Diastolic Dysfunction and Diastolic Heart Failure

2. Diastolic Dysfunction and Diastolic Heart Failure By Mohammad M. Al-Daydamony (MSc., Cardiology)

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.

4. Definitions: Diastolic Dysfunction VS Diastolic Heart Failure

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.

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.

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].

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.

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 HCMandRCM.

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.

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.

17. Changes in 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.

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.

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.

20. Collagen synthesis is altered by: • Load, including preload and afterload. • Neurohumoral activation, including the renin angiotensin-aldosterone system (RAAS) and sympathetic nervous system. • Growth factors. Collagen degradation is under the control of proteolytic enzymes, which includes a family of zinc-dependent enzymes, the matrix metallo-proteinases (MMPs).

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.

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.

23. Causes: * Hypertension. * Ischemia. * Heart Rate. * Atrial Fibrillation. * Ventricular Load. * Mitral Stenosis. * Constrictive Pericarditis. * Restrictive CM. * Aging.

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.

27. * The Working Group for the European Society of Cardiology proposed that: diagnosis of primary diastolic heart failure requires three obligatory conditions: • Presence of signs or symptoms of CHF. • Presence of normal or only mildly abnormal LV systolic function. • Evidence of abnormal LV relaxation, filling, diastolic distensibility or diastolic stiffness. Eur Heart J, 1998

28. * Vasan and Levy; 2000, proposed an expansion and refinement of these diagnostic criteria by dividing them into: I. Definite diastolic HFrequires: 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.

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.

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%.

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.

32. Doppler echocardiography: It has assumed the primary role in the noninvasive assessment of cardiac diastolic function. For example, echocardiographic measurement of tau index τ, (the time constant of LV pressure decay during IVR), can be performed to assess LV stiffness.

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

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.

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.

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.

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.

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).

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.

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 τ of LV pressure decline is calculated. In slow myocardial relaxation t may be prolonged and vice versa.

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.

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.