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Conventional, Metabolic, and Neuroendocrine Imaging in the Selection of Patients for Bypass vs. Transplant SurgeryJosef Machac, M.D.
|Introduction||Assessment of Ischemia|
|Therapy||Assessment of Viability|
|Clinical Risk Stratification||Selection for Transplantation|
|Ventricular Function||Neuroendocrine evaluation|
|Selection for Bypass||Sympathetic receptor imaging|
Congestive heart failure (CHF) is a leading cause of mortality and morbidity in the industrialized world1,2. The leading causes of CHF are ischemic heart disease and hypertension. Other etiologies include valvular disease, viral, idiopathic, and alcoholic cardiomyopathy, and less commonly, thyroid disease and hemachromatosis3,4.
Most experts agree that CHF stems from inadequate cardiac output, due to systolic or diastolic left ventricular (LV) dysfunction. It results in inadequate flow to the peripheral tissues at rest and with exertion. This leads to a series of compensatory responses designed to maintain perfusion pressure to vital organs. Such responses lead to the clinical expression of CHF and likely contribute to the progression of the syndrome. The neurohumoral systems include the sympathetic nervous system, the renin-angiotensin system, and circulating plasma vasopressin5,6. The extent of their activation correlates only modestly with the degree of hemodynamic derangement. This suggests that multiple factors control the systemic response. The model accepted today is that inadequate flow activates vasoconstrictor forces that eventually lead to excessive impedance to left ventricular ejection and further reduction in cardiac output, allowing a vicious cycle to be set in motion.
Despite or because of neuroendocrine activation, patients with CHF have a blunted sympathetic and vasopressin response to orthostatic tilt or exercise, expressed as blunted responses in heart rate, blood pressure, forearm flow, and hepatic vascular resistance. This abnormality appears to be related to the severity of the resting hemodynamic abnormality7,8,9,10. Patients with more modest degrees of CHF may retain their reflex ability to increase norepinephrine levels during uppright tilt and nitroprusside infusion10,11. This suggests that sympathetic responsiveness is a useful index of the progression of CHF.
The diagnosis is usually made on the basis of symptoms of dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and edema, but which are relatively nonspecific12. In fact, clinical symptoms and signs may be misleading in many patients13,14. The diagnosis is aided by the more specific physical signs of third heart sound, elevated jugular venous pressure, and the presence of pulmonary crackles by auscultation15. The chest radiograph is helpful in correlating signs and symptoms with heart enlargement and pulmonary venous distension16. To distinguish CHF secondary to LV systolic from diastolic dysfunction17, echocardiography or radionuclide gated blood pool imaging are commonly employed.
It is not the purpose of this section to comprehensively review therapy of CHF. However, the general tools of diagnosis and therapy are important for prognostic stratification, for selection among alternatives in therapy. The standard therapy for CHF are diuretics18,19,20 and ACE inhibitors21. The role of digoxin was clarified by the DIG study. It did not reduce mortality, but did result in a reduction of hospitalizations22. A number of trials confirmed the benefit of beta blocker therapy, resulting in increased ejection fraction and reducing the risk of dying by some 30%. Benefit was noted even and especially in patients with the lowest LVEF23,24,25,26,27 in spite of the possibility of exacerbation of the heart failure, bradycardia, and AV block in some patients. The combined alpha/beta blocker carvedilol suggests an advance in therapy, with a 65% reduction in total mortality caused by both progressive CHF and sudden death28.
Sudden death accounts for about a half of all deaths in CHF, presumably, due to arrhythmias29,30. Earlier attempts to treat arrhythmias with class I agents have led to increased mortality31. On the other hand, the class 3 drug amiodarone has been found to reduce mortality from sudden death by 29% and overall mortality by 15%32. Another option in the prevention of sudden death is prophylaxis with an implantable defibrillator in patients with non-sustained ventrycular tachycardia and coronary artery disease33.
Another cause of morbidity and mortality in CHF is the risk of embolic stroke, particularly, after the appearance of intermittent or permanent atrial fibrillation. Warfarin has been shown to reduce the risk of embolic stroke by 68% in patients with nonvalvular atrial fibrillation. The added benefit appears to be greater than the risk of a serious hemorrhage34.
Of benefit in some patients with CHF due to ischemic heart disease is revascularization, either using percutaneous methods, or coronary artery bypass surgery (CABG), by controlling symptoms of ischemia, improving function, and preventing further deterioration. Heart transplantation provides a last resort for some patients with severe CHF. Exciting research is being conducted in the new field of induction of angiogenesis35.
Much of the literature and understanding for the treatment of heart failure is based on the hemodynamic paradigm of heart failure. If a decrease in LVEF portends a poor prognosis, then interventions that improve the LVEF or its surrogates (exercise time, symptoms), should improve survival. However, a lack of direct connection between inotropy and survival is shown by the lack of life prolongation with digoxin therapy36 and the increased mortality with milrinone, amrinone, and enoximine, despite improvements in hemodynamics and symptoms37,38,39.
Not to be overlooked is the value of exercise rehabilitation40, in conjunction with patient education, dietary modification, social services, and intensive medical follow up41.
Clinical Risk Stratification
An important determinant of therapy of CHF is based on the response to initial empirical therapy, evaluation of disease severity, and an estimation of the patients prognosis. A leading clinical index of prognosis is the New York Heart Association (NYHA) functional class. Despite its subjectivity and limited inter-observer reproducibility42, it provides a useful index. The risk of mortality and sudden death increases with advancing LV dysfunction and higher NYHA class43,44. The annual mortality rate in ambulatory patients approaches 10% to 20%45,46,47. Older patients with severe CHF have 1 year survival rates of less than 50%48. Risk is particularly high in those with a history of sustained VT or syncope49,50, or the combination of low LVEF, frequent ventricular ectopy, and a positive signal averaged electrocardiogram51. The substrate for ventricular arrhythmias is the replacement of myocytes with fibrous tissues, due to healed infarctions and/or programmed apoptosis52,53. The neurohumoral response in CHF provides arrhythmogenic triggers, including electrolyte abnormalities, sympathetic stimulation, increased wall stress, and consequent myocardial ischemia even in the absence of CAD.
Racial and socioeconomic factors play a role. Blacks appear to be at higher risk of progression of heart failure and death than similarly treated whites54. Black race, Medicare or Medicaid insurance, CAD, idiopathic cariomyopathy, prior cardiac surgery, peripheral vascular disease, diabetes mellitus, and anemia yield greater risk of readmission for CHF55.
In view of the expense, lack of ready availability of donors, and the subsequent morbidity of heart transplantation, only a small number of patients actually benefit from transplantation56. The high mortality in end-stage CHF and risk of sudden death in even mild to moderate CHF pose a challenge to devise an effective means of risk stratification which would optimally classify patients for revascularization, implanted pacemakers-defibrillators, as well as heart transplantation.
The single most important measurement in CHF is the assessment of LV function (ejection fraction), since this identifies patients with systolic dysfunction among other causes of CHF and is an important index of survival57. This can be done with 2-D echocardiography, radionuclide gated blood pool imaging, gated myocardial perfusion imaging, MRI ventriculography, or contrast ventriculography. Assessment of LV size and diastolic dimension is also useful. Repeat measurements of LVEF are justified if the patient has an important change in clinical status or has received an intervention that might have a significant effect on LV function58.
RV function also appears to be very important. In one study of patients with ischemic cardiomyopathy and an LVEF <40%, a depressed RVEF of <35% was a very important prognostic indicator59.
One subset of patients studied closely by radionuclide imaging methods is the iatrogenically produced cardiac dysfunction complicating doxorubicin therapy in patients with cancer. With its high reproducibility and widespread availability, radionuclide gated blood pool imaging has been extremely helpful in following patients with LV dysfunction, in guiding maximal doxorubicin therapy while avoiding CHF, and once LV dysfunction develops, in monitoring progression and therapy. Careful monitoring of resting LV function has been associated with a low incidence of CHF, benign course and reversible degree of doxorubicin-induced CHF. Serial testing also reliably identified patients who safely tolerated high doses of doxorubicin60.
As much as the measurement of LVEF is an important prognostic index, the extent of LV dysfunction, as measured by invasive and non-invasive methods, correlates poorly with the extent of disability, as measured by exercise tolerance tests61,62.
Selection for Bypass
Coronary artery bypass surgery (CABG) plays an important role in the control of symptoms due to medically intractable ischemia, and has been demonstrated to improve mortality is some patients with CAD, particularly those with multi-vessel disease and LV dysfunction63. Generally, studies conducted to assess the role of CABG in the treatment of CAD have excluded patients with CHF or severe LV dysfunction. The CASS registry showed that patients with CHF and 3 vessel CAD who underwent CABG had a 9% incidence of sudden cardiac death at 5 years, compared with 31% in patients who did not undergo CABG64. The CABG Patch Trial suggested that CABG in patients with an LVEF less than 36% and a positive signal averaged ECG offers some protection against the risk of sudden death. Lansman et al showed that it was possible to perform CABG safely (mortality of 4.8%) even in patients with LVEFs less than 20%65. Reduced survival was noted for patients with an RVEF less than 30%. The following sections outline factors which, in individual patients, make a compelling case fior revascularization.
Assessment of Ischemia
In the general group of patients referred for diagnostic imaging, myocardial stress perfusion SPECT imaging has been shown to be very useful in prognostic risk stratification. In a review of recent studies, Iskander and Iskandrian found that the average annual cardiac event rate was 12 fold higher in patients with abnormal images than in patients with normal images. Both fixed and reversible defects were prognostically significant. Fixed defects were a predictor of death, whereas reversible defects were an important predictor of nonfatal myocardial infarction66. The event rate was significantly greater in patients with severe than mild abnormalities (10.6% annual hard event rate vs 3.5%)67. Incorporation of other SPECT variables, such as LV dilation, LVEF and LV volumes, further enhance the prognostic power of SPECT iamging68,69,70. A high likelihood of multivessel (hence surgical) CAD is indicated by the presence of perfusion defects in each of the three coronary artery territories, diffuse slow washout of thallium-201, prominent pulmonary thallium-201 activity, transient LV dilation, and the "left main patttern" of defects in the anterior, septal, and posterolateral myocardial segments71. Stress echocadiography has also been shown to have a high accuracy in the detection of CAD. While the accuracy of the two tests are similar, a recent analysis of previously published data showed that in exercise testing, myocardial perfusion imaging tended to have higher sensitivity, while stress echocardiography tended to be more specific72.
While the above methodologies are excellent markers of low vs high risk in the general CAD-prone population, patients with clinical CHF usually present with already severe LV dysfunction, and if due to CAD, with extensive areas of hypoperfusion at rest or with stress. Therefore, much of the above experience is moot. The value of rest and stress imaging lies in (1) establishing LV vs RV dysfunction, (2) in the presence of normal LV function or only mild to moderate LV dysfunction, the presence of extensive stress-induced ischemia, which clinically presents as heart failure, a high risk combination that suggests need for CABG, (3) in the presence of severe LV dysfunction, the presence of stress induced ischemia that helps clarify vague symptoms or document silent ischemia, and (4) to help distinguish ischemic from non-ischemic heart disease.
Assessment of Viability
The rationale for making the diagnosis of ongoing resting ischemia, hibernation or stunning, stems from their role as a cause of or exacerbation of LV dysfunction, CHF symptoms, sudden death and hemodynamic deterioration. It can assist in the decision whether the patients should be referred for high-risk revascularization versus cardiac transplantation. A variety of imaging techniques have been refined for the identification of nonfunctioning but viable myocardium and those patients where regional and global function may be improved with revascularization.
The definition of myocardial viability in various writings has been nebulous at best. Viable myocardium includes (1) mycardium which is functional, well perfused at rest, and non-ischemic during stress. This category contributes positively towards global function and reduction of risk, although may eventually undergo remodeling due to chronically elevated wall stress.
The second category (2) consists of myocardium which is functional and well perfused at rest, but becomes ischemic with stress, the so-called jeopardized myocardium, contributing to diastolic and systolic dysfunction during ischemia. Its identification is the subject of the preceding dicussion.
The third category (3) is stunned myocardium. It is manifested by transiently decreased contractility after an episode of prolonged ischemia, but intact blood flow at the time of observation73. Oxygen-derived free radicals contribute to post-ischemic dysfunction, leading to oxidative stress74. Stunned myocardium generally improves without further intervention. This may occur over a few minutes in most cases of exercise-induced ischemia , or over several hours uncommonly. After an acute coronary occlusion and thrombolysis, most of the improvement takes place over 7-10 days, but may take longer in the presence of residual stenosis and/or repeated stunning75. Patients may experience repeated episodes of ischemia, often silent, in the same territory, and the stunned myocardium may not be able to recover, leading to a quasi-permanent state of stunning76,77. When stunning is superimposed on an already severely dysfuntional heart, it may become dangerous, and may require hemodynamic support, such as preload and afterload reduction, inotropic stimulation, balloon pump, or other heart assist devices. Restoration of vessel patency or prevention of ischemic episodes due to coronary spasm or thrombosis is required to reverse this precarious state.
The fourth category (4) is hibernation, referring to myocardium that has undergone a down-regulation of contractile function, thus reducing cellular demand for energy, in response to chronic ischemia78. Hibernation, by definition, requires the restoration of blood flow through intervention, in order to improve function. Benefit also may be expected from reduced metabolic demand via hemodynamic support.
In the literature, these category labels have been used interchangeably, mainly because in many instances, especially when using wall motion imaging alone, they can not be distinguished. One might get the impression that hibernation is the more common category when dealing with hypofunctioning, viable myocardium clinically. Studies have found that the majority (72%) of segments of dysfunctional but viable myocardium, in fact, are due tp stunning, and a minority (28%) show hibernation79. The definition of either stunning or hibernation requires the recovery of funciton, either spontaneously, or after intervention. This hemodynamic paradigm ignores other potential benefits from the reversal of stunning or hibernation, including prevention of remodeling or arrhythmias. Likewise, the above artificial definitions ignore the possibility that all four types may coexist in the same or adjacent myocardial segments. Melon et al. showed that dysfunctinal but "viable" myocardium is a heterogeneous condition80. This may partially explain the limitations in predictive abilities for all imaging techniques.
How prevalent is dysfunctional but viable myocardium? Up to 50% of patients with previous infarction may have areas of dysfunctional viable myocardium mixed with scar tissue, even in areas with Q-waves on the ECG81. In the various published studies on techniques of detection of viable myocardium, functional recovery can occur in 24 to 82% of all dysfunctional segments82. Therefore, the importance of this subject cannot be overemphasized when dealing with the management of CHF.
Resting wall motion imaging identifies myocardium which is thickening and moving well and that which is not. It cannot differentiate dysfunctional and recoverable (viable) myocardium from permanently scarred myocardium, except by documenting serial changes in function over time. Stimulation of function by exercise, catecholamines, nitrates, or post- exercise and post-PVC potentiation are all evidence of viability, albeit with limited sensitivity. Dobutamine echocardiography, using low dose (5 and 10 mcg/kg/min) (LDDE) and high dose dubutamine, showed that both a biphasic response (improvement at low dose and deterioration at high dose) and sustained improvement of wall motion (improvement at both low dose and high dose) in dysfunctional segments was highly predictive of reversible dysfunction83, in contrast to clinical factors and angiographic results. Multiple studies with LDDE showed a combined sensitivity of 84% and 81% specificity84. Direct comparisons with thallium-201 imaging showed LDDE to be slightly less sensitive but more specific. Likewise, rest-dobutamine MRI wall motion imaging was shown to be slightly less sensitive (50%), but specific (81%), compared to thallium-201 imaging85.
Myocardial perfusion imaging has been studied extensively for detection of myocardial viability. The uptake and retention of myocardial perfusion agents is good evidence of myocardial viability. However, defects in retention of perfusion tracers can be seen in dysfunctional, stunned myocardium, while decreased uptake due to decreased perfusion is often seen in hibernation86. Simple stress-redistribution imaging with thallium-201 has been shown to underestimate the presence of viability. Stress-redistribution imaging, augmented with late (12-24 hours) imaging and/or resting reinjection, was found to increase sensitivity for viability87,88,89,90,91. The latter approach yielded a combined mean sensitivity of 86% and specificity of 47%92. In those patients who cannot exercise due to poor LV function and clinical CHF, rest-redistribution Tl-201 imaging has been employed. Results from multiple studies has shown a combined sensitivity of 90%, and specificity of 54%93. Myocardial perfusion imaging with Tc-99m Sestamibi have yielded a slightly lower sensitivity of 83% but higher specificity of 69%94, reflecting results of direct Tl-201 and Tc-99m sestamibi comparisons95. Tc-99m sestamibi imaging combined with nitrate administration has yielded an improved sensitivity of 91% and specificity of 88%96. Gated Tc-99m sestamibi imaging with NTG administration can be used successfully instead of rest-redistribution thallium-201 SPECT imaging97. Studies that examined Tc-99m tetrofosmin for myocardial viability showed similar performance as Tl-201 stress-redistribution imaging, and stlightly lower sensitivity than rest-late redistribution thallium-201 imaging98.
It is evident that neither myocardial perfusion imaging or LDDE imaging can supply both high sensitivity and high specificity. Bax et al demonstrated that sequential testing by Thallium-201 and LDDE imaging in an identifiable subgroup of patients with intermediate probability of viable myocardium by either test alone enhances the prediction of post-revascularization improvement of the LVEF99.
Another strategy is the addition of metabolic imaging to perfusion imaging using analogues of either free fatty acids or glucose imaging. Injured but recoverable myocardium has been shown to demonstrate impaired oxidative metabolism and an excess of glucose utilization relative to flow. F-18 fluorodeoxyglucose (FDG) is an analogue of glucose, which is transported into cells via a specific glucose membrane transporter and is phosphorylated by hexokinase. Unlike glucose, FDG is trapped and is not metabolized further. Its accumulation is an index of glucose utilization100. Myocardial flow can be imaged with N-13 ammonia or rubidium-82 with PET imaging, or thallium-201 or Tc-99m sestamibi imaging using SPECT. Stunned myocardium has been demonstrated to show preserved flow, and either matched or excessive FDG accumulation101,102. Occasionally, stunning, in combination with exercise-induced ischemia, results in impaired FDG accumulation, producing an underestimation of viability103. Hibernation has been shown to demonstrate decreased perfusion, and relatively preserved, or disproportionaetely increased FDG accumulation104,105.
Early studies with FDG have utilized positron emmision tomography (PET) imaging, requiring an expensive cyclotron for isotope produciton and a dedicated PET scanner for imaging of the high energy coincident emissions of F-18 FDG and either N-13 ammonia or Rb-82 for perfusion imaging . PET imaging with FDG has yielded a combined 88% sensitivity and 73% specificity106. More recently, F-18 FDG could be imaged as a SPECT study with specially designed high energy collimators for conventional SPECT gamma cameras, together with Tl-201 or Tc-99m sesntamibi.107 Sveral groups have shown the sensitivity and specificity of FDG/Tl-201 SPECT imaging to be 87% and 78%, respectively, similar in magnitude to corresponding studies using PET imaging108,109,note1. In the last few years, hybrid coincidence cameras have been developed, that can image both the coincident gamma photons of FDG, similar to PET but at a lower cost., while able to perform, sequentially or simultaneously, SPECT imaging of perfusion with thallium-201 or Tc-99m sestamibi. The need for an on site cyclotron has been made unnecessary with the establishment of commercial FDG production centers in most major metropolitan regions. FDG metabolic/perfusion imaging has become a clinical tool in many centers around the world, and is no longer only an investigational technique.
A somewhat different approach uses labeled fatty acid (FFA) analogues. Myocardial uptake of fatty acids is proportional to blood flow, as well as FFA concentration. In the presence of ischemia, stunning, and hibernation, beta-oxidation is reduced, which increases the proportion of FFAs accumulating in the triglyceride pool. Myocardial imaging with iodine-123 labeled FFAs show uptake and rapid clearance in normal myocardium, and delayed clearance, or accumulation in the presence of impaired oxidation. Thus impaired FFA clearance is likely to represent recoverable (stunned or hibernating) myocardium110,111. Because the image quality with labeled FFAs is poor, the situation was remedied by blocking beta-oxidation of labeled FFAs with an extra methyl group at the beta carbon of the FFA chain, to yield an analogue called BMIPP. This analogue shows prolonged retention of the BMIPP in the myocardium, thus iproving image quality. Under conditions of ischemia or oxidative impairment, BMIPP retention is reduced, quite the opposite of normal labeled FFAs. Thus, a disproportionate reduction in BMIPP retention is an indicator of stunning or hibernation112,113. This pattern predicts improvement in left ventricular function, strongly associated with the recovery of oxidative metabolism114. BMIPP is an approved radiotracer for clinical use in Japan. Labeled FFAs are investigational in the U.S, and thus not routinely used. On the other hand in other countried, where FDG and the associated required edquipment is unavailable, and there is an available source of low cost iodine-123, labeled FFA imaging is a feasible alternative to FDG imaging.
How much impaired but viable tissue is needed in order to result in functional improvement after revascularization? Recently, Bax et al conducted ROC analysis on the results of Tl-201 / FDG SPECT imaging in 32 patients . The amount of viable myocardium was closely related to the magnitude of LVEF improvement after revsculariztion. An LVEF improvement greater than 5% could be expected when 3 or more impaired but viable segments (out of 13 segments) were present115. This supports similar findings from the pioneering study by Tillisch et al, which showed that at least two large segments were required to demonstrate an appreciable increase in LVEF116. The ultimate function of imaging for myocardial viability lies in its prognostication value., beyond the prediction of an increase in LVEF afer revascularization, and potentially, in decreaseing the rate of sudden death, while avoiding unnecessary or futile high risk intervention in patients who are not likely to benefit from it. Pasquet et al showed that the presence of ischemic myocardium (determined by thallium scintigraphy) and viable myocardium, (determined by LDDE) are independent predictors of subsequent mortality117. Layher et al showed higher risk of arrhythmic death in patients with PET mismatch patterns118. Huiting et al showed with Tl-201 and F-18 FDG planar imaging usiing a portable gamma camera., that patients who had Tl-201/FDG mismatch (n=39) experienced 19 cardiac events, (deaths, reinfarction, late revascularizations, and unstable angina) vs 1 event (1death) in the matched group (n=20)119. Bax et al showed that patients with substancial viability on LDDE demonstrated not only mprovement in LVEF and NYHA functional class after revascularization; but also a favorable prognosis after revascularization120.
Some patients may appear to be too sick to under surgery, particularly in the absence of evidence that their LV function will improve afterwards. Several centers have demonstrated that patients with severe LV dysfunction can undergo surgery with acceptable risk (<10% mortality) even in the absence of consistent screening for the presence of viable myocardium before surgery121,122,123 . Nevertheless, the presence of viable myocardium does predict a more favorable outcome124,125,126,127. Viability studies permit selection of patients at low risk for serious post-operative complications128. In patients with evidence of significant recoverable myocardium preop, the preoperative mortality rate was significantly increased in those patients operated more than 35 days after the PET viability study, compared to those operated on less than 35 days after the PET study. In post-operative follow up, cardiac events were similar, although the LVEF increased after the early revascularization, but not in the late group129. Although no randomized trials exist that test the risk-stratifying power of viability imaging, these studies suggest that surgery brings a survival benefit beyond wall motion enhancement or an increase in LVEF, possibly due to protection against sudden death, or protection from further remodeling and dilatatiion. The question of possible benefit from CABG, even in the absence of an increase in LVEF needs to be ascertained. Clearly, better identification of patients suitable for surgery under otherwise high-risk conditions is needed, through standardized protocols tested in randomized trials.
Experience in a center with established PET imaging in patients with CHF showed that 34% of patients had extensive, 21% had little, and 43% had no impaired viable myocardium. 68% of patients with extensive viability, 52% with little viability, but only 36% of those without any impaired viable myocardium underwent CABG. 31% of patients without viability underwent CABG because of anginal symptoms. When available, PET viability imaging demonstrates a significant impact on management of patients with ischemic heart disease and CHF symptoms.
Some patients with angina undergo CABG even without hope of likely improvement in LVEF130. A desirable aim of identification of patients with impaired viable myocardium, is documentation of ischemia in patients with symptoms, or explanation of episodes of exacerbation of CHF., and prediction of resolution of ischemic episodes after even limited revascularization.
Selection for Transplantation
Despite the reduction of mortality in patients with CHF as a result of ACE inhibitor and beta blocker therapy, and in ischemic patients, despite advances in selecting patients for CABG and technical advances in safely performing CABG leading to improvement in function, survival and functional state, the prognosis of patients suffering from end-stage CHF remains grim, especially in patients with CAD in whom medical therpy has failed. The only alternative then is heart transplantation. This option is limited by available organs, and in much of the world, by finances. While heart ransplatnation can substancially modify the prognosis in these patients, leading to a prolonged and potentially productive life131, only a small proportion of patients actually undergo transplantation132. Many patients die while undergoing evaluation for heart transplantation and then waiting for a donor heart. Therefore, an effective prioritation or triage of pre-transplant patients is necessary.
The severity of heart failure is mainly evaluated by symptoms, clinical findings, hemodynamic measurements, and exercise tolerance133,134,135,136,137 , and assessment of the degree of activation of the neuro-hormonal system138,139,140,141. Despite these efforts, an accurate risk stratification system that would predict survival or mortality has to date been elusive.
Despite important advances in direct in vivo evaluation of the functional status of autonomic innervation and receptors in the heart, these methods have not yet been evaluated in any significant large clinical trials in patients with CHF. The following section reviews some exciting tools that offer the potential of improved risk stratification and more specific therapy manipulating the autonomic milieu.
The heart is richly supplied with autonomic sympathetic and parasympathetic innervation. Their major transmitters are norepinephrine and acetylcholine, producing, respectively, stimulatory and inhibitory actions of each system. Sympathetic innervation originates from the right and left stellate ganglia, which provide the neurons to form the cardiac plexus of the heart. They travel along the coronary vessels, in the epicardium, to reach the myocardium. Sympathetic nerves synthesize and store norepinephrine, which is released during stimulation into the neuromuscular synaptic junction. Presynaptic receptors mediate reuptake of the neurotransmitter. Post-synaptic membrane receptors are linked with their effector mechanisms. The neurotransmitters are subject to metabolism both within the synapse, the nerve terminals, and in the liver.
Activation of the sympathetic nervous system and parasympathetic withdrawal plays an important part in the progression of CHF. Plasma norepinephrine is elevated. Its plasma level is one of several independent prognostic indicators in heart failure142. There is decreased clearance of norepinephrine by sympathetic neurons in the myocardium. As a result of increased synaptic norepinephrine levels, post-synaptic adrenegic receptors become desensitized to catecholamine stimulation due to decoupling of receptors from effector systems, and due to loss of beta receptors143. While uncoupling affects all cadiac beta receptors, beta receptor down-regulation is specific to B1 receptors, with relative sparing of the B2 receptors.
The etiology of CHF may result in different mechanisms of decreased responsiveness to catecholamine stimulation. Bristow et al showed that myocardium from hearts with idiopathic cardiomyopathy showed a greater degree of B1 receptor downregulation. Ischemic disease in the right and left ventricles showed a greater degree of subsensitivity to the inotropic effects of isoproterenol, demonstrating greater degree of uncoupling144. This has not resulted in different approaches in beta-blocker therapy, however.
The loss of responsiveness may be overcome through short-term administration of beta-receptor agonists. Long-term administration of such agents, however, may lead to further beta-adrenoreceptor desensitization, myocardial injury, and increased incidence of arrhythmias. In contrast, cautious use of beta-blocking agents can restore responsiveness of the beta-receptor system. Treatment with beta blockers has emerged as a successful approach in some patients, producing up-regulation of post-synaptic receptors through protection against excess levels of circulating and local catecholamines, and restoration of response to direct stimulation145.
Sympathetic receptor imaging
A number of radiotracers have been developed to study cardiac presynapticautonomic neuronal function. The norepinephrine analog I-123 metaiodobenzyl-guanidine has been widely used in experimental and clinical studies, using conventional planar and SPECT imaging146,147, and C-11 hydroxyephedrine with PET imagingnote2. Postsynaptic beta-adrenergic receptors have been studied with C-11-CGP-12177, a nonselective beta antagonist and PET imaging148, and iodine-123-cyanopindolol with SPECT imaging149.
Meta-I-123-iodobenzylguanidine (MIBG) is an analog of the adrenergic-neuron-blocking agent guanethidine. It has been used in a large number of studies involving ischemic heart disease and cardiomyopathies. MIBG is taken up and stored by the same mechanism as norepinephrine, but is not metabolized by catechol-o-methyltranferase or monoamine oxidase150. Accumulation in the heart is composed of both specific intravesicular (uptake-1 system) and non-specific non-vesicular accumulation (uptake-2 system). Imaging at 4 hours after injection is the best time for assessment of specific neuronal accumulation of MIBG in various pathological conditions151.
Uptake of MIBG in the heart is related to the level of circulating plasma catecholamines, although it is not known if this is due to direct competition, or secondary to sympathetic nerve dysfunction . Increased cardiac sympathetic nervous system activity has been associated with increased myocardial MIBG clearance, measured by the heart to mediastinum activity ratio and the heart to lung ratio, late MIBG uptake, and decreased heart rate variability. Decreased heart MIBG appears to be due to impaired retention of MIBG, rather than impaired uptake153. Sisson et al have shown that patients with autonomic neuropathy but intact cardiac function and perfusion show marked diminution of cardiac MIBG uptake154.
Schofer et al demonstrated that scintigraphically and biopsy-measured cardiac MIBG activity was significantly related to myocardial norepinephrine concentration and LV ejection fraction, but not with plasma norepinephrine. Thus, elevated circulating catecholamines in CHF do not directly affect cardiac norepinephrine and MIBG content155. Other studies also also showed poor cardiac retention of MIBG in patients with IDC, in proportion with the severity of LVEF impairment156,157. Merlet et al, on the other hand, showed that the inotropic response to dobutamine infusion correlated with both increased plasma NE concentration and diminished cardiac MIBG concentration, suggesting that the desensitization is related to both. In a subset of patients with moderate heart fialure, they showed diminished cardiac MIBG uptake but normal plasma NE levels, sugggesting that neuronal dysfunction is an early mechanism of desensitization in IDC158.
Cardiac MIBG retention was studied in patients with dilated CMP after beta blocker and ACE inhibitor therapy. LVEF improved only after beta blockers, but not with ACE inhibitor therapy. NYHA score and MIBG retention improved in both groups, but more in the group treated with beta blockers159. In a small, randomized trial, patients who received carvedilol showed an increase in LVEF after one year, but the placebo group did not. The initial cardiac MIBG uptake showed an inverse relationship with the improvement in LVEF. In this preliminary study, MIBG predicted which patients would improve after carvedilol therapy160.
Merlet et al tested the ability of MIBG to predict patient survival in 112 patients with CHF due to IDC, in comparison with circulating plasma norepinephrine, LVEF, peak VO2, X-ray cardiothoracic ratio, M-Mode echo end-diastolic diameter, and right sided heart catheterization parameters. After a follow up of 27 months, the only independent predictors for mortality were low MIBG uptake and LVEF. MIBG uptake and plasma NE were the only independent predictors for life duration. MIBG was a better discriminator between high and low-risk patients than LVEF or plasma NE161. In another preliminary study, Agostini et al analyzed NYHA functional class, LVEF, peak VO2, and cardiac MIBG uptake in predicting cardiac events in 89 patients with CHF. VO2 and MIBG uptake had the higher risk odds ratio independently. Patients with VO2>50% maximal predicted, or MIBG uptake >125%, had a risk of cardiac events less than 10%, while patients with VO2< 50% or MIBG uptake <125%, had a cardiac event rate of >60%162.
In patients with CHF complicating doxorubicin therapy, radionuclide angiography or echocardiography have been used in monitoring LV function. In spite of a reasonably good performnce, the LVEF is sometimes insensitive, and with exercise, is frequently nonspecific. In some patients, the resting LVEF does not decrease linearly with doxorubicin dose and LV function is preserved until a critical dose is reached163,164. In a rat model, Wakasugi et al showed that MIBG accumulation in the heart decreased in a doxorubicin dose-dependent manner, and MIBG accumulation was a useful index of myocardial fibrosis165. Another study showed that in comparison with clinical indices and LVEF, cardiac MIBG uptake was the strongest predictor of prognosis in patients with doxorubicin-induced CMP166.
The status of cardiac sympathetic neuron dysfunction is of relevance not only when assessed as global uptake in the myocardium, but also in its regional distribution. In ischemic myocardial disease, it has been observed that myocardial infarction produces sympathetic denervation in noninfarcted myocardium distal to the infarct site. Since the sympoathetic nerves run along the epicardial vessels, denervation occurs distal to a proximal occlusion and myocardial injury. This viable apical tissue demonstrates denervation supersensitivity to exogenous norepinephrine and isoproterenol167,note3, presumably due to the absence of local sympathtic stimulation and lack of removal of exogenous catecholamines. Stanton et al showed that 10 of 12 patients with spontaneous ventricular tachyarrhythmias after myocardial infarction exhibited regions of thallium-201 uptake, indicating viable and perfused myocardium, with no MIBG uptake, indicating regional denervation. 11 of these 12 patients had ventricular tachycardia induced by programmed stimulation. This induction could not be prevented by beta-blockers. Sympathetic denervation was seen in only 2 of 7 patients without ventricular tachycardia. Normal subjects showed a normal perfusion and MIBG uptake pattern. This study showed that some patients susceptible to tachyarrhythmias could be identified non-invasively168.
In a specialized subset of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), Wichter et al, documented that regional abnormalities of sympathetic innervation are frequent and can be demonstrated by I-123-MIBG scintigraphy. Sympathetic denervation appears to be the underlying mechanism of frequent provocation of VT by exercise or catecholamine exposure169. In these patients and their asymptomatic relatives, susceptibility to arrhythmias and sudden death can be predicted noninvasively, aside from mechanical dysfunction.
Transplantation results in total denervation of the donor heart, resulting in an increase in cardiac beta-adrenergic sensitivity. Gilbert et al measured beta-adrenergic receptor density in vitro from biopsy specimens. They found receptor density not significantly different in transplant recipients compared to normal controls. Isoproterenol response curves for native and transplanted atria were not different, either. The authors concluded that transplant supersensitivity is not post-synaptic in origin, but that it is likely due to presynaptic denervation170. Glowniak et al showed nearly absent uptake of MIBG in the transplanted myocardium171.
While MIBG can be used to assess pre-synaptic sympathetic function, other tracers have been used to study post-synaptic receptor function non-invasively. Merlet et al demonstrated a 53% decrease in the number of beta-adrenergic receptors in patients with congestive heart failure, which was concordant with in vitro biopsy studies172. It has been appreciated that receptor density is dynamic, and changes with presynaptic function, and neurotransmitter level173,174. Indeed, Buja et al found that beta-receptors density increases during the early stages of myocardial ischemic injury and decreases in cells irreversibly injured. The initial increase in reversibly injured myocytes could be reversed on withdrawal of the insulting agent. They showed that changes in circulating catecholamines are not required to cause changes in sensitivity to catecholamines175.
At this time and the foreseeable future, quantification of post-synaptic receptors, employing cyclotron-produced tracer-labeled neurotransmitter ligands imaged with PET is limited to few experimental centers, although other post-synaptic tracers such as I-123 cyanopindolol can be imaged with conventional instrumentation. Interestingly, Qing et al found a concordant relationship of beta-receptor density in the lung and mononuclear leukocytes and the myocardium after albuterol treatment in normal subjects176. The reduction of receptor density by the B2-agonists was less in the myocardium than those in the leukocytes, presumed to be due to differential B2 and B1 concentrations. This suggested that it would be possible to monitor the beta receptor milieu remotely by in vitro assays available in most laboratories. On the other hand, it is unanswered to what extent monocyte sampling misdiagnoses the influence of the local myocardial milieu. For example, in RV heart failure due to pulmonary hypertension, only right ventricular beta-adrenergic receptors are decreased. These findings were confirmed in a dog model177.
These studies show that assessment of the functional state of myocardial sympathetic neurons in CHF by MIBG is a powerful predictor of a high risk for cardiac events, in those, who, if eligible, would least likely survive waiting for cardiac transplants. On the other hand this index alone or in combination, can predict a low cardiac event rate in other patients, those who could survive with medical therapy, and thereby waiting longer. In order for this approach to be useful, it needs to be tested in a larger multicenter trial. In many countries, I-123-MIBG is an investigational agent not available widely. That could change if large trials were to verify its prognosticating value in steering therapy. Although neuroendocrine imaging techniques remain investigative, they have a promising potential for developing and selecting more specific management strategies in the treatment of patients with heart failure.
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