Produção Nacional
Revisado por pares
Abnormal adrenergic activation is the major determinant of reduced functional capacity in heart failure with preserved ejection fraction
2015; Elsevier BV; Volume: 203; Linguagem: Inglês
10.1016/j.ijcard.2015.10.224
ISSN1874-1754
AutoresLeandro Rocha Messias, Ana Messias, Sandra Marina Miranda, Christiane Wiefels, Aryanne Guimarães Ferreira, Luís M.G. Santos, José Antônio Caldas Teixeira, Elisabeth Maróstica, Cláudio Tinoco Mesquita,
Tópico(s)Cardiovascular Function and Risk Factors
ResumoHeart failure (HF) can be classified into HF with reduced ejection fraction (HFrEF), when the main altered mechanism is myocardial contractility or HF with preserved ejection fraction (HFpEF), when the diastolic dysfunction is the main mechanism [[1]Coats A. Shewan L. The management of heart failure with preserved ejection fraction (HFpEF).Int. Cardiovasc. Forum J. 2014; 1: 108-112Crossref Google Scholar]. However, both the substrates can be present in the same patient and the standard treatment probably should be used despite the lack of mortality data [[1]Coats A. Shewan L. The management of heart failure with preserved ejection fraction (HFpEF).Int. Cardiovasc. Forum J. 2014; 1: 108-112Crossref Google Scholar]. Sympathetic nervous system activation plays an important role in the progression of HF and cardiac imaging with iodine-123 metaiodobenzylguanidine (123I-MIBG) was developed to visualize sympathetic innervation and was used to study myocardial adrenergic nerve activity [[2]Cohen-Solal A. Esanu Y. Logeart D. et al.Cardiac metaiodobenzylguanidine uptake in patients with moderate chronic heart failure: relationship with peak oxygen uptake and prognosis.J. Am. Coll. Cardiol. 1999; 33: 759-766Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar]. The early and late heart-to-mediastinum ratio (H/M) can evaluate the integrity and function of the nervous terminal and the washout rate (WR) may reflect the adrenergic activity [[3]Agostini D. Carrio I. Verberne H.J. How to use myocardial 123I-MIBG scintigraphy in chronic heart failure.Eur. J. Nucl. Med. Mol. Imaging. 2009; 36: 555-559Crossref PubMed Scopus (72) Google Scholar]. Few studies [4Katoh S. Shishido T. Kutsuzawa D. et al.Iodine-123-metaiodobenzylguanidine imaging can predict future cardiac events in heart failure patients with preserved ejection fraction.Ann. Nucl. Med. 2010; 24: 679-686Crossref PubMed Scopus (38) Google Scholar, 5Sugiura M. Yamamoto K. Takeda Y. et al.The relationship between variables of 123-I-metaiodobenzylguanidine cardiac imaging and clinical status of the patients with diastolic heart failure.Int. J. Cardiol. 2006; 113: 223-228Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] have demonstrated that 123I-MIBG imaging was independently associated with an increased risk for cardiac events in HFpEF. HFpEF patients have been characterized by an impaired peak oxygen consumption (VO2) [6Phan T.T. Shivu G.N. Abozguia K. et al.Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction.Circ. Heart Fail. 2010; 3: 29-34Crossref PubMed Scopus (153) Google Scholar, 7Dhakal B.P. Malhotra R. Murphy R.M. et al.Mechanisms of exercise intolerance in heart failure with preserved ejection fraction the role of abnormal peripheral oxygen extraction.Circ. Heart Fail. 2015; 8: 286-294Crossref PubMed Scopus (257) Google Scholar, 8Guazzi M. Labate V. Cahalin L.P. Arena R. Cardiopulmonary exercise testing reflects similar pathophysiology and disease severity in heart failure patients with reduced and preserved ejection fraction.Eur. J. Prev. Cardiol. 2014; 21: 847-854Crossref PubMed Scopus (40) Google Scholar] and a steep slope of the relationship between minute ventilation and carbon dioxide production (VE/VCO2 slope) [[8]Guazzi M. Labate V. Cahalin L.P. Arena R. Cardiopulmonary exercise testing reflects similar pathophysiology and disease severity in heart failure patients with reduced and preserved ejection fraction.Eur. J. Prev. Cardiol. 2014; 21: 847-854Crossref PubMed Scopus (40) Google Scholar]. The relationship between adrenergic activity and exercise parameters in HFpEF is unknown. Our purpose was to evaluate the association between 123I-MIBG imaging and cardiopulmonary exercise testing (CPET) parameters in HFpEF. The patients were recruited through a clinical screening. Eligibility criteria involved age ≥ 18 years, signs and symptoms of HF [[1]Coats A. Shewan L. The management of heart failure with preserved ejection fraction (HFpEF).Int. Cardiovasc. Forum J. 2014; 1: 108-112Crossref Google Scholar], LVEF >50% with evidence of diastolic dysfunction by echocardiography [[9]Paulus W.J. Tshoupe C. Sanderson J.E. et al.How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection by the heart failure and echocardiography associations of the European society of cardiology.Eur. Heart J. 2007; 28: 2539-2550Crossref PubMed Scopus (2118) Google Scholar]: HFpEF was diagnosed if tissue Doppler E/E' > 15; if E/E' ratio 15 > E/E′ > 8, additional investigation is required (ex: left atrial volume index >40 ml/m2 or E/A < 0.5); and if E/E′ < 8, the patient was not included. We excluded diabetes, atrial fibrillation, pacemaker and any conditions that contraindicate CPET. Eligible patients provided a consent form after receiving verbal and written details regarding the procedures adopted in the study, which was approved by the Ethics Committee of our institution. Subjects underwent 123I-MIBG imaging acquired 30 min and 4 h after 5 mCi 123I-MIBG administration. We evaluated the sympathetic neuronal integrity, quantified by the early and late H/M [2Cohen-Solal A. Esanu Y. Logeart D. et al.Cardiac metaiodobenzylguanidine uptake in patients with moderate chronic heart failure: relationship with peak oxygen uptake and prognosis.J. Am. Coll. Cardiol. 1999; 33: 759-766Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 3Agostini D. Carrio I. Verberne H.J. How to use myocardial 123I-MIBG scintigraphy in chronic heart failure.Eur. J. Nucl. Med. Mol. Imaging. 2009; 36: 555-559Crossref PubMed Scopus (72) Google Scholar, 4Katoh S. Shishido T. Kutsuzawa D. et al.Iodine-123-metaiodobenzylguanidine imaging can predict future cardiac events in heart failure patients with preserved ejection fraction.Ann. Nucl. Med. 2010; 24: 679-686Crossref PubMed Scopus (38) Google Scholar, 5Sugiura M. Yamamoto K. Takeda Y. et al.The relationship between variables of 123-I-metaiodobenzylguanidine cardiac imaging and clinical status of the patients with diastolic heart failure.Int. J. Cardiol. 2006; 113: 223-228Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. Sympathetic activation was estimated by WR [2Cohen-Solal A. Esanu Y. Logeart D. et al.Cardiac metaiodobenzylguanidine uptake in patients with moderate chronic heart failure: relationship with peak oxygen uptake and prognosis.J. Am. Coll. Cardiol. 1999; 33: 759-766Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 3Agostini D. Carrio I. Verberne H.J. How to use myocardial 123I-MIBG scintigraphy in chronic heart failure.Eur. J. Nucl. Med. Mol. Imaging. 2009; 36: 555-559Crossref PubMed Scopus (72) Google Scholar, 4Katoh S. Shishido T. Kutsuzawa D. et al.Iodine-123-metaiodobenzylguanidine imaging can predict future cardiac events in heart failure patients with preserved ejection fraction.Ann. Nucl. Med. 2010; 24: 679-686Crossref PubMed Scopus (38) Google Scholar, 5Sugiura M. Yamamoto K. Takeda Y. et al.The relationship between variables of 123-I-metaiodobenzylguanidine cardiac imaging and clinical status of the patients with diastolic heart failure.Int. J. Cardiol. 2006; 113: 223-228Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]. All patients performed a symptom-limited treadmill CPET using ramp protocols. Peak VO2 was measured with commercially available metabolic carts (MedGraphics VO2000, Brazil) and was defined as the highest VO2 during the last 30 s of exercise [2Cohen-Solal A. Esanu Y. Logeart D. et al.Cardiac metaiodobenzylguanidine uptake in patients with moderate chronic heart failure: relationship with peak oxygen uptake and prognosis.J. Am. Coll. Cardiol. 1999; 33: 759-766Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 7Dhakal B.P. Malhotra R. Murphy R.M. et al.Mechanisms of exercise intolerance in heart failure with preserved ejection fraction the role of abnormal peripheral oxygen extraction.Circ. Heart Fail. 2015; 8: 286-294Crossref PubMed Scopus (257) Google Scholar, 8Guazzi M. Labate V. Cahalin L.P. Arena R. Cardiopulmonary exercise testing reflects similar pathophysiology and disease severity in heart failure patients with reduced and preserved ejection fraction.Eur. J. Prev. Cardiol. 2014; 21: 847-854Crossref PubMed Scopus (40) Google Scholar]. VE/VCO2 slope was calculated using the spreadsheet software package [[8]Guazzi M. Labate V. Cahalin L.P. Arena R. Cardiopulmonary exercise testing reflects similar pathophysiology and disease severity in heart failure patients with reduced and preserved ejection fraction.Eur. J. Prev. Cardiol. 2014; 21: 847-854Crossref PubMed Scopus (40) Google Scholar]. Standard 12-lead ECGs, blood pressure systolic (SBP) and heart rate (HR) were obtained at rest, each minute during exercise and recovery. The HR reserve was determined by the method of Kallistratos et al. [[10]Kallistratos M.S. Dritsas A. Laoutaris I.D. Cokkinos D.V. Chronotropic and neurohumoral markers for the evaluation of functional capacity in patients with impaired left ventricular function.Hell. J. Cardiol. 2008; 49: 26-32PubMed Google Scholar]. The HR recovery (HRR) was defined by the method of Phan et al. [[6]Phan T.T. Shivu G.N. Abozguia K. et al.Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction.Circ. Heart Fail. 2010; 3: 29-34Crossref PubMed Scopus (153) Google Scholar]. Data are presented as median, interquartile range and percentage. Spearman coefficient was used as univariate analysis and stepwise linear regression as multivariate analysis. Statistical significance was accepted at the 0.05 level. Twenty-five patients were evaluated in the present study. Baseline characteristics, results of echocardiography, exercise testing and 123I-MIBG imaging are shown in Table 1. By univariate analysis, there was a negative correlation between the early (r = −0.463, p = 0.02) and late H/M (r = −0.486, p = 0.014) with the VE/VCO2 slope. The Peak VO2 presented positive correlation between with the late H/M (r = 0.452, p = 0.023) and negative with WR (r = −0.449, p = 0.024). WR had negative correlation with peak HR (r = −0.465, p = 0.019) and HR reserve (r = −0.553, p = 0.004). Other variables such as peak and variation of SBP and HRR did not demonstrate significant correlation with other parameters.Table 1Baseline characteristics, 123I MIBG imaging and CPET parameters.VariablesN=25Age57 (52–67) yearsFemale76%Hypertensive etiology92%Echocardiogram LVEF64 (60.5–71.5) % LAVI44.6 (40.49–48.1) ml/m2 E/E′16 (14.45–17) E/A0.39 (0.28–0.6) LVMI124 (110–129.85) g/m2Medications Beta-blocker52% ACEI84% Hydralazine16% Nitrate24% Spironolactone20% Diuretic64%Early H/M1.80 (1.58–1.94)Late H/M1.65 (1.48–1.96)WR29 (19.7–38.5) %Rest SBP152 (143–170) mmHgRest DBP90 (78–104) mmHgRest HR72 (63–82) bpmPeak SBP232 (217–246) mmHgPeak HR121 (110.5–143.5) bpmΔ SBP72 (58–99) mmHgHR reserve59.79 (42.77–83.44) %HRR 1st minute12 (5–19) bpmHRR 2nd minute19 (14–31.5) bpmPeak VO212.75 (10.13–17.19 ml.(kg·min)−1VE/VCO2 slope23.37 (21.14–26.79)LVEF: left ventricular ejection fraction; LAVI: left atrial volume index; E/E': ratio of early mitral diastolic inflow velocity to early diastolic mitral annular velocity; E/A: ratio of early to late mitral inflow velocities; LVMI: left ventricular mass index;ACEI: Angiotensin converting enzyme inhibitors; H/M: the heart/mediastinum uptake ratio; WR: washout rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HR: heart rate; Δ SBP: variation in systolic blood pressure during exercise; HRR: heart rate recovery; VO2: oxygen consumption; VE/VCO2 slope: a steep slope of the relationship between minute ventilation and carbon dioxide production. Open table in a new tab LVEF: left ventricular ejection fraction; LAVI: left atrial volume index; E/E': ratio of early mitral diastolic inflow velocity to early diastolic mitral annular velocity; E/A: ratio of early to late mitral inflow velocities; LVMI: left ventricular mass index; ACEI: Angiotensin converting enzyme inhibitors; H/M: the heart/mediastinum uptake ratio; WR: washout rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; HR: heart rate; Δ SBP: variation in systolic blood pressure during exercise; HRR: heart rate recovery; VO2: oxygen consumption; VE/VCO2 slope: a steep slope of the relationship between minute ventilation and carbon dioxide production. Using multivariate analysis, we observed that the VE/VCO2 slope was the variable that was best associated with late H/M (r2 = 0.236, p = 0.011), and the HR reserve with WR (r2 = 0.375, p = 0.001), as shown in Fig. 1. The presence of the variable "beta-blockers users" had no influence on our results (late H/M p = 0.1; WR p = 0.4; peak VO2: r2 = 0.386 p = 0.8). We observed an association between CPET parameters with the 123I-MIBG imaging in HFpEF. The intensity in cardiac adrenergic innervation abnormalities was associated with the degree of cardiovascular impairment during exercise. Katoh et al. [[4]Katoh S. Shishido T. Kutsuzawa D. et al.Iodine-123-metaiodobenzylguanidine imaging can predict future cardiac events in heart failure patients with preserved ejection fraction.Ann. Nucl. Med. 2010; 24: 679-686Crossref PubMed Scopus (38) Google Scholar] reported that lower late H/M and higher WR were associated with worse prognosis. The WR was the best predictor of adverse events in their study. We found WR values within the group of higher risk of events according to the authors' data [[4]Katoh S. Shishido T. Kutsuzawa D. et al.Iodine-123-metaiodobenzylguanidine imaging can predict future cardiac events in heart failure patients with preserved ejection fraction.Ann. Nucl. Med. 2010; 24: 679-686Crossref PubMed Scopus (38) Google Scholar]. These data, associated with low peak VO2, confer to these patients additional risk of adverse events, demonstrating the need for optimal medical treatment. Sugiura et al. [[5]Sugiura M. Yamamoto K. Takeda Y. et al.The relationship between variables of 123-I-metaiodobenzylguanidine cardiac imaging and clinical status of the patients with diastolic heart failure.Int. J. Cardiol. 2006; 113: 223-228Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] reported that 123I-MIBG imaging parameters were correlated with the severity of diastolic dysfunction, neurohumoral markers and functional capacity as determined by Specific Activity Scale. In their study, late H/M and WR were correlated with functional capacity, as observed in our analysis, which employed the most accurate values of CPET. The authors [[5]Sugiura M. Yamamoto K. Takeda Y. et al.The relationship between variables of 123-I-metaiodobenzylguanidine cardiac imaging and clinical status of the patients with diastolic heart failure.Int. J. Cardiol. 2006; 113: 223-228Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] suggested that 123I-MIBG imaging could be a useful tool for risk stratification in HFpEF. We observed that an altered adrenergic activity is associated with an inadequate HR response during exercise. This abnormal behavior of the HR could be the determinant of a lower peak VO2 in HFpEF [6Phan T.T. Shivu G.N. Abozguia K. et al.Impaired heart rate recovery and chronotropic incompetence in patients with heart failure with preserved ejection fraction.Circ. Heart Fail. 2010; 3: 29-34Crossref PubMed Scopus (153) Google Scholar, 7Dhakal B.P. Malhotra R. Murphy R.M. et al.Mechanisms of exercise intolerance in heart failure with preserved ejection fraction the role of abnormal peripheral oxygen extraction.Circ. Heart Fail. 2015; 8: 286-294Crossref PubMed Scopus (257) Google Scholar]. The adrenergic hyperactivity in rest is associated to the abnormal behavior of HR during exercise due to refractory sympathetic stimulation, and not because of ineffective sympathetic stimulation [[10]Kallistratos M.S. Dritsas A. Laoutaris I.D. Cokkinos D.V. Chronotropic and neurohumoral markers for the evaluation of functional capacity in patients with impaired left ventricular function.Hell. J. Cardiol. 2008; 49: 26-32PubMed Google Scholar]. Our sample consisted of patients with HFpEF with low VE/VCO2 slope, which may be a limitation to our study. We believe that this is due to the fact that our sample consisted of outpatient basis. Despite a low functional capacity, they were clinically stable. Our data are superposed to the lower VE/VCO2 slope values of Guazzi et al. [[8]Guazzi M. Labate V. Cahalin L.P. Arena R. Cardiopulmonary exercise testing reflects similar pathophysiology and disease severity in heart failure patients with reduced and preserved ejection fraction.Eur. J. Prev. Cardiol. 2014; 21: 847-854Crossref PubMed Scopus (40) Google Scholar] indicating that our findings are compatible with stable HFpEF patients. VE/VCO2 slope relatively normal may be explained by a preserved cardiac output during exercise. In summary, our data showed an association between severity of sympathetic neuronal dysfunction and the degree of cardiovascular impairment during exercise. These findings suggest that 123I-MIBG imaging may contribute to a better understanding of the pathophysiology and risk stratification in HFpEF.
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