experimental & clinical cardiology

EXPERIMENTAL & CLINICAL CARDIOLOGY

Volume 20, Issue 9, 2014

Title: "Relationship Between Aerobic Exercise Responses and Tissue Doppler Imaging in Chagasic and Ischemic Heart Failure."

Authors: Alexandra Lima, Maria Estefania Otto, Marianne Lucena Da Silva, Laura Maria Tomazi Neves, Janaina Fernandes, Vinicius Maldaner Da Silva, Graziela Bernardelli Cipriano, Ross Arena and Gerson Cipriano Jr.

How to reference: Relationship Between Aerobic Exercise Responses and Tissue Doppler Imaging in Chagasic and Ischemic Heart Failure./Alexandra Lima, Maria Estefania Otto, Marianne Lucena Da Silva, Laura Maria Tomazi Neves, Janaina Fernandes, Vinicius Maldaner Da Silva, Graziela Bernardelli Cipriano, Ross Arena and Gerson Cipriano Jr./Exp Clin Cardiol Vol 20 Issue9 pages 4698-4714 / 2014

Relationship Between Aerobic Exercise Responses and Tissue Doppler Imaging in Chagasic and Isch...

Experimental and Clinical Cardiology

Relationship between Aerobic Exercise Responses and Tissue Doppler Imaging in Chagasic and Ischemic Heart Failure. Original Article

Alexandra Corrêa Gervazoni Balbuena de Lima1,2, Maria Estefânia Bosco Otto1, Marianne Lucena da Silva2, Laura Maria Tomazi Neves2, Janaina Albuquerque Fernandes2, Vinícius Zacarias Maldaner da Silva2, Graziela França Bernardelli Cipriano2, Ross Arena3, Gaspar R. Chiappa4, Gerson Cipriano Júnior2 1

Heart Institute of Distrito Federal – BR;

2

University of Brasilia – BR;

3

University of Illinois Chicago, College of Applied Health Sciences, Department of Physical Therapy and Integrative Physiology Laboratory, Chicago, IL – USA; 4

Serra Gaucha College, Caxias do Sul and Federal University of Rio Grande do Sul, BR

_____________________________________________________________________________________ © 2014 et al.; licensee Cardiology Academic Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

________________________ Abstract Background: Echocardiographic assessment of diastolic and right ventricular function by tissue Doppler imaging (TDI) has demonstrated important prognostic value in patients with ischemic heart failure (HF). However, the correlation of TDI and the aerobic response to exercise in Chagas cardiomyopathy has not been evaluated. Objective: Assess the relationship between the aerobic exercise

response with TDI echocardiography in Chagas HF compared to Ischemic HF and healthy controls. Methods: Fifty-eight male HF patients (31 ischemic and 27 Chagas) and 19 controls matched by age (P = 0.30) and body mass index (P = 0.17) underwent echocardiography with TDI and cardiopulmonary exercise testing. Results: Ischemic and Chagas patients did not demonstrate differences between left ventricular ejection fraction (P = 0.14), left ventricular diastolic function (P = 0.68), right ventricular

Exp Clin Cardiol, Volume 20, Issue 9, 2014 - Page 4698


(RV) function (P = 0.72) and peak oxygen consumption (VO2peak) (P = 0.97), whereas both HF groups were different compared to controls (P < 0.05). In both Chagas and ischemic groups, there was a inverse correlation between VO2peak and diastolic parameters (P < 0.05). In a multivariate analysis, RV function emerged as an independent predictor of VO2peak in Chagas (R² = 0,68) and ischemic (R2 = 0,48) HF subjects. Conclusion: In patients with ischemic and Chagas HF, VO2peak was significantly correlated with diastolic filling pressures and the RV function. These variables may provide an accurate depiction of disease severity and therefore risk for adverse events. Key Words: Diastolic Function; Right Ventricular Function; Exercise Capacity. 1. Introduction Heart failure (HF) is the final common pathway of numerous diseases affecting the heart(1). Despite major improvements in the treatment of all cardiac disorders, HF is an exception in that its prevalence is rising and only small prolongations in survival are occurring, with continued poor clinical outcomes and large health-care costs(2). Several pathogenetic mechanisms appear to be operative in HF. These include increased hemodynamic overload, ischemia-related dysfunction, ventricular remodeling, excessive neurohumoral stimulation, abnormal myocyte calcium cycling, excessive or inadequate proliferation of the extracellular matrix, accelerated apoptosis, and genetic mutations(3). A primary etiology of HF is ischemic heart disease, which has been a wellstudied mechanism. Other conditions lead to HF and are less studied(2). For example, according to the World Health Organization, there are approximately 8 million people diagnosed with Chagas disease globally, particularly concentrated in South America(4). However, due to international migration, it is estimated 720,000 people have Chagas disease outside of South America, particularly in the United States, Australia, Europe, Canada and Japan(5). Moreover, Chagas HF appears to carry a particularly poor prognosis(6). The identification of Chagas etiology in patients with dilated cardiomyopathy is of prognostic significance. Chagas cardiomyopathy is associated with poorer survival compared with idiopathic disease, irrespective of other clinical and echocardiographic parameters related to a poor prognosis in HF. New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF), right ventricular (RV) function and left atrial volume (LAV) are also predictors of adverse events(6)(7). Decreased aerobic exercise performance is the main symptom in patients with HF(8). Among the methods used to assess disease severity and prognosis in HF, cardiopulmonary exercise testing (CPX) and transthoracic echocardiography are two of the more well established clinical assessments in this

population(9)(10). Peak oxygen consumption (VO2peak) and the slope of the relationship between minute ventilation and carbon dioxide production (VE/VCO2) portend robust prognostic value and provide insight into disease severity in HF(11)(12). Echocardiographic and Doppler techniques provide useful structural and functional information related to the detection of early myocardial damage, risk assessment, disease progression, and management of patients with HF(13). Of all echocardiographic parameters at rest, RV function and diastolic function are independently and significantly associated with VO2peak, whereas resting LVEF is not (8). More recently, echocardiographic assessment of diastolic function by tissue Doppler imaging (TDI) has demonstrated a statistically significant relationship with CPX variables in patients with ischemic HF(14)(15). In patients with advanced HF, the main focus has traditionally been placed on the functional assessment of the left ventricle. Therefore, the current body of literature examining the RV and its influence on the pathophysiological processes in HF has been limited. RV dysfunction has been shown to be a powerful predictor of reduced exercise capacity and survival. This relationship holds true for patients with HF secondary to either ischemic or non-ischemic dilated cardiomyopathy(16). RV involvement is a typical feature of Chagas disease(6)(17). As such, RV function assessed by TDI has been shown to add significant prognostic information, incremental to the NYHA clinical classification and to the standard echocardiographic measures of LV systolic function in patients with Chagas HF(18). There are small studies examining the relationship between VO2peak and RV funtion in Chagas HF(18)(19). Determining if CPX can reflect cardiac function in Chagas HF, similar to what has been found in patients in ischemic HF, has important clinical implications given this exercise assessment is used to estimate disease severity and prognosis(16). Thus, the purpose of the current study was to assess the relationship between key CPX variables and TDI measures of diastolic and RV function in Ischemic and Chagas HF cohorts as well as healthy controls. 2. Methods 2.1. Subject characteristics: The study population consisted of fifty-eight male patients with compensated HF (31 ischemic and 27 Chagasic) and nineteen apparently healthy male controls, undergoing a clinical evaluation at the Cardiology Institute of the Federal District in Brasilia - Brazil. The Chagasic patients were selected based on the presence of at least two positive serological tests using distinct techniques (ELISA, indirect hemagglutination or indirect immunofluorescence) and the ischemic patients with the evidence of arterial coronary disease by cyneangiocoronaryography. Heart failure patients were included if they satisfied the



criteria for dilated sytolic cardiomyopathy by echocardiogram (LV diastolic diameter ≥ 56 mm and LVEF ≤ 40%)(20) All patients were in a stable condition for at least 3 months and were receiving stable pharmacologic management prior to initiation of the study. Inclusion criteria for the patients consisted of a clinical diagnosis of HF(3) and evidence of severe LV dysfunction by echocardiography. Any patient with a previous diagnosis of moderate to severe chronic obstructive pulmonary disease or were unable to perform a maximal exercise test, were excluded from the study. In the control group, inclusion criteria was absence of clinical symptons of HF and normal LVEF by echocardiography. Individuals participating in regular physical activity were also excluded. Informed consent and institutional review board approval was obtained prior to study initiation. 2.2.Echocardiography: Images were acquired using a Sonos 5500 (Hewlett-Packard, Andover, MA, USA) with 2.5– 3.5 MHz transducers. Standard M-mode and 2dimensional echocardiography as well as Doppler blood flow measurements were performed in accordance with the American Society of Echocardiography Guidelines(20). Septal and posterior LV wall thickness was obtained from the parasternal long-axis view. LV end-systolic volumes (LVESV) were obtained from 2-dimensional apical images. Left ventricular ejection fraction was calculated according to Simpson's method from 2dimensional apical images(20)(12). 2.2.1 Conventional Doppler and Tissue Doppler Imaging (TDI): Mitral inflow measurements included peak early (E) and late (A) flow velocities and the E/A ratio. Tissue Doppler imaging of the mitral annulus was obtained from the apical 4-chamber view. A 1.5 sample was placed sequentially at the lateral and septal annular sites. Analysis was performed for the early (e′) diastolic peak velocity. The ratio of early transmitral flow velocity to annular mitral velocity of the lateral LV wall (E/e′) was taken as an estimate of LV filling pressure(14). The RV morphology and function was evaluated qualitatively by multiple echocardiographic views. The RV diastolic diameter (RVDD) was measured in the apical four-chamber view. Peak systolic RV (SRV) tissue Doppler velocity was acquired at the tricuspid annulus. Three cardiac cycles were measured during complete expiration and averaged for all Doppler measurements(21). 2.3.Cardiopulmonary Exercise Testing: Each individual performed a CPX to maximum tolerance on an treadmill ergometer (T2100, General Eletrics, EUA) using an individualized ramp protocol.. All subjects were monitored for

at least 6 minutes in the recovery phase. The aim was to achieve peak exercise in ≈ 10 min. Ventilatory expired gas analysis was obtained using a metabolic cart (Medgraphics VO2000, Minneapolis, MN). The oxygen and carbon dioxide sensors were calibrated prior each test. Monitoring consisted of continuous 12-lead electrocardiography obtained from a CASE system (Cardiosoft, General Eletrics, EUA), manual blood pressure measurements every stage with aneroid sphigmomanometer (Tycos, Welch Allyn, EUA), heart rate recordings every stage via the electrocardiogram, and rating of perceived exertion (Borg 1 to 10 scale) each stage. Test termination criteria consisted of patient request, ventricular tachycardia, ≥ 2mm of horizontal or down-sloping ST segment depression or a drop in systolic blood pressure ≥ 20 mm/Hg during exercise. A qualified exercise physiologist with physician supervision conducted each test. Oxygen consumption (VO 2, ml.kg−1.min− 1), VCO2 (L/min), and VE (L/min) were collected continuously throughout the exercise test. Peak VO2 was expressed as the highest 30-second average value obtained during the last stage of the exercise test. Peak respiratory exchange ratio (RER) was the highest 30-second averaged value during the last stage of the test. Ten second averaged VE and VCO2 data, from the initiation of exercise to peak, were input into spreadsheet software (Microsoft Excel, Microsoft Corp., Bellevue, WA) to calculate the VE/VCO2 slope via least squares linear regression (y = mx+ b, m = slope)(22). 2.4. Statistical analysis: Descriptive and correlation statistical calculations were performed using GraphPad Prism (version 5.03, GraphPad Software Inc., San Diego, CA, USA). Descriptive characteristics of normally distributed continuous variables were expressed as mean and standard deviation (mean ± SD) and categorical variables were presented as absolute numbers and/or percentages. Non parametric data were presented as median and interquartile range. One-way ANOVA with a Newman-Keus posttest was used to compare means between groups. Correlations between variables of interest was assessed by the Pearson’s or Spearman correlation coefficient for categorical data. Either the unpaired Student t-test or the Mann – Whitney U test was used, as appropriate to compare subgroups of interest. Multivariate statistical analyses were carried out with SPSS (version 22.0, SPSS, Chicago, IL, USA). A twotailed significance level of 0.05 was considered statistically significant for all tests. 4. Results Fifty-eight male HF patients (31 ischemic and 27 Chagas) and 19 healthy controls matched by age (Ischemic: 56 ± 9,1 years, Chagase: 50 ± 10,7, Control: 55 ± 6,5 years, p = 0,30) and body mass index (Ischemic: 26 ± 3,2 kg/m2, Chagase: 24 ± 2,9 kg/m2, Control: 26 ± 3,4 kg/m2, p = 0,17) were included in this analysis (Figure 1).



Chagasic: VO2peak = 439,6 + 241,9 (S RV) – 12 (LAVindex) – 13,4 (Age) VO2peak = L/min; S RV = cm/s; LAVindex = ml/m2; Age = years Ischemic: VO2peak = 1071 +99,5 (S RV) – 4,3 ( LV mass index) VO2peak = L/min; S RV = cm/s; Mass LVindex = g/m2

TABLE 1 AND 2 AT THE END Figure 1: Study Design

Baseline, epidemiological, TDI echocardiography and CPX characteristics are listed in Table 1. In all groups – ischemic HF, Chagas HF and healthy controls – the most prevalent cardiovascular risk factor was hypertension. Pharmacologic management was consistent with current clinical standards. Both HF groups presented with similar LV systolic and diastolic dysfunction. However, both HF groups were significantly diferent from the control group. Ischemic HF exhibited a larger LV mass than Chagas HF and control subjects. The Chagas HF group demonstrated a larger LV diameter compared to the ischemic and control groups. The ischemic and Chagas HF groups presented with similar RV systolic dysfunction. CPX results demonstrated similar functional limitations and abnormalities in the HF groups, consistent with exercise responses in this chronic disease population. The groups had a similar duration of exercise testing, but the HF patients had a lower VO2peak and higher VE/VCO2 slope compared to healthy controls. In the correlation analysis, both ischemic and Chagas HF groups presented with a slighltly inverse correlation between VO2peak and diastolic parameters. There was a stronger correlation between VO2peak and RV function and a inverse correlation between VO2peak and RV morfology. Although we have found there was a correlation between VO2peak and LV systolic function in the ischemic HF group, a similar trend did not occur in the Chagas HF group (Table 2). In the Chagas HF group there was a significant correlation between the VE/VCO2 slope and both the left atrial volume index (LAVindex) and the RV morfology. There was no correlation between the VE/VCO2 slope and any TDI echocardiography marker in the ischemic HF group. (Table 2). We developed the prediction rule with multivariable linear regression analysis and stepwise backward elimination. Internal validation was assessed with bootstrap sampling to obtain an estimate of model performance;R² = 0,68 and 0,48 for the Chagasic and Ischemic HF groups, respectively. Regression equations are listed below:

5. Discussion The current literature emphasized the role of left-sided diastolic function and RV function as new and an importants determinants of aerobic exercise intolerance in patients with HF(16)(23) (24). In the current study, we evaluated patients with dilated cardiomyopathy, both with ischemic and chagas etiologies, finding VO 2peak better correlated with diastolic filling pressures and RV function compared to LV systolic function. Our findings are in agreement with previous studies in ischemic HF and is one of the first to correlate CPX variables with TDI echocardiography in a Chagas HF cohort, emphasizing the potential value of these latter measures in predicting aerobic capacity. One mechanism by which diastolic parameters may affect aerobic capacity relates to their role in generating a maximal cardiac output. During exercise, the maintenance of adequate LV filling to ensure a normal cardiac output includes the ability to achieve diastolic filling rates greater than the ejection rates during systole. In the setting of exercise induced tachycardia, abnormalities in diastolic relaxation and filling of the LV can result in filling rates that might be too low to achieve adequate cardiac output during exercise, even if ventricular systolic properties are normal(15)(25)(26). In patients with cardiomyopathy, an abnormal LAVindex is a marker of chronically elevated LV filling pressure and a predictor of prognosis(27). Patients with HF have a significant increase in LA pressure that varies in magnitude. In these patients, an increased LAVindex reflects elevated LV filling pressures that negatively effect aerobic capacity(27). We demostrated that the LAVindex was inversely associated with VO2peak in both ischemic and Chagasic HF groups, and in the multivariable analysis, the LAVindex was a primary predictor of VO2peak in subjects with Chagas HF. Previous studies have suggested that LVEF does not predict aerobic capacity in individuals with normal or impaired LV systolic function(26)(28) . Tissue Doppler echocardiography can now characterize LV diastolic function through a combination of measurements (LAVindex, E/A, ratio E/e’), which show evidence of slowed ventricular relaxation, increased LV stiffness, or abnormal LV filling. These parameters have



previously been shown to correlate with aerobic capacuty(25)(29). Of these variables, the ratio between mitral peak early (E) and annular (e′) flow velocity appears to be particularly robust(14)(30). Our results also confirm that the E/e` ratio was correlated with VO2peak in patients with both ischemic and Chagas HF. A primary limiting feature in HF related to exercise maybe the inability of the RV to eject blood into the pulmonary circulation during exertion at a level sufficient to perfuse all areas. Thus there will be areas of the lung ventilated but under-perfused, increasing dead space ventilation. Central to this hypothesis should be a relation between RV function and an increased VE/VCO2 slope(16). The VE/VCO2 slope is significantly correlated with aerobic capacity, cardiac function, and pulmonary ventilationperfusion matching. The VE/VCO2 slope has been shown consistently to be a significant predictor of mortality and hospitalization in patients with HF(31). There is an excessive ventilatory response to exercise in patients with chronic HF as indicated by the oftentimes observed increase in the VE/VCO2 slope(12)(29). Both HF groups, ischemic and Chagas, presented with an elevated VE/VCO2 slope. But, there was only a significant correlation between the VE/VCO2 slope and RV morfology in the Chagas HF group. This increase in the VE/VCO2 slope has been attributed to an increase in pulmonary dead space ventilation and appears to be closely aligned with a reduction in VO2peak(12)(32). An important finding of this study is that it appears neither LV diastolic or systolic function is as important in explaining functional capacity than RV systolic function in patients with systolic HF of ischemic and Chagas etiology. RV performance is now well established as a powerful predictor of prognosis in patients with HF of both ischemic and non-ischemic origin with a reduced RV ejection fraction, estimated by radionuclide ventriculography or by the thermodilution method. In patients with HF of other etiologies, RV dysfunction is a strong indicator of poor prognosis(18)(31). Previous studies have suggested that exercise capacity appears to be more closely related to RV function than to LV function. Nevertheless, only a few studies have addressed the role of RV function in predicting exercise capacity in patients with HF (15) (18)(19) As in these previous studies, the present study also found RV function, assessed by TDI, to be predictor of functional capacity in compensated HF due to ischemic and Chagas cardiomyopathy. Our finding is in agreement with previous studies and emphasizes the role of LV diastolic(25) and RV function(31) in predicting aerobic capacity regardless of etiology.

9. References: 1.Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348:2007–18.

The present data suggests that patients with HF who exhibit poorer echocardiography with TDI values (higher LV mass, higher E/ E′, higher LVESV and lower LVEF) are more likely to present with a poorer CPX response (higher VE/VCO2 slope, lower VO2peak) and vice versa. This relationship supports the importance of the assessment of RV function as a predictor of aerobic exercise performance in patients with HF irrespective of etiology. 6. Clinical Implications The relationships between echocardiography with TDI and CPX are not strong enough to make one method a surrogate for the other. Combining these variables may provide a better overall depiction of disease severity and therefore risk for adverse events. Cardiac transplantation has become an accepted therapy for many patients with end-stage HF. Heart failure patients with RV dysfunction have low cardiac output without clinical evidence of elevated filling pressure, so they may be surprisingly stable clinically and often do not present with urgent symptoms(33)(10). The results of the current study influence the management of patients with chronic dilated cardiomyopathy, identifying patients with a worse prognosis, so that it may be used to select the proper time for heart transplantation. 7. Limitations of Study No perfect method to analyze the RV has been described and thus an ideal tool needs to be established. Magnetic resonance imaging is emerging as a very promising technique, but its use is not yet widely available. Although echocardiography is far from being perfect to analyze the RV, it is a good method to detect clinically significant RV failure. This study was a cross-sectional analysis with a relatively small sample. Thus, new prospective studies evaluating the association between key CPX and TDI echocardiography variables and their ability to predict cardiovascular events and mortality in larger independent cohorts are necessary to validate our finds. 8. Conclusion In summary, both echocardiography with TDI and CPX provide valuable information regarding cardiac function and prognosis in patients with ischemic and Chagas HF. This study showed a potentially useful synergy (TDI echocardiograph plus CPX) to assess disease severity in patients with HF due to Chagas disease. It seems that the degree of impairment of myocardial relaxation and RV function play an important role in HF-associated limitations in aerobic exercise performance. 2.Krum H, Abraham WT. Heartfailure. Lancet. 2009;373:941–55. 3.Braunwald E. Heart failure. JACC Hear Fail 2013;1:1–20.



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28. Grewal J, McCully RB, Kane GC, Lam C, Pellikka PA. Left ventricular function and exercise capacity. JAMA. 2009;301:286–94. 29. Guazzi M, Myers J, Arena R. Cardiopulmonary exercise testing in the clinical and prognostic assessment of diastolic heart failure. J Am Coll Cardiol. 2005;46:1883–90. 30. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr. 2009;22:107–33.

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Table 1: General Characteristics of HF patients

Variables

Ischemic HF

Chagas HF

Control

Age (years)

56 ± 9.1

50 ± 10.7

55 ± 6.5

0.30≈

BMI (Kg.m-2)

26 ± 3.2

24 ± 2.9

26 ± 3.4

0.17≈


P value


Risk Factors

Hypertension

27 (87%)

9 (50%)

7 (36%)

Diabetes Mellitus

9 (29%)

2 (7%)

1 (5%)

Dyslipidemia

25 (80%)

6 (28%)

3 (15%)

Smokers

9 (29%)

1 (3%)

0 (0%)



Medications

ACE

29 (93%)

27 (100%)

5 (26%)

Beta-Blocker

29 (93%)

24 (88%)

1 (5%)

Spironolactone Furosemide

23 (74%) 18 (58%)

24 (88%) 21 (77%)

0 (0%) 0 (0%)

Digoxin

6 (19%)

13 (48%)

0 (0%)

Statin

30 (96%)

4 (14%)

2 (10%)



Echocardiography

LVEF (%)

27.52 ± 8.3*

24.63 ± 6.18∞

62.95 ± 4.7

< 0.0001≈

LV Mass (g/m2)

219 ± 68.55*

151 ± 52.83∞≠

75 ± 14.16

< 0.0001≈

LVSD (mm)

55.37 ± 9.25*

62.83 ± 11.63∞

30.63 ± 2.14

< 0.0001≈

LVDD (mm)

55.37 ± 7.83*

73.33 ± 9.81∞≠

47.53 ± 2.24

< 0.0001≈

LAV index (ml/m2)

28.7 ± 9.1*

39.3 ± 14.8∞

16.8 ± 2.6

0.0002≈

E/A ratio

1.76 ± 1.3

1.73 ± 1.06

1.03 ± 0.29

0.086≈



E/e’ ratio

13.90 ±9.67*

12.07 ±6.32∞

6.5 ± 0.97

0.0003≈

RVDD (mm)

29.2±6.35*

31.11±6.23∞

25.42±2.22

0.0034≈

S RV (cm/s)

9.46±2.52*

9.23±2.28∞

12.23±2.21

0.0002≈

499.45±155.19*

505.11±194.30∞

591.47±98.39

0.0364≈

70.52±11.11

70±12.72

69.58±12.54

0.6783≈

Cardiopulmonary Exercise Testing

Duration (s)

HR rest (hpm)



HR peak (hpm)

132±26.32*

116.14±27.60∞

159.78±14