of the stimulus, physiological hypertrophy is reversed and the heart returns to its original dimensions • no interstitial or replacement fibrosis or cell death • pathways: cell survival signalling, increased energy production and efficiency, angiogenesis proportional to the ventricular wall growth, antioxidant systems, mitochondrial quality control, and cardiomyocyte proliferation and regeneration • pathological • initially develops as an adaptive response, but pathological hypertrophy generally progresses to diastolic dysfunction and heart failure Cardiac hypertrophy – physiological vs. pathological Pathological cardiac hypertrophy Nature Reviews Cardiology ISSN 1759-5010(online) In fact, there are many LV remodelling patterns Various progression/prognosis of HF according to type od remodelling Comparison Nature Reviews Cardiology ISSN 1759-5010(online) Summary – compensatory mechanisms operating in HF HEART FAILURE AS A CLINICAL SYNDROME Signs and symptoms of HF • result of the clinical sequelae of inadequate CO • fatigue is common as the failing heart cannot sustain enough CO to meet the body's metabolic needs and conserves blood flow to the heart and brain • nausea and lack of appetite may also occur as blood is shifted from the gastrointestinal tract to the more vital organs. • palpitations can occur as the failing heart tries to accommodate for the lack of CO with a faster heart rate (HR) • and lack of efficient venous return • dyspnea, cough, and wheezing result from increased pressure in the pulmonary capillary bed due to ineffective forward flow from the left ventricle • lower extremity edema, as well as ascites, occurs when the right ventricle is unable to accommodate systemic venous return = congestive heart failure Alveolar-capillary barrier  pulmonary edema (1) interstitial edema (2) alveolar edema Pathophysiology of pulmonary congestion/edema • accumulation of fluid in the lungs, resulting in impaired gas exchange and arterial hypoxemia • occurs sequentially • first developing in the hilar region of the lungs, • followed by filling of the interstitial space (= interstitial edema) • and finally, in its most severe form, by alveolar flooding (= alveolar edema) • pulmonary edema is the result of an imbalance between the forces that drive fluid into the alveoli and the mechanisms for its removal • Starling equation • simplistic model, pulmonary edema has been traditionally classified into 2 categories • cardiogenic or hydrostatic pulmonary edema results from high pulmonary capillary hydrostatic pressures • non-cardiogenic or high permeability edema is characterized by injury to the alveolarcapillary barrier with leakage of protein-rich fluid into the interstitium and air spaces • Studies based on the ratio of edema fluid protein to serum protein in patients with cardiogenic and noncardiogenic pulmonary edema have shown that frequently there is a combination of high hydrostatic pulmonary capillary pressure and high permeability of the alveolar-capillary barrier, leading to a significant overlap between the two groups • if increased hydrostatic pulmonary capillary pressure per se were responsible for pulmonary edema formation, protein concentration of the alveolar lining fluid would be expected to decrease due to the influx of plasma ultrafiltrate • paradoxically, it nearly doubles Pulmonary hypertension Alveolar-capillary barrier dysfunction • whether a rise in the pulmonary capillary wedge pressure (PCWP) results in pulmonary oedema seems to depend on the rate at which this pressure rises • rapid rises in PCWP (as in acute HF) can result in pulmonary oedema at relatively low pressures • whilst those with longstanding pulmonary hypertension can tolerate remarkably high pressures without production of pulmonary oedema • two fundamental processes may lead to alveolar-capillary barrier dysfunction in AHF • mechanical injury of the barrier due to increased hydrostatic pulmonary capillary pressures • inflammatory and oxidative lung injury • ACM remodelling process (mainly excessive deposition of collagen type IV) may be protective against further high pressure damage and may increase resistance of the lung to the development of pulmonary edema in chronic HF patients • increased capillary basement membrane thickness and capillary dilatation, whilst overall capillary density falls 2 • intimal thickening of the arteries and veins with muscularisation of the arterioles and venules • circumferential fibrosis of both veins and arteries • alveolar wall changes including increased interstitial tissue, interstitial pericapillary oedema, haemosiderin deposition and alveolar wall thickening due to excess collagen, cuboidal (as opposed to flat) epithelium and increased type II pneumocytes • compression of the peripheral airways by increased amounts of connective tissue 6. Bronchial smooth muscle hypertrophy • problems with breathing and gas exchange • effect of posture on lung function • in the supine position (fluid from lower limbs to lungs) • restrictive ventilatory deficit ( FVC) with impaired diffusing capacity • airway obstruction ( FEV1, RV) by excess fluid possible too • central sleep apnoea (CSA) • known as Cheyne-Stokes respiration or periodic breathing Thank you for your attention !