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Slide 2 Diastolic Dysfunction and Diastolic Heart Failure By Mohammad M. Al-Daydamony (MSc., Cardiology) By Mohammad M. Al-Daydamony (MSc., Cardiology) Slide 3 There is growing recognition that CHF caused by a predominant abnormality in diastolic function is both common and causes significant morbidity and mortality. However, there is continued controversy surrounding the definition of diastolic dysfunction and the diagnostic criteria for diastolic heart failure. As a result, clinical therapeutic trials have been slow to develop and difficult to design. Slide 4 Definitions: Diastolic Dysfunction VS Diastolic Heart Failure Slide 5 Diastolic Dysfunction: Diastole is the time period during which the myocardium loses its ability to shorten and to generate force, and returns to an unstressed length and force. So, diastolic dysfunction occurs when these processes are prolonged, slowed, or incomplete. If diastolic function measurements are normal at rest, they must remain so during the stress of a variable heart rate, stroke volume, end-diastolic volume, and blood pressure. Slide 6 Heart Failure: * Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood. Slide 7 Diastolic Heart Failure: Diastolic heart failure is a clinical syndrome characterized by the symptoms and signs of HF, a preserved EF, and abnormal diastolic function. It occurs when the ventricular chamber is unable to accept an adequate volume of blood during diastole, at normal diastolic pressures and at volumes sufficient to maintain an appropriate stroke volume. Diastolic heart failure may even produce symptoms that occur at rest [NYHA-class IV]. Slide 8 Pathophysiology: *During diastole, the heart returns to its relaxed state; it is the time for cardiac perfusion. *During diastole, drastic changes in cardiac pressure-volume relationships occur. *The relaxation process has 4 phases: 1) IVR from the time of AV closure to MV opening. 2) Early rapid filling after MV opening; diastasis. 3) A period of low flow during mid-diastole. 4) Late filling of the LV from atrial contraction. Slide 9 Slide 10 Slide 11 Slide 12 Slide 13 Mechanisms That Cause Diastolic Dysfunction: *They can be divided into myocardial and extramyocardial factors. *Myocardial factors could be within the myocytes, within the extracellular matrix, and that activate the autocrine or paracrine production of neurohormones. *Each of these mechanisms are active in the major pathological processes that result in diastolic dysfunction and heart failure as IHD, HPN, and HCM and RCM. Slide 14 Slide 15 Cardiomyocytes: Changes in Ca ++ Homeostasis: 1. Abnormalities in Na + -Ca ++ exchanger and the Ca ++ pump. 2. Abnormal sarcoplasmic reticulum Ca ++ reuptake (caused by a decrease in SR Ca ++ ATPase). 3. Changes in the phosphorylation state of the proteins that modify SR Ca ++ ATPase. diastolic cytosolic Ca ++ active relaxation and passive stiffness. Slide 16 Changes in Myofilaments: *Contractile proteins; actin, myocin. *Regulatory proteins; tropomyosin, and troponin (Tn-T, C, I). *ATP hydrolyses is required during relaxation, thus, relaxation is an energy-consuming process. *ADP and inorganic phosphate (Pi) must remain. Diastolic dysfunction will occur if the absolute concentration of ADP or inorganic phosphate (Pi) increases or if the relative ratio of ADP/ATP rises. Slide 17 Changes i n cardiomyocyte cytoskeleton: *It is composed of microtubules, intermediate filaments (desmin), microfilaments (actin), and endosarcomeric proteins (titin, nebulin, actinin, myomesin, and M-protein). *During contraction, potential energy is gained when titin is compressed, and during diastole, titin expends this stored potential energy, recoil of myocytes to its resting length. * Changes in proteins. * microtubule density and distribution. * Changes in titin isotypes. Slide 18 Extracellular Matrix: 1.Fibrillar protein, such as collagen type I, collagen type III, and elastin. 2.Proteoglycans. 3.Basement membrane proteins, such as collagen type IV, laminin, and fibronectin. The role played by other fibrillar proteins, the basement membrane proteins, and the proteoglycans remains largely unexplored. Slide 19 1) Disease processes that alter diastolic function also alter ECM fibrillar collagen, particularly in terms of its amount, geometry, distribution, degree of cross- linking, and ratio of collagen type I versus collagen type III. 2) Treatment of these disease processes, which is successful in correcting diastolic function, is associated with normalization of fibrillar collagen. 3) Experiments in which a chronic alteration in collagen metabolism is accomplished result in an alteration of diastolic function. Slide 20 Collagen synthesis is altered by: 1) Load, including preload and afterload. 2) Neurohumoral activation, including the renin angiotensin-aldosterone system (RAAS) and sympathetic nervous system. 3) Growth factors. Collagen degradation is under the control of proteolytic enzymes, which includes a family of zinc-dependent enzymes, the matrix metallo-proteinases (MMPs). Slide 21 Neurohumoral and Cardiac Endothelial Activation * Acute and chronic, neurohormonal and cardiac endothelial activation and/or inhibition have been shown to alter diastolic functions. * Chronic activation of RAAS ECM fibrillar collagen stiffness. * Inhibition of RAAS prevents or reverse ECM fibrillar collagen, and generally stiffness. Slide 22 * Acute activation or inhibition of neurohumoral and cardiac endothelial systems has been shown to alter relaxation and stiffness. * These acute pharmacological interventions act in a too short time to alter the ECM; therefore, their effect on diastolic function must be caused by direct action on the cardiomyocyte. * For example, acute treatment of patients with LV pressure overload with an ACE inhibitor, a NO donor, caused LV pressure decline and LV filling to be more rapid and complete, and stiffness to decrease. Slide 23 Causes: * Hypertension. * Ischemia. * Heart Rate. * Atrial Fibrillation. * Ventricular Load. * Mitral Stenosis. * Constrictive Pericarditis. * Restrictive CM. * Aging. Slide 24 Slide 25 Diagnosis: * The diagnosis of diastolic HF cannot be made at the bedside. * Differentiation between systolic and diastolic heart failure cannot be made on the basis of history, physical examination, ECG, or chest radiograph alone. * Markers from these examinations occur with the same relative frequency in both systolic and diastolic HF. Slide 26 Slide 27 * The Working Group for the European Society of Cardiology proposed that: diagnosis of primary diastolic heart failure requires three obligatory conditions: 1)Presence of signs or symptoms of CHF. 2)Presence of normal or only mildly abnormal LV systolic function. 3)Evidence of abnormal LV relaxation, filling, diastolic distensibility or diastolic stiffness. Eur Heart J, 1998 Slide 28 * Vasan and Levy; 2000, proposed an expansion and refinement of these diagnostic criteria by dividing them into: I. Definite diastolic HF requires: 1) definitive evidence of CHF; 2) objective evidence of normal systolic function, with an EF 50% within 72 hours of the CHF event; and 3) objective evidence of diastolic dysfunction on cardiac catheterization. II. If objective evidence of diastolic dysfunction is lacking but the first 2 criteria are present, this fulfills the criteria for probable diastolic HF. III. If the first criterion is present and EF is 50% but not assessed within 72 hours of the CHF event, this fulfills the criteria for possible diastolic HF. Slide 29 Gandi et al., 2001 addressed the requirement for the presence of an EF 50% within 72 hours of the CHF event. They demonstrated that in patients presenting with acute pulmonary edema and systolic hypertension (160 mm Hg), there were no significant differences between EF at the time of presentation, and 72 hours after the event, (after stabilization). Therefore, under most circumstances, EF does not need to be measured coincident with the acute HF event. Slide 30 Zile et Al, 2001 examined the necessity of obtaining objective evidence of diastolic dysfunction. In this study, patients with a history of CHF and had an EF 50% underwent diagnostic left heart catheterization and simultaneous Doppler echocardiography. They concluded that the diagnosis of diastolic HF can be made without measurement of diastolic function if 2 criteria are present: (1) Symptoms and signs of HF (BNP). (2) LV EF 50%. Slide 31 Measurement of Diastolic Function Cardiac catheterization remains the gold standard for demonstrating impaired relaxation and filling, because it provides direct measurement of ventricular diastolic pressure. The balance of benefit, harm, and cost argue against its routine use in diagnosing diastolic dysfunction. Slide 32 It has assumed the primary role in the noninvasive assessment of cardiac diastolic function. For example, echocardiographic measurement of tau index , (the time constant of LV pressure decay during IVR), can be performed to assess LV stiffness. Doppler echocardiography: Slide 33 Also, Doppler echocardiography is used to evaluate the characteristics of diastolic trans- mitral-valve blood flow. The peak velocities of blood flow during early diastolic filling (E wave) and atrial contraction (A wave) are measured, and the ratio is calculated. Under normal conditions, the early-filling E-wave velocity is greater than the A-wave velocity, and the E-to-A-wave ratio is about 1.5 Slide 34 Slide 35 In early diastolic dysfunction, this relationship reverses, because the stiffer heart relaxes more slowly. The E-to-A-wave ratio drops below 1.0. Slide 36 Slide 37 As diastolic function worsens and LV diastolic pressure rises, LV diastolic filling occurs primarily during early diastole, because the LV pressure at end-diastole is so high that atrial contraction contributes less to LV filling than normal. At this point, the E-to-A-wave ratio rises, often to greater than 2.0. This so-called restrictive pattern confers a poor prognosis. Slide 38 Slide 39 The E- and A-wave velocities are affected by blood volume and MV anatomy and function. They are less useful in the presence of AF. Despite these limitations, Doppler echocardiography provides essential information about the diastolic functions. It also allows the physician to identify and rule out other potential causes of the patient s symptoms, such as valvular lesions, pericardial disease, systolic dysfunction, and pulmonary hypertension. Slide 40 Slide 41 Slide 42 Slide 43 Radionuclide angiography: The assessment of global LV diastolic function with radionuclide angiography is derived from the time activity curve of the LV, which closely matches the LV volume curve. It therefore represents relative volume changes throughout the cardiac cycle. This volume curve is used for assessment of global, LV-EF, and may also be used to study LV filling, which, is dependent on diastolic LV function. Slide 44 Parameters of diastolic function include those expressing the filling rate at a certain moment (peak filling rate), the timing of this event (time to peak filling rate), and relative filling fractions (early diastolic filling fraction and atrial contribution to diastolic filling). Slide 45 Slide 46 Cardiac catheterization: With cardiac catheterization it is possible to collect measures of LV function invasively. When focusing on diastolic function, the parameters can be divided into those expressing passive compliance, and those expressing active relaxation of the LV. Chamber compliance, the inverse of chamber stiffness can be defined as the instantaneous volume change per unit change in pressure (dV/dP) and can be calculated when measures of diastolic LV volume and pressure have been gathered together. Slide 47 Relaxation can be described with help of the LV pressure curve during IVR. The first derivative of this curve describes the rate of LV pressure decline (dP/dt). Although relaxation can be described by peak-dP/dt, this factor is influenced by changes in loading. A better parameter to describe LV relaxation is obtained when the time constant of LV pressure decline is calculated. In slow myocardial relaxation t may be prolonged and vice versa. Slide 48 Magnetic Resonance Imaging: With MRI it is not only possible to collect anatomic data, but also functional data of the heart. These functional data can be obtained using different MR techniques, including cine MR imaging and myocardial tagging with radiofrequency pulses. With phase velocity mapping it is possible to evaluate parameters of diastolic LV function, i.e. LV inflow propagation and vortex flow in the LV. How these parameters relate to specific cardiac disease remains to be investigated. Slide 49 Computed Tomography: The cine mode imaging protocol is used to provide precise assessment of RV and LV global and regional systolic and diastolic function. The flow mode imaging protocol is employed to measure cardiac output, myocardial blood flow and diastolic function. Slide 50 Slide 51 Treatment: Unfortunately, there have been no randomized, double- blind, placebo-controlled, multi-center trials performed in patients with diastolic HF. Consequently, the guidelines for the management of diastolic HF are based on clinical investigations in relatively small groups of patients, clinical experience, and concepts based on patho-physiological mechanisms. The treatment regimen applies to those patients with symptomatic diastolic HF. Whether treatment of asymptomatic diastolic dysfunction confers any benefit has not been examined. Slide 52 Slide 53 Treatment of diastolic heart failure can be framed in 3 steps: 1)Symptom reduction, by decreasing PV pressure at rest and during exertion. 2)Treating the pathological disease that caused the diastolic HF (CAD, HPN, and AS). 3)Treating the underlying mechanisms that are altered by the disease processes. Slide 54 Symptom-Targeted Treatment: Decrease LV Diastolic Pressure The initial step in treating patients presenting with diastolic heart failure is to reduce pulmonary congestion by decreasing LV volume, maintaining synchronous atrial contraction, and increasing the duration of diastole by reducing heart rate. By decreasing LV diastolic volumes, LV pressures slide down the curvilinear diastolic pressure-volume relationship toward a lower, less steep portion of this curve. Slide 55 LV diastolic pressures can be decreased by reducing total blood volume, decreasing central blood volume (nitrates), and blunting neurohumoral activation. Treatment with diuretics and nitrates should be initiated at low doses to avoid hypotension and fatigue. Hypotension can be a significant problem. Slide 56 Tachycardia is poorly tolerated in patients with diastolic HF for several reasons. -Blockers and some calcium channel blockers can thus be used to prevent excessive tachycardia and produce a relative bradycardia (60-70 bpm). Slide 57 Improve Exercise Tolerance: Patients with diastolic HF have a marked limitation in exercise tolerance. This could be due to: -The inability to use the Frank-Starling mechanism. -The abnormal relaxation velocity versus heart rate relationship. -The presence of an exaggerated rise in blood pressure in response to exercise. Slide 58 -Blockers, calcium channel blockers, and AT 1 antagonists may have a salutary effect on symptoms and exercise capacity in many patients with diastolic HF. However, the beneficial effect of these agents on exercise tolerance is not always paralleled by improved LV diastolic function or increased relaxation rate. Slide 59 Use Positive Inotropic Drugs With Caution: They are generally not used in the treatment of patients with isolated diastolic HF (little potential benefit, potential to worsen the pathophysiological) May be beneficial in the short-term treatment of pulmonary edema associated with diastolic heart failure because they enhance SR function, promote more rapid and complete relaxation, increase splanchnic blood flow, increase venous capacitance, and facilitate diuresis. Slide 60 Treatment of Systolic Versus Diastolic HF With a number of notable exceptions, many of the drugs used to treat diastolic heart failure are in fact the same as those used to treat systolic heart failure. However, the rationale for their use, the patho- physiological process that is being altered by the drug, and the dosing regimen may be entirely different depending on whether the patient has systolic or diastolic heart failure. Slide 61 For example, -blockers. In diastolic heart failure, however, -blockers are used to decrease heart rate, increase the duration of diastole, and modify the hemodynamic response to exercise. In systolic HF, -blockers are used chronically to increase inotropic state and modify LV remodeling. In systolic heart failure, -blockers must be titrated slowly and carefully over an extended time period. This is generally not necessary in diastolic HF. Slide 62 Diuretics, the doses of diuretics used to treat diastolic HF are generally smaller than the doses used in systolic HF. Some drugs are used only to treat either systolic or diastolic HF but not both. For example, calcium channel blockers such as diltiazem, nifedipine, and verapamil have no place in the treatment of systolic HF. Slide 63 Mechanism-Targeted Treatment (Future Directions): An ideal therapeutic agent should target the underlying mechanisms that cause diastolic HF. A therapeutic agent might improve Ca ++ homeostasis and energetics, blunt neurohumoral activation, or prevent and regress fibrosis. Fortunately, some pharmaceutical agents that fit these design characteristics are already in existence, and many more are under development. Slide 64 Unfortunately, randomized, double-blind, placebo- controlled, multicenter trials that examine the efficacy of these agents used either singly or in combination have been slow to develop. Difficulties for these kinds of studies: - Lack of recognition of the importance of diastolic HF. - Inability to define a homogeneous study population. - Lack of agreement on the definition and diagnostic criteria for diastolic HF. Slide 65 Prognosis: Prevalence: The prevalence of diastolic dysfunction without diastolic HF and the prevalence of mild diastolic HF (NYHA class II) are not known. Early studies suggested that as many as one third of patients presenting with overt CHF have a normal EF; isolated diastolic heart failure. Patients 70 years old, the prevalence of diastolic heart failure approaches 50%. Slide 66 Mortality: The prognosis of patients with diastolic heart failure, although less ominous than that for patients with systolic HF, does exceed that for age-matched control patients. The annual mortality rate for patients with diastolic HF approximates 5% to 8%. In comparison, the annual mortality rate for patients with systolic HF approximates 10% to 15%, whereas that for age matched age matched controls approaches 1%. Slide 67 In patients with diastolic HF, the prognosis is also affected by the pathological origin of the disease. Thus, when patients with CAD are excluded, the annual mortality rate for isolated diastolic HF approximates 2% to 3%. Slide 68 Morbidity: Morbidity from diastolic HF is quite high, which necessitates frequent outpatient visits, hospital admissions, and the expenditure of significant healthcare resources. The 1-year readmission rate approaches 50% in patients with diastolic HF. This morbidity rate is nearly identical to that for patients with systolic heart failure. Slide 69 Slide 70 Slide 71