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Diastology Stress Test
Case Study
A 71-year-old man presents with exertional dyspnea progressing over several months. He has known diabetes mellitus and hypertension, both well controlled on medications. Chest x-ray and electrocardiogram (ECG) are unremarkable. His resting transthoracic echocardiogram shows normal-size cardiac chambers and left ventricular (LV) ejection fraction of 70%. Mitral inflow shows reduced early (E) to late (A) diastolic filling ratio and prolonged deceleration time of E velocity, suggesting impaired relaxation. E/e′ ratio of 12 suggests normal LV filling pressure at rest. No other valvular or pericardial abnormalities are observed. Diastolic stress echocardiography (SE) is performed with supine bicycle exercise, and exercise is stopped at 50 W due to severe dyspnea. During exercise there is significant increase in mitral E velocity with shortened deceleration time, but minimal change in mitral annular e’ velocity suggests elevated LV filling pressure with exercise ( Fig. 18.1 ).
Epidemiology
Exertional dyspnea is one of the most common presenting symptoms in our routine practice. The mechanisms responsible for dyspnea may vary significantly. Although cardiac or pulmonary diseases are major causes of pathologic dyspnea, other systemic conditions such as anemia, obesity, neuromuscular diseases, and metabolic acidosis should be suspected as possible causes. By accurately identifying the correct etiology of dyspnea in a patient, the appropriate treatment can be implemented. Cardiac causes of dyspnea include right, left, or biventricular heart failure with systolic dysfunction, coronary artery disease, hypertensive heart disease, cardiomyopathy, valvular dysfunction, pericardial disease, arrhythmia, congenital heart disease, and pulmonary arteriovenous malformations. Regardless of ejection fraction, demonstration of an elevated LV filling pressure is the most important hemodynamic parameter when a cardiac etiology is suspected. Frequently, exertional dyspnea cannot be explained by the variables of LV systolic and diastolic functions at rest. Therefore, for patients who report severe exertional symptoms, it may be desirable to measure the hemodynamic response to exercise to ensure that these symptoms are due to LV dysfunction.
Heart failure is the most common hospital discharge diagnosis in patients 65 years or older and is a major cardiovascular disorder that is still increasing. It has become increasingly evident that LV diastolic function has a major role in producing signs and symptoms in patients presenting with heart failure. Primary diastolic dysfunction is the cause of up to 50% of cases of heart failure, and it is also a determinant of prognosis. Impaired myocardial relaxation, manifested echocardiographically as reduced early to late (E/A) ratio or prolonged deceleration time of E velocity, is the most common finding in LV diastolic dysfunction, and it is recognized as an early manifestation in the spectrum of diastolic abnormalities. However, because of its ubiquity, this abnormality is often recognized as an incidental finding. Many elderly subjects and patients with hypertension or LV hypertrophy have Doppler echocardiographic evidence of impaired diastolic function but do not have any symptoms of heart failure at rest. More commonly, symptoms of diastolic dysfunction occur only during exertion when filling pressures are normal at rest and increase only with exertion. Therefore exercise could unmask diastolic abnormalities not evident under resting conditions. Despite this, the majority of measures used to characterize the severity of heart failure and prognosis are obtained at rest.
Pathophysiology
Abnormalities of ventricular relaxation and filling contribute to heart failure because these result in an abnormally high ventricular diastolic pressure in relation to diastolic volume. The most important factors that determine the relation between pressure and volume during ventricular diastole are the rate and extent of myocardial relaxation and the generation of restoring forces, both of which are important determinants of early diastolic filling. The passive pressure-volume relationship (PVR) of the ventricle determines mid- to late diastolic filling after the relaxation is complete.
Myocardial Relaxation
The normal cardiac contraction/relaxation cycle requires a precise, transient rise and fall of intracellular calcium ions (see Chapter 2 ). The sarcoplasmic reticulum (SR) has a central role in orchestrating the movement of calcium during each contraction and relaxation. Contraction of cardiac muscle is initiated by the cellular action potential that causes the opening of L-type sarcolemmal calcium channels, through which calcium ions enter the cytosol. Influx of calcium ions through L-type channels results in the release of large amounts of calcium ions from the adjacent SR through ryanodine receptor channels, a process termed calcium-induced calcium release. These calcium ions bind to troponin C, which ultimately disinhibits the interaction of actin and myosin with resultant cross-bridge formation. Myocardial relaxation is accomplished primarily by removal of calcium ions from troponin C by an enzyme located in SR, called SR calcium ATPase or SERCA 2 and the sarcolemmal sodium-calcium (Na-Ca) exchanger. In humans, approximately 75% of calcium ions are removed by SERCA 2 and 25% by the Na-Ca exchanger. The activity of SERCA 2 is modulated by phospholamban, another SR protein located near SERCA 2 . By virtue of phosphorylation by protein kinase A and other kinases, phospholamban enhances the calcium ion uptake by SERCA 2 . Failure of normal mechanisms of reuptake and extrude calcium ions released during contraction can result in the slowing of relaxation or an inability to return cytosolic calcium concentration to normal diastolic levels. The latter causes diastolic calcium overload and incomplete relaxation with excessive diastolic tension or stiffening. In an experimental model of senescence, it has been demonstrated that the decrease in SR Ca 2+ uptake during relaxation is associated with a decrease in the content and activity of SERCA 2 . More recently, SERCA 2 protein levels were found to be significantly decreased in senescent human myocardium. This decrease in SERCA 2 levels was associated with impaired myocardial function at baseline, and further deterioration occurred during hypoxic conditions. Thus decrease in SERCA 2 content and an associated decrease in SR Ca 2+ uptake has been suggested to play a major role in the diastolic dysfunction. The vulnerability of calcium reuptake is a contributing factor for abnormal LV relaxation early in cardiac disease states despite normal systolic function.
Myocardial relaxation is also modulated by external factors. Endocardial and vascular endothelial modulators have been proposed as important factors for the physiology of myocardial relaxation. Vascular endothelium also appears to play an important role in these responses. In an experimental papillary muscle preparation, Brutsaert et al. found that denudation of the endocardium resulted in an earlier and rapid relaxation in conjunction with a very modest reduction of developed force. Although effects are less clear in normal hearts, angiotensin II has been shown to slow myocardial relaxation in hypertrophied hearts. Other locally released substances that may influence myocardial relaxation include endothelin-1, natriuretic peptides, prostaglandins, and adenyl purines. The physiologic and pathophysiologic significance of these modulators of relaxation remains to be elucidated.
Interestingly, the relevance of caffeine for facilitating diastolic dysfunction in the intact heart was demonstrated in the experimental canine model of demand ischemia. It was also suggested that caffeine affected myocardial relaxation favorably without altering contractility.
Restoring Forces
Restoring forces are generated when the ventricle contracts to an end-systolic volume (ESV) less than its equilibrium volume (Vo), the volume in the fully relaxed state when transmural pressure is zero, thereby storing energy by compressing the elastic elements in the myocardium. The physical properties of the normal ventricular chamber allow potential energy to be stored during systole in the form of a lower ventricular pressure. This potential energy is converted to kinetic energy in the form of elastic recoil, with the resultant suction of blood from the left atrium into the ventricle early during diastole. Other factors, especially complex shape changes during systole, may also play a role in causing suction during subsequent diastole. During systole, the left ventricle demonstrates a counterclockwise twist extending from apex to base, and in early diastole the left ventricle untwists clockwise releasing the stored energy and creating a suction force not unlike the release of a compressed spring. Suction is most important under conditions of stress, when contractility is high and ESV is small, and filling must be enhanced such as during exercise. Conversely, when contractility is impaired, ESV is larger and suction is reduced or lost as a mechanism of filling.
The Passive Pressure-Volume Relation of the Ventricle
The Laplace law provides the relationship between pressure and chamber geometry when a stress is applied to the ventricle. In the simplest case of a sphere, the Laplace law states that pressure is proportional to the radius of the chamber divided by its wall thickness. Thus a chamber with thicker walls requires a larger distending pressure to achieve a given volume. The intrinsic stiffness of the tissue in the ventricular wall is the other key determinant of the distending force required to passively fill the chamber. At low filling pressures, the elastic properties are most responsible for wall stiffness. At higher distending pressures, the myocardial connective tissue matrix assumes a key role. The intrinsic passive stiffness of any tissue, including the myocardium, can be quantified as the change in stress required to produce a given change in stretch (or strain). Biologic tissues have a curvilinear passive stress-strain relationship. The amount of blood contained in the vessels in the wall is also a determinant of the stiffness of the myocardial tissue, contributing to the pressure-volume relationship. As a result, a greater distending pressure is required to fill the chamber when the myocardial blood volume increases. The PVR of the passive ventricle is curvilinear, paralleling the passive stress-strain relationship. At any point on this curve, the ratio of change in pressure to change in volume represents the operating chamber stiffness; its inverse is operating compliance. Like the stress-strain relationship, the PVR can be converted into a linear relationship by the plotting of operating chamber stiffness versus pressure ( Fig. 18.2 ). The slope of this relation is the chamber-stiffness constant. The parietal pericardium and right ventricle form external constraints to filling that influence the PVR as well. The parietal pericardium has a very compliant PVR at low volumes but then makes a sharp transition to a very steep relationship. Increases in right ventricular (RV) diastolic volume and pressure influence the LV PVR similarly, albeit more modestly, because the RV changes are transmitted to the left ventricle via the ventricular septum. This phenomenon is termed diastolic ventricular interaction and is based on the fact that total cardiac volume within the pericardial sac remains constant, hence overfilling of the right ventricle will result in reduced filling of the left ventricle, and vice versa. This is most dramatically manifested in constrictive pericarditis. The ventricular and pericardial effects on the LV PVR are often linked.
During exercise there is less time for diastolic filling of the left ventricle because tachycardia decreases the duration of diastole. To maintain or augment the stroke volume, myocardial relaxation should be faster and LV suction should be exaggerated. There can be a spectrum of alterations in diastolic function during exercise. Therefore exercise could unmask diastolic abnormalities not evident under rest conditions.
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