Lavoro_CPX_review 10 2014 - EA

Cardiopulmonary responses and prognosis in hypertrophic cardiomyopathy: a potential role for comprehensive non-invasive hemodynamic assessment Authors: Gherardo Finocchia ro a MD, Francois Haddad a d MD, Joshua W Knowles a , d MD PhD, Colleen Caleshu a ScM, Aleksandra Pavlovic a BS, Julian Homburger BS a , Yael Shmargad , Gianfranco Sinagra b MD, Emma Magavern a BA, Myo Wong MD c , Marco Perez a MD, Ingela Schnittger MD a - d , Jonathan Myers PhD c , Victor Froelic her MD c , Euan A Ashley a , d MRCP DPhil Institutions: a Stanford University School of Medicine, Department of Medicine, Division of Cardiovascular Medic ine b Cardiovascular Department, Ospedali Riuniti and University of Trieste, Italy c Veterans Affairs Palo Alto Health Care System, Palo Alto d Stanford Cardiovascular Institute Short heading: Cardiopulmonary test in Hypertrophic Cardiomyopathy Total word count: 3990 Key words: Hypertrophic cardiomyopathy, heart failure, cardiopulmonary test, echocardiography Corresponding author: Please address correspondence to Gherardo Finocchiaro, MD, Divis ion of Cardiovascular Medicine, Stanford Universit y Email: gherardobis@yahoo.it and Euan Ashley MD, PhD, Division of Cardiovascular Medic ine, Stanford University Email: euan@stanford.edu FAX: (650) 725-1599 AB S T RACT B ack grou n d an d aims: The i nt ri nsic m ec nism s l ea di ng t o reduc ed func t i onal t ol era nc e in hyp ert rop hi c c a rdi om yopa thy (HC M) a re unc l ea r Our a im wa s t o di sc over t he key det erm i na nt s of exerc i se ca pa ci t y, ma xim al oxygen c onsum pt i on (VO2) and vent i la t ory effi c i enc y (VE/ VC O2 sl op e) a nd assess t he prognost ic p ot ent ia l of m et ab oli c exerc i se t est i ng M eth od s an d resu lt s: The st udy sa mp l e inc l uded 156 HC M pa ti ent s consec uti vel y enrol l ed from 2007 t o 2012 w it h a c omp l et e cl i nic al a ssessm ent , i ncl udi ng rest a nd st ress ec hoc a rdi ogra phy a nd c ardi opul m ona ry exerc i se t est (C PET) w it h im p eda nc e ca rdi ogra phy Pa t i ent s were al so fol l ow ed for t he c om posi t e out com e of ca rdia c- rel a t ed dea t h, hea rt t nsp la nt and func ti ona l det eri ora t i on l ea di ng to sept a l reduc ti on t hera py (m yec t om y or sept al a lc ohol ab la ti on) A bnorma l it i es i n C PET resp onses w ere frequent , wi th 39% (n= 61) of t he sam pl e showi ng a reduc ed exerc i se t ol era nc e (VO2 m ax < 80% of predi ct ed) a nd 19% (n= 30) cha c t eriz ed by i mp red vent i l at ory effi c i enc y (VE/ VC O2 sl op e >34) The va ri ab l es m ost st rongl y a ssoci at ed wi t h exerc i se c ap ac it y (exp ressed i n m et ab ol i c equi va l ent s, METs), w ere pea k ca rdi ac i ndex (C I ) (r= 51, p 40 ml/m (HR: 3.32 CI 1.08-10.16, p=0.036) (Table 5) In a model considering genotyped patients, w e did not find a significant association w ith the presence of a know n disease causing mutation and the composite end-point Figure shows the Kaplan-Meier survival curves stratified by NYHA III, peak VO2 less than 80% of predicted, VE/VCO2 less than 34, and LAVi greater than 40 ml/m2 DISCUSSION The study offers three contributions to an ongoing discussion of exercise intolerance and adverse events in the HCM patient population Our data strongly suggests that peak exercise cardiac output and left ventricular diastolic parameters are the primary determinants of exercise tolerance in HCM patients Furthermore, indices of ventilatory inefficiency are only w eakly associated with diastolic parameters Finally, w e observed that peak VO2, ventilatory inefficiency and left atrial dimension are the principal predictors of the above measured outcomes in this demographic 10 Previously Sharma et al studied a population of 135 HCM patients, and found that dynamic obstruction of the LVOT w as associated with low er peak VO2, providing support for septal reduction therapy More recently, Efthimiadis et al performed CPET in 68 patients w ith HCM, and found that male sex, atrial fibrillation, presence of obstruction and heart rate reserve were independent predictors of exercise capacity In previous w ork from our group on 68 patients with HCM, Le et al reported a significant association between lateral E′ and indexed LA volume and peak VO2 The current study confirms previous reports demonstrating reduced exercise capacity in patients w ith HCM (in our series, 39% of the patients with reduced peak V02 and 19% w ith significantly impaired VE/VCO2) Peak CI emerged as the strongest independent determinant of exercise tolerance, expressed as either estimated METs or peak VO2 A linear relationship between cardiac output and peak VO2 has previously been demonstrated in normal subjects and in patients w ith HF Frennaux et al showed on a cohort of 23 patients w ith HCM studied invasively, that maximal oxygen consumption and anaerobic threshold are related to peak cardiac index, but not to peak and rest pulmonary capillary w edge pressure Lele et al , confirmed that stroke volume is the major determinant of peak exercise capacity in HCM Given the risk and challenge of invasive hemodynamic assessment, we took advantage of the recent validation of non-invasive exercise bio-impedance To the best of our knowledge the present study is the first to demonstrate a consistent relationship between an impaired increase in CI and exercise intolerance in a large cohort of HCM patients In agreement w ith previous studies, age, male sex as well diastolic parameters of the LV emerged as independent correlates of peak VO2 Our findings underscore the importance of RV size and function in HCM Several studies have also recently demonstrated that RV function is a key determinant of exercise capacity in HF w ith reduced systolic function In contrast to the strong association with peak VO2, there was no significant association between peak CI and VE/VCO2 Ventilatory effic iency is a variable w ith a complex set of determinants and in systolic HF an abnormal VE/VCO2 slope characterizes patients with more severe heart failure and is an independent marker of event free survival , We did not find any significant relationship between CPET variables and the presence of a disease causing sarcomere variant Efforts to characterize patients w ith clear sarcomeric variants and distinguish them from those w ithout are ongoing but remain power limited 11 Although our outcome evaluation was exploratory in nature, the results highlight an important prognostic role of CPET for patients w ith HCM Several previous studies have considered various clinical and echocardiographic parameters in risk stratification of these patients , In the specific setting of HCM, studies analyzing the role of CPET variables in predicting outcomes are lacking Peak oxygen consumption (peak VO2) measured during a CPET has been considered a reliable variable in the assessment and risk stratification of patients with HF Other variables derived from CPET have also been linked to mortality in HF, including peak VO2 expressed as a percentage of predicted, chronotropic index, and ventilatory inefficiency expressed as the VE/VCO2 slope The prognostic role of CPET in HCM has never been clearly established In a recent study Sorajja et al examined 182 minimally symptomatic patients w ith HCM In a multivariate analysis, the independent predictors of death and severe symptoms were the severity of LVOT gradient at rest and the percentage of predicted peak myocardial consumption during exercise From our study both parameters of exercise tolerance (peak VO2 and the VE/VCO2 slope) and indirect indices of diastolic dysfunction (LAVi) emerged as the most important and independent determinants of outcome These results underscore that CPET is not limited to the general evaluation of patients or to an objective assessment of exercise tolerance, but it is also an important tool for predicting outcomes and in the general management of this disease Limitations Our study has limitations First, impedance cardiography is an indirect measure of cardiac index The validity and reproducibility of these methods have been documented by several studies how ever Second, because of referra l bias, our sample may not represent the general HCM population, as patients with more advanced disease are over- represented in specialist centers w here invasive options such as myectomy are offered We have how ever recruited consecutive patients seen in our clinic where more than 95% of patients get a baseline CPET Finally, we chose a composite outcome, with a limited number of total events (n= 21) and a relatively short mean follow-up; thus, these findings should be viewed as preliminary CONCLUSIONS Exercise intolerance is common in patients w ith HCM Peak cardiac index is the main determinant of exercise tolerance, as w ell as other variables such as diastolic parameters, 12 age and sex The failure of stroke volume augmentation during exercise seems to be influenced by age, diastolic dysfunction and right ventricular longitudinal dysfunction Abnormalities in ventilatory effic iency are relatively frequently observed in these patients and can be partially explained by the degree of diastolic dysfunction From our study, peak VO2, ventilatory inefficiency and parameters of diastolic function seem to be main predictors of prognosis in patients with HCM These results remain to be validated by furt her multicenter studies, but they underscore an important role for CPET in the assessment of patients affected by cardiomyopathies and heart failure COM PETENCY IN MEDICAL KNOWLEDGE: Exercise intolerance is common in hypertrophic cardiomyopathy and peak cardiac index is the main determinant of exercise capacity Cardiopulmonary test is a helpful tool not only in diagnosis of hypertrophic cardiomyopathy but also in the prognostic assessment TRANSLATIONAL OUTLOOK: Further studies are warranted to determine the mechanisms underlying the reduced cardiac output 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R, Myers J, Aslam SS, Varughese EB, Peberdy MA Peak vo2 and ve/vco2 slope in patients with heart failure: A prognostic comparison American heart journal 2004;147:354-360 15 34 35 Sorajja P, Allison T, Hayes C, Nishimura RA, Lam CS, Ommen SR Prognostic utility of metabolic exercise testing in minimally symptomatic patients with obstructive hypertrophic cardiomyopathy The American journal of cardiology 2012;109:1494-1498 Yoshino T, Nakae I, Matsumoto T, Mitsunami K, Horie M Relationship between exercise capacity and cardiac diastolic function assessed by time-volume curve from 16-frame gated myocardial perfusion spect Annals of nuclear medicine 2010;24:469-476 FIGURE LEGENDS: Figure 1: distribution of functional and hemodynamic parameters in the total population A peak VO2; B VE/VCO2 slope; C peak CI; D peak HR Figure 2: peak CI and relationship with maximal w orkload (Mets) 16 Figure 3: peak VO2 and relationship with clinical and instrumental parameters A peak CI; B sex; C age; D E/E' Figure 4: CPET and bioimpedance values according to the presence of known disease causing mutation(s) Figure 5: event-free survival according to the presence of of NYHA III at enrolment (A), peak VO2 less than 80% of predicted (B), VE/VCO2 less than 34 (C) and indexed left atrial volume (LAVi) more than 40 ml/m2 (D) Source of Funding: Stanford Cardiovascular Institute and Biotronik Italia Emma Magavern is funded by the Sarnoff Cardiovascular Research Foundation Conflicts of interest: None 17 ... acquired breath-by-breath, averaged over 20 seconds, and expressed in 10 second intervals VE and VCO2 responses throughout exercise were used to calculate the VE/VCO2 slope via least squares linear... during exercise, and during recovery and yield breath- by-breath measures of oxygen uptake (VO2), carbon dioxide output (VCO2), and ventilation (VE) Non-invasive methods for quantifying cardiac output,... sample of 25 studies w as chosen to calculate the intra- and inter- reader variabilit y Intra- and interreader variability was quantified using mean diffe rences as w ell as intraclass correlation