Keywords Diastolic function, exercise echocardiography, cardiopulmonary exercise testing, hypertension

Transcription

1 Original scientific paper The combined exercise stress echocardiography and cardiopulmonary exercise test for identification of masked heart failure with preserved ejection fraction in patients with hypertension EU RO PEAN SOCIETY OF CARDIOLOGY European Journal of Preventive Cardiology 2016, Vol. 23(1) 71 77! The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: / ejpc.sagepub.com Ivana Nedeljkovic 1,2, Marko Banovic 1,2, Jelena Stepanovic 1,2, Vojislav Giga 1,2, Ana Djordjevic-Dikic 1,2, Danijela Trifunovic 1,2, Milan Nedeljkovic 1,2, Milan Petrovic 1,2, Milan Dobric 1,2, Nenad Dikic 3, Milan Zlatar 1 and Branko Beleslin 1,2 Abstract Background: Heart failure with preserved ejection fraction (HFpEF) is commonly associated with hypertension (HTN). However, resting echocardiography (ECHO) can underestimate the severity of disease. Exercise stress echocardiography (ESE) and the cardiopulmonary exercise testing (CPX) appeared to be useful tests in dynamic assessment of HFpEF. The value of combined exercise stress echocardiography cardiopulmonary testing (ESE-CPX) in the identification of masked HFpEF is still undetermined. Objective: The purpose of this study was to analyse the value of the combined ESE-CPX in the identification of masked HFpEF in patients with HTN, dyspnoea and normal resting left ventricular (LV) systolic and diastolic function. Methodology: We studied 87 patients with HTN, exertional dyspnoea and normal resting LV function. They all underwent ESE-CPX testing (supine bicycle, ramp protocol, 15 W/min). ECHO measurements were performed at rest, and at peak load. Achievement of peak E/e ratio>15 was a marker for masked HFpEF. Results: Increase of E/e >15 occurred in 8/87 patients (9.2%) during ESE-CPX. Those patients had the lower peak VO2 (p ¼ 0.012), the lower VO2 at anaerobic threshold (p ¼ 0.025), the lower workload (p ¼ 0.026), the lower peak partial pressure end tidal carbon dioxide (PetCO2) (p < ), and the higher VE/VCO2 slope (p < ) which was an independent multivariate predictor of HFpEF (p ¼ 0.021), with the cut-off value of according to the receiveroperator characteristic (ROC) curve (sensitivity (Sn) 100%, specificity (Sp) 90%). Conclusion: The combined ESE-CPX test is feasible and reliable test that can unmask HFpEF and may become an important aid in the early diagnosis of HFpEF, excluding the other causes of exertional dyspnoea. Keywords Diastolic function, exercise echocardiography, cardiopulmonary exercise testing, hypertension Received 18 May 2015; accepted 18 August 2015 Background Heart failure with preserved ejection fraction (HFpEF) is responsible for about 50% cases of the overall heart failure (HF) population, and in at least 74% of the HF cases in patients with arterial hypertension (HTN). 1 3 The main symptoms are dyspnoea and exercise intolerance caused by the increase of diastolic filling pressures (DFPs). 4 6 Therefore, the dynamic assessment is a physiological approach to evaluation of the 1 Cardiology Clinic, Clinical Center of Serbia, Serbia 2 School of Medicine, University of Belgrade, Serbia 3 Outpatient Clonoc for Sport Medicine Vita Maxima, Belgrade, Serbia Corresponding author: Ivana Nedeljkovic, Cardiology Clinic, Clinical Center of Serbia, 26 Visegradska, Belgrade, Serbia. ivannanedeljkovic@yahoo.com

2 72 European Journal of Preventive Cardiology 23(1) effort-induced changes, as the DFP can be normal at rest and increases during the effort. 7 9 This was confirmed by the invasive measurements during exercise testing, 10 with the comparable data observed with the non-invasive studies during the exercise stress echocardiography (ESE) Cardiopulmonary exercise testing (CPX) is also recommended for the assessment, and the stratification of the patients with HF, as well as for the patients with HFpEF. 18,19 We hypothesized that combined exercise stress echocardiography cardiopulmonary testing (ESE-CPX) may improve the identification of masked HFpEF in patients with HTN, exertional dyspnoea, and normal left ventricular systolic and diastolic function (LVSF and LVDF) at rest. Methods Study population The ESE-CPX test was performed in 87 patients (54 men, 33 women; mean age of years) with arterial HTN, 20 exertional dyspnoea and normal resting LVSF and LVDF. The study was conducted from May 2013 January 2014, at the Cardiology Department of the Clinical Center of Serbia. The study was approved by the Ethical Committee. All the patients were under stable medical treatment for at least one month before, and all signed informed consent. The exclusion criteria were: left ventricular ejection fraction (LVEF)<50%, known HFpEF, ischaemic heart disease, valvular heart disease or documented cardiomyopathy, severe uncontrolled HTN (systolic pressure 80 mm Hg and diastolic pressure 110 mm Hg), recent malignant ventricular arrhythmias and chronic obstructive pulmonary disease. Concomitant betablockers were used in 72% (63/87), calcium antagonists in 79% (69/87), and angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-converting receptor blockers (ARBs) in 92% (80/87) of patients. Stress test protocol All of the patients underwent the maximal ESE-CPX test on supine bicycle with the continuous ramp protocol with 3 min of unloaded pedalling, followed by 15 W/min load increments. Expiratory gases were collected on a breath-by-breath basis, and analysed by metabolic cart (Schiller CS 200, Germany).Ventilatory anaerobic threshold (VAT) was determined by the V-slope analysis on oxygen consumption (VO2) vs carbon dioxide production (VCO2). The values of VO2 at VAT and at peak exercise (peak VO2) are expressed as ml O2/kg/min during the 30 s in which the examined event occurred and printed using rolling averages every 10 s. Ventilatory efficiency VE/VCO2 slope was measured by excluding data points after the onset of maximal hyperventilation at the maximal effort. The respiratory exchange ratio (RER) 1.10 at the end of the ESE-CPX test was considered as the achievement of the maximal effort. The echocardiography (ECHO) measurements were performed at rest and at peak exercise (3.5-MHz transducer, Esaote, MyLab60, Spain). The LVEF and volumes were calculated by the modified Simpson s method. We used the cut-off of 50% for the preserved LVEF. The peak velocity of the tricuspid regurgitant (TR) jet by continuous-wave (CW) Doppler together with systolic right atrial (RA) pressure were used to derive pulmonary artery systolic pressure (PASP). 21 The transmitral inflow pattern was determined by the pulsed-wave (PW) Doppler with the early (E) and the late (A) wave of mitral peak flow velocity and E deceleration time (Dt) (the apical four-chamber view, the sample volume positioned at the level of the mitral valve tips, the mean value over five cardiac cycles was used). The tissue Doppler imaging (TDI) was used for the measurement of the early diastolic peak of the mitral annular e 0 from both the medial and the lateral segments (over the five cycles, with the sample volume of 5 mm). 5,6 We used e 0 value as the average of medial and the lateral measurements. The peak E/e 0 ratio>15 was considered as a marker for the significant ESE- CPX test-induced increase in left ventricular (LV) filling pressure typical for the presence of HFpEF. 5,6,8 The ECHO images were acquired, digitised, and analysed off-line by the two experienced observers unaware of patients clinical data and the CPX parameters. Electrocardiography Standard 12-lead electrocardiographic (ECG) monitoring was performed continuously and recorded at rest, at the end of each stage, and during the recovery period. Heart rate (HR), systolic (SBP) and diastolic (DBP) were measured at rest, at the end of each stage and during the recovery. The reasons to terminate test before the maximal effort were: the severe chest pain, development of the horizontal or downsloping ST segment depression 1 mv at least 0.08 s after J point, decrease in SBP >20 mm Hg, or increase in SBP > 220 mm Hg, malignant arrhythmias, and exercise-limiting dyspnoea, fatigue and claudication, 22 and also represented the exclusion criteria. Statistical analysis The normality assumption for continuous variables was evaluated by the Kolmogorov-Smirnov test.

3 Nedeljkovic et al. 73 Continuous variables are expressed as mean standard deviation (SD). Between-groups comparisons of continuous variables were performed by using the Student s t-test for the independent samples. Categorical variables are presented as counts and percentages and were compared with the chi-square or Fisher s exact test. Receiver-operator characteristic (ROC) curves were plotted to determine the sensitivity and the specificity of the VE/VCO2 slope in order to predict the exercise induced increase of E/e 0 values > 15 as evidence for masked HFpEF. The optimal cut-off value of E/e 0 was determined from the ROC curve. The univariable logistic regression analysis was used to determine the CPX variables significantly related with masked HFpEF. Multivariable logistic regression analysis was performed afterwards by using a forward stepwise approach to assess the significant independent predictors of masked HFpEF. For all analyses, a twosided p < 0.05 was considered statistically significant. We used the SPSS statistical software (version 15.0, SPSS Inc., Chicago, Illinois, USA). Results The increase of the E/e 0 ratio > 15 during the ESE-CPX test occurred in 9.2% of patients (8/87), and was considered as evidence of masked HFpEF. These patients were older (p ¼ 0.004), regardless of gender and concomitant medical therapy. The ECHO parameters at rest, were similar between the patients with and without HFpEF, except for the lower e 0 velocity and the higher PASP (p ¼ and p ¼ 0.001) (Table 1). The CPX variables are presented in Table 2. Patient without masked HFpEF had higher VO2 on VAT (p ¼ 0.025), higher peak VO2 ( vs ; p ¼ 0.012), and higher O2 pulse (p ¼ 0.023). The patients with masked HFpEF had a significantly higher VE/VCO2 slope ( vs ; p < ) and poor increase in partial pressure end tidal carbon dioxide (PetCO2) (p < ). The ECHO parameters at peak exercise are shown in Table 3. The peak E/e ratio was significantly higher in patients with masked HFpEF ( vs ; p ¼ 0.038). The CPX variables significantly related to masked HFpEF were: the peak workload and the total exercise duration, as well as VO2 at VAT, peak VO2, VE/VCO2 slope and peak PetCO2 values (Table 4). The multivariate logistic regression analysis showed that the VE/ VCO2 slope was the only independent predictor of masked HFpEF (Table 4). According to the ROC curve analysis, the value of the VE/VCO2 slope which was the best predictor for masked HFpEF was (Sn 100%, Sp 91%; area Table 1. Baseline characteristics of patients with and without masked heart failure with preserved ejection fraction (HFpEF). Variable under curve (AUC) 0.99; 95% confidence interval (CI): ) (Figure 1). Discussion With HFpEF (n ¼ 8) Without HFpEF (n ¼ 79) Male, n (%) 7 (87) 47 (59) Age 59 6 a LA (mm) IVS (mm) LVEDd (mm) LVESd (mm) LVEF (%) LVEDV(ml) LVESV (ml) E (m/s) A (m/s) E/A Dt (s) e 0 (m/s) b E/e PASP (mm Hg) a HR (beat/min) SBP (mm Hg) DBP (mm Hg) 92 7 b 86 8 DBP: diastolic blood pressure; Dt: mitral E deceleration time; e 0 : early diastolic mitral annular velocity; E/A: mitral E to mitral e wave velocity; E/ e 0 : mitral E to mitral annular e 0 velocity ratio; HR: heart rate; IVS: interventricular septum; LA: left atrium; LVEDd: left ventricular diastolic dimension; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction; LVESD: left ventricular systolic dimension; LVESV: left ventricular end-systolic volume; PASP: pulmonary artery systolic pressure; SBP: systolic blood pressure. a p < 0.01; b p < According to our knowledge, this is the first study with the use of the combined ESE-CPX test for the identification of masked HFpEF in patients with HTN, exertional dyspnoea and with normal ECHO parameters at rest. The increase of E/e 0 > 15 during the test was detected in 9.2% of our patients and was considered as the marker of masked HFpEF. These patients had the lower peak VO2, the lower peak PetCO2 values, and the higher VE/VCO2 slope, which was also the independent predictor of masked HFpEF. This was consistent with the previous findings where a steep VE/VCO2 slope, compared with the peak VO2, was a more powerful prognostic marker in patients with HFpEF. 18

4 74 European Journal of Preventive Cardiology 23(1) Table 2. Cardiopulmonary exercise testing (CPX) parameters in patients with and without masked heart failure with preserved ejection fraction (HFpEF). Variable Patients with HFpEF n ¼ 8 Patients without HFpEF n ¼ 79 Work load (Watts) a Test duration (s) a Time to VAT (s) VAT (VO2) (ml/kg/min) a Peak VO2 (ml/kg/min) a VE/VCO2 slope b PetCO2 (mm Hg) b O2 pulse (ml/beat) a Peak HR (beat/min) Peak SBP (mm Hg) Peak DBP (mm Hg) 93 7 a 86 8 Peak DBP: peak diastolic blood pressure; peak HR: peak heart rate; peak SBP: peak systolic blood pressure; PetCO2: partial pressure end tidal carbon dioxide; VAT: ventilator anaerobic threshold; VE/VCO2 slope: ventilation to carbon dioxide output; VO2: oxygen uptake. a p < 0.05; b p < Table 3. The peak echocardiography parameters during combined exercise stress echocardiography cardiopulmonary testing (ESE-CPX) in patients with and without masked heart failure with preserved ejection fraction (HFpEF). Variable Patients with HFpEF n ¼ 8 Patients without HFpEF n ¼ 79 Peak E (m/s) a Peak A (m/s) Peak E/A Peak Dt (s) b Peak e 0 (m/s) c Peak E/e b Peak PASP (mm Hg) a Dt: mitral E deceleration time; e : early diastolic mitral annular velocity; E/ A: mitral E to mitral A wave velocity; E/e: mitral E to mitral annular e 0 velocity ratio; PASP: pulmonary artery systolic pressure. a p < 0.01; b p < 0.05; c p < All these findings can be explained by pathophysiological mechanisms of diastolic dysfunction (DD) which refers to an abnormality of LV diastolic distensibility, filling or relaxation which reduce the LV filling and aerobic capacity regardless of the LV function. 23 HFpEF is the main cause of HTN. However, ischaemic and valvular heart disease, primary restrictive, infiltrative and storage cardiomyopathies or comorbidities can Table 4. Logistic regression analysis between the different variables and heart failure with preserved ejection fraction (HFpEF). Variable p RR 95% CI Lower limit Upper limit Univariate logistic regression analysis Age (y) E (m/s) E/A Dt (s) e 0 (m/s) Peak E (m/s) Peak E/A Peak Dt (s) Peak PASP (mm Hg) Work load (Watts) Test duration (s) VAT (VO2) (ml/kg/min) Peak VO2 (ml/kg/min) VE/VCO2 slope PetCO2 (mm Hg) O2 pulse (ml/beat) Multivariate logistic regression analysis VE/VCO2 slope CI: confidence interval; Dt: mitral E deceleration time; e 0 : early diastolic mitral annular velocity; E: mitral peak velocity of early filling at rest; E/A: mitral E to mitral peak velocity of late filling; PASP: pulmonary artery systolic pressure; PetCO2: partial pressure end tidal carbon dioxide; VAT: ventilatory anaerobic threshold; VE/VCO2 slope: ventilation to carbon dioxide output slope; VO2: oxygen uptake. cause the development of HFpEF by nonhomogenous contraction and relaxation, myocardial ischaemia, and LV concentric remodelling and hypertrophy. 24 The clinical symptoms and the signs are similar to the systolic and the diastolic HF and, during the past decade, non-invasive tools have made a strong impact in better understanding of the diastolic abnormalities. The TDI is the easiest and the most reproducible non-invasive technique for the assessment of the myocardial relaxation. Nagueh et al. showed good correlation between the increased mean pulmonary capillary wedge pressure (PCWP) and the E/e 0 ratio > Likewise, Ommen et al. confirmed the strong relationship between the E/e 0 > 15 with the increased LVEDP measured during LV catheterisation. 25 It has been shown that exercise may reveal the diastolic abnormalities not evident under the resting conditions. 9 The ESE, which examines LV filling on exertion, is shown to be a potent test because the initial stages of DD may be hidden by compensatory mechanisms, and the most of the patients

5 Nedeljkovic et al ROC Curve 0.8 Sensitivity VE/VCO2 slope cut off: (Sn 100%, Sp 91%;AUC 0.99; 95%CI: ) Specificity Diagonal segments are produced by ties. Figure 1. Receiver-operating characteristic (ROC) curve analysis using the ventilation to carbon dioxide output (VE/VCO2) slope to identify heart failure with preserved ejection fraction (HFpEF). AUC: area under the curve; CI: confidence interval; E/e: mitral E to mitral annular e 0 velocity ratio; Sn: sensitivity; Sp: specificity. with chronic HF are asymptomatic at rest. 26 Thus, we performed the combined ESE-CPX test for the assessment of the patients with HTN and dyspnoea using the value of the E/e 0 > 15 as the marker of masked HFpEF. Guazzi et al. analysed the relationship between the TDI at rest and CPX variables in the 32 patients with HFpEF. They found the significant correlation between the E/e ratio at rest with the peak of the VO2, VE/ VCO2 slope, resting and the peak PetCO2. 19 We used the TDI measurements both at rest and at maximal effort during the combined ESE-CPX test for identification of the patients with masked HFpEF, showing the strong relationship between the VE/VCO2 slope, peak PetCO2, and peak VO2 with the increase of the peak E/e 0 ratio > 15 in patients with normal ECHO findings at rest. In our study the VE/VCO2 slope was the best multivariate predictor for identification of masked HFpEF during the combined ESE-CPX test, with the cut-off value of Our results are consistent with the previous research of Guazzi et al. who demonstrated the superiority of the VE/VCO2 slope in comparison to the peak VO2 in the diastolic HF group. 18 They assessed the value of the peak VO2 and the VE/VCO2 slope in prediction of mortality and hospitalization in HFpEF vs heart failure (HF) with reduced EF (HFrEF) in 409 patients divided into three groups according to different LVEF cut-offs. In their study the peak VO2 and the VE/VCO2 slope were significant univariate predictors both in HFpEF and in HFrEF. However, in patients with HFpEF, the VE/VCO2 slope was the only predictor regardless of LVEF. They identified a cut-off of the VE/VCO2 slope: 32.6, 33.1, and 33.3 for an LVEF cut off of 40%, 45%, and 50%, respectively. Abnormal increase of the VE/VCO2 slope during exercise in patients with HF is a consequence of the ventilation-perfusion abnormalities and inability to maintain the optimal cardiac output However, this ventilatory limitation with dyspnoea is more exaggerated in patients with HFpEF, followed by intolerance due to increase of the PCWP. A distinction between HFrEF and HFpEF is important because these two forms have different pathophysiologies and thus might require different therapeutic approaches. Several established interventions that improve the outcome in the HF population can also affect the VE/VCO2 slope. Exercise training may improve the effort tolerance with the decrease of the VE/VCO2 slope. 31,32 Drugs like ACEIs, angiotensin II receptor antagonists and beta-blockers may also improve the VE/VCO2 slope in patients with HF Likewise, the reduction in the VE/VCO2 slope was obtained by cardiac resynchronization therapy. 36 These findings collectively support the serial assessment

6 76 European Journal of Preventive Cardiology 23(1) of the VE/VCO2 slope to monitor the response to a treatment in patients with HF. 37 The combined ESE- CPX test may improve the identification of patients with masked HFpEF and, therefore, may have an impact on specific management. However, this should be an objective for future research, including other causes of HFpEF, where simultaneous evaluation of both ESE and CPX variables can facilitate earlier diagnosis and understanding of pathophysiological mechanisms. Study limitations A relatively small sample size with the limited number of identified cases with masked HFpEF is the main limitation of our study. However, the prevalence of HFpEF in our hypertensive patients is similar to the one described in the real-life clinical practice. 38 Nevertheless, the assessment of diastolic function in patients with HTN, exertional dyspnoea and normal LV function at rest, represents a new contribution for the early detection of HFpEF and therefore needs to be further tested in a larger number of patients with suspected HFpEF, as well as in the patients with different risk factors for HFpEF. Conclusion The combined ESE-CPX test is a feasible and reliable test that can identify patients with masked HFpEF. Impaired ventilation rather than peak VO2 is the main indicator of significantly impaired diastolic function. In the presence of preserved LVSF, the combined ESE-CPX test may become an important aid in the diagnosis of HFpEF, excluding the other causes of exertional dyspnoea. Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was partially supported by a grant of the Ministry of Science of the Republic of Serbia (Project Number 41022). Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. References 1. Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure; The Framingham Heart Study. Circulation 2002; 106: Vasan RS, Benjamin EJ and Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: An epidemiologic perspective. J Am Coll Cardiol 1995; 26: Levy D, Larson MG, Vasan RS, et al. The progression from the HTN to congestive heart failure. JAMA 1996; 275: McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33: Paulus WJ, Tscho pe C, Sanderson JE, et al. How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with the normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28: Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of the left ventricular diastolic function by echocardiography. Eur J Echogrdiogr 2009; 10: Oh KJ, Park SJ and Nagueh FS. Established and novel clinical applications of the diastolic function assessment by echocardiography. Circ Cardiovasc Imaging 2011; 4: Burgess IM, Jenkins C, Sharman EJ, et al. Diastolic stress echocardiography: Hemodynamic validation and clinical significance of estimation of ventricular filling pressure with the exercise. J Am Coll Cardiol 2006; 47: Ha JW, Oh JK, Pellikka PA, et al. Diastolic stress echocardiography: A novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle exercise doppler echocardiography. J Am Soc Echocardiogr 2005; 18: Kitzman DW, Higginbotham MB, Cobb FR, et al. Exercise intolerance in patients with the heart failure and with the preserved left ventricular systolic function: Failure of the Frank Starling mechanism. J Am Coll Cardiol 1991; 17: Little WC, Zile MR, Klein A, et al. Effect of losartan and hydrochlorothiazide on exercise tolerance in the exertional HTN and left ventricular diastolic dysfunction. Am J Cardiol 2006; 98: Warner Jr JG, Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients with the diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999; 33: Little WC, Wesley-Farrington DJ, Hoyle J, et al. Effect of candesartan and verapamil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol 2004; 43: Mezzani A, Agostoni P, Cohen-Solal A, et al. Standards for the use of cardiopulmonary exercise testing for the functional evaluation of cardiac patients: A report from

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