Curr Heart Fail Rep (2014) 11:80–87 DOI 10.1007/s11897-013-0183-3 NONPHARMACOLOGIC THERAPY: SURGERY, VENTRICULAR ASSIST DEVICES, BIVENTRICULAR PACING, AND EXERCISE (AK HASAN, SECTION EDITOR)

Abnormalities in Cardiopulmonary Exercise Testing Ventilatory Parameters in Heart Failure: Pathophysiology and Clinical Usefulness Marco Guazzi

Published online: 10 January 2014 # Springer Science+Business Media New York 2014

Abstract Heart failure (HF) is a complex syndrome characterized by myocardial dysfunction, derangement of multiple organ systems and poor outcome. Out of several markers of severity, abnormalities in exercise ventilation (VE) offer relevant insights into the pathophysiology of dyspnea, lung gas exchange, and control of ventilation and are now recognized as meaningful indicators of disease severity and prognosis. Ventilation inefficiency, identified as an increased slope of VE vs carbon dioxide production (VCO2) recognizes as major determinants an increased waste ventilation due to enhanced dead space, early occurrence of lactic acidosis, and an abnormal chemoreflex and/or metaboreflex activity. In some cases of HF, especially associated with advanced hemodynamic and neural deregulation, an exercise oscillatory ventilatory (EOV) pattern may occur. According to an increasing number of studies, EOV identifies the 15–30 % of higher-risk HF patients requiring aggressive treatment and provides an even more robust prediction of outcome compared to VE/VCO2 slope. Overall, a refined prevalence definition and more comprehensive use of these markers in a clinical environment and in future interventional trials seem challenging for the years to come.

Keywords Heart failure Pulmonary hypertension Prognosis

. Preserved ejection fraction . . Exercise ventilation inefficiency .

M. Guazzi Heart Failure Unit, Cardiology, IRCCS, San Donato University Hospital, Milan, Italy M. Guazzi (*) Heart Failure Unit-Cardiology, IRCCS Policlinico San Donato, University of Milano, Piazza E. Malan 2, 20097 San Donato Milanese, Milano, Italy e-mail: [email protected]

Introduction Since cardiopulmonary exercise testing (CPX) was introduced and proposed for standard cardiological practice in the early 1980s [1], there has been a progressive appreciation on the clinical and prognostic significance of abnormalities in gas exchange and ventilation (VE) in heart failure (HF) patients with different degrees of left ventricular dysfunction [2, 3]. Specifically, an abnormal ventilatory response to exercise during incremental workload is now a recognized hallmark manifestation of HF syndrome that reflects the mixed impairment of multiple organ systems and pathways, correlates with dyspnea sensation and provides relevant clinical insights [4•]. The origin of an increased and inefficient ventilatory response to exercise is multifactorial and primarily reflects how left ventricular dysfunction may impair lung physiology and both central and peripheral ventilatory control. Interest has also been progressively addressed to the pathophysiology and clinical meaning of an exercise oscillatory ventilation (EOV) and gas exchange kinetics; a pattern that resembles, in some instances, the occurrence of Cheyne Stokes respiration during sleep [5]. This article highlights the proposed pathogenetic pathways for an abnormal ventilatory response to exercise with special emphasis on their prognostic value in patients with HF syndrome.

Exercise VE Inefficiency The normal VE response to exercise implies a near-linear increase that is proportional to the progressive rise in carbon dioxide (VCO2) production. For low and moderate intensity of work, this response is tightly regulated by arterial carbon dioxide partial pressure (paCO2). At higher work intensities the development of lactic acidosis and H+ production from

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VE ¼ 863  VCO2 =½PaCO2  ð1−VD=VTފ: Accordingly, the increased ventilator requirement in HF patients is determined by the behaviour of arterial CO2 tension during exercise and the fraction of the tidal volume going to the dead space. At rest, a normal PaCO2 would be around 40 Torr and VD/VT around 0.3-0.4, meaning that for a VT of 500 mL, VD would be 150 ml. Therefore, for an abnormal VE/VCO2 slope during exercise there must be some alterations, either singularly or combined in the degree of increased ventilator response influenced by VD/VT and PaCO2. Three different mechanisms for an increased ventilatory requirement to a given CO2 production have been reported in HF: 1) an increased waste ventilation, 2) early occurrence of decompensated acidosis and 3) an abnormal chemoreflex and/ or metaboreflex control. Increased Waste Ventilation A number of factors may explain an increased waste ventilation in HF patients, either from increased anatomic dead space

60

VE (L/min)

anaerobic prevailing metabolism further increases CO2 release and the consequent amount of VE. An inefficient VE typically occurs in HF with either reduced [6–9, 10•] and preserved ejection fraction correlates [11, 12] and is defined by different relationships, the ratio between VE and VCO2 assessed at nadir or ventilator threshold and peak exercise and the slope of progressive VE increase vs VCO2 production (Fig. 1). VE/VCO2 slope, rather than their ratio, is generally endorsed by most laboratories and has been repeatedly identified as a strong and independent prognostic marker in different stages of heart disease including the large subset of HF patients with exercise limitation of mild to intermediate entity and still preserved peak VO2 [6–9, 10•]. A cutoff of 34 is consistently viewed as the upper normal limit. While, in some studies the slope has been calculated as the slope from rest to ventilator threshold [13, 14], in others it has been reported by including all data points from rest to exercise [11]. A significant strength of this latter method is to rely on an uniform measure irrespective of a true detection of ventilator threshold that may not actually be identified with accuracy in around 30 % patients, especially with advanced HF [15] and coexistent atrial fibrillation [16]. Also, calculation of VE vs VCO2 slope linear relationship may represent an issue in HF patients with an EOV [17]. Comparison of different methods for measuring VE/VCO2 slope has provided a clear superior utility for the entire measurement rather than the first slope calculation [18, 19]. Mathematically, the VE/VCO2 slope is determined by three factors: the amount of CO2 produced; the physiological dead space/tidal volume ratio (VD/VT) and the PaCO2 and can be explained using the modified alveolar equation.

81 Slope 55

Slope 44

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Dyspnea y= mx+b , b= slope

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0

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Fig. 1 Examples of three different ventilatory responses to exercise with the upper normal range limit identified at 34

(relative to low tidal volume) [13, 20], or intrinsic pulmonary vascular changes and impaired vasoregulation [21, 22] responsible for regional dishomogeneities in lung perfusion [23] and distribution of pulmonary blood flow [24]. Additional hemodynamic factors are an impaired right ventricular (RV) function and pulmonary hypertension that may generate some degree of RV-pulmonary circulation uncoupling [25, 26]. In stable HF patients a reduction in static lung mechanics (i.e., reduced vital capacity and forced expiratory volume in 1 sec) [13] is a common finding. The occurrence of restrictive lung changes is implicated in a lower rate of increase in tidal volume (VT), higher respiratory rate (RR) and dead space to tidal volume ratio (VD/VT) for a given workload [20]. In agreement with an increased dead space ventilation role there is also the demonstration that lung interstitial fibrosis and remodeling of alveolar-capillary membrane is an additional feature of changes occurring at the lung level in these patients [27]. Thus, occurrence of ventilation/ perfusion mismatching and abnormalities in alveolar gas membrane conductance seem to be the pulmonary mediators of an uneven exercise VE in the increased ventilatory requirement during exercise. Recent data from our group obtained in a mixed HF population of both reduced and preserved ejection fractions [26] suggest that an increased slope is predominantly seen in patients that already show some degree of pulmonary hypertension at rest and a linear correlation exists between the entity of ventilation efficiency and impaired pulmonary hemodynamics. Lewis et al., [25] in a group of patients with HFrEF followed up in a pharmacological randomized trial and found that modulation of excess ventilation was closely related to RV function and pulmonary vascular tone. Metabolic Acidosis A limited increase in cardiac output is certainly central to exercise intolerance, and fatigue in these patients. The imbalance between cardiac output and metabolic request by working muscles is basically the development of early lactic acidosis during exercise that may well explain the occurrence of an increased inefficient ventilation since the early stages of exercise.

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Impaired Chemoreflex and Ergoreflex Activity There is no doubt that most of the pathophysiological evidence for an increase in the ventilatory response to exercise is related to an impaired control for breathing. This may occur at several levels and involve the chemoreflex control as well as the increased neural reflexogenic activity arising from working muscle – ergoreceptors [31, 32]. Chemoreflex deregulation is a typical abnormality of chronic HF that may impact even early stages of the disease. In 60 patients with ischaemic heart disease without overt heart failure [33], VE/VCO2 slope was found to correlate with the level of central chemosensitivity and changes in VE/ VCO2 slope after a period of three months exercise training correlated with an improved chemoreflex sensitivity. Although an increased chemoreflex activation in patients with overt HF is well established, it is partially undefined for the relative contributory role of central vs peripheral activation. Interestingly, Ciarka et al. [34] have reported that in heart transplant recipients, central chemoreflexegic activity may reverse to normal instead of a persistent peripheral impairment and this positively correlates with the still abnormal VE/VCO2 during exercise. Overactivation of ergoreceptors (amielinic fibers located in the skeletal muscles) to metabolic bioproducts, such as K+ and H+ [32], triggers a series of reflex responses such as sympathetic activation, vasoconstriction and hyperventilation [35]. Ergoreflex activation independently correlates with VE/ VCO2 slope and inversely with exercise tolerance in HF patients [31]. Notably, the central nervous system processing has been tested to see if it is involved in the deregulated ventilation; nevertheless, Rosen et al. [36] did not find major differences between the regional activation of the brain at rest, after exercise and during isocapnic hyperventilation in HF vs control subjects. Interestingly, in an isolated report [37] of HF patients, leptin, a hormone that is associated with central regulation of satiety and energy, emerged as a marker of increased VE/VCO2 slope likely because it may be involved in the control activity of central chemosensitivity and the respiratory mechanism. VE/VCO2 Slope: Implications for Prognosis and Target of Therapy VEVCO2 slope has been repeatedly found as an independent powerful prognostic marker in HF patients in the large

spectrum of HF with different stages and variable functional limitation. Following the landmark paper published by Mancini et al. [38] in the early 1990s, VE/VCO2 slope prognostic superiority over peak VO2 has been progressively documented and strengthened by a series of studies. As originally proposed by Chua et al. [6] , the large majority of these studies have identified a cut-off of 34 as prognostic; VE/ VCO2 slope provides an additive incremental prognostic role in patients with preserved peak VO2 (> 18 ml/min/kg) [8] and in patients with diastolic heart failure [11]. Given the strong amount of evidence accumulated in the last ten years, Arena et al. [10•], proposed a new classification based on VE/VCO2 slope identifying four classes (Fig. 2). The prognostic ability of VE/VCO2 slope increases to some extent when considering the ventilator power (ratio of systolic blood pressure to VE/VCO2 slope), which an easy measure that may reflect 1

0.8

Event free surival

Evidence for a major putative role of lactic acidosis in the augmented ventilatory response is supported by the finding of reduced PaCO2 levels in HF compared to control subjects [28–30] and by the demonstration that patients with a lower PaCO2 at peak exercise are those exposed to a high risk of death [27]. This mechanism is nevertheless debated. Wensel et al. [24] showed that during the recovery phase of exercise, high levels of lactate do not correlate with VE/VCO2 slope.

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VE/VCO2slope 30.0-35.9 149

22 (3 LVAD implantations)

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VE/VCO2slope 36.0-44.9 112

72.3% 31 (3 LVAD implantations, 2 heart transplants)

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44.2% 24 (2 LVAD implantations, 5 heart transplants)

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Subjects meeting criteria 144

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Major Cardiac Events Percent Event Free 4 (2 Heart transplants) 97.2%

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Fig. 3 a Kaplan-Meier analysis according to VD/VT and PaCO2. A PaCO2 0.22. The worse survival rate was observed when both abnormal variables coexisted. b Inverse signficant correlation between PaCO2 and VE/VCO2 slope in survivors (open symbols) and nonsurvivors (full

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symbols). From Guazzi et al., “Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure,” European Heart Journal, 2005, 26(5):472–80, by permission of Oxford University Press

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chemosensitivity [55]. Similarly, exercise-training programs improve VE efficiency by several mechanisms: (i) reduced sympathetic nerve activity and catecholamine concentration [56], (ii) restoration of normal muscular metabolism [57], (iii) reduction in metabolic mediators involved in ergoreflex activation [58] and (iv) improved alveolar-capillary membrane diffusion properties [52].

of oscillations higher than 15 % amplitude at rest that may persist at least 60 % of the entire exercise duration [3]. This criterion certainly incorporates all phenotypes but lacks in a fine definition of how different phenotypes relate to specific patients categories. Figure 4 shows three different oscillatory patterns with high frequency/amplitude and low length (A), moderate frequency, frequency/amplitude and length (B) and very low frequency, very high amplitude/length (C).

Exercise Oscillatory Ventilation (EOV)

Prognostic Implications

Pathophysiology

Independently of the precise categorization of each EOV phenotype and the criteria used for its definition, in all studies

An oscillatory pattern in VE has been characterized under different physiological conditions, during sleep and exercise [59]. These two conditions may coexist in a high rate of patients [60] but the lack of overlap between exercise and sleep manifestations indicates at least in part different pathogenetic mechanisms. Major differences between these two conditions are the lack of apnea periods, typically of sleep, during exercise, with a cyclic up and down of VE that occurs at variable frequency, amplitude and duration accompanied by an oscillatory kinetics in measured gases and definitively leading to a significant degree of exercise limitation and symptoms [61–63]. Nonetheless, ventilatory patterns may share similar mechanisms, and EOV may reflect a less severe form of central sleep apnea or Cheyne-Stokes respiration. Although initial evidence reported EOV as a rare phenomenon [64–66] mostly observed in advanced HF, it is now considered a marker of disease severity even stronger than VE/VCO2 slope itself [61, 62, 67, 68, 69•]. EOV has been recognized in up to 30 % of symptomatic HF patients with a similar rate in HFrEF and HFpEF [5]. Several postulated pathogenetic mechanisms for EOV have been proposed: 1) a low cardiac output that generates an augmented lung to chemoreceptor circulation time [66, 70], with a response time delay in the negative feedback loop that modulates VE and blood gas tension and 2) an impaired ventilator control that leads to excessive VE due to increased central and or peripheral chemoreceptor sensitivity [71]. From a hemodynamic standpoint, a specific role for RV to pulmonary circulation uncoupling [72] and the interstitial pulmonary edema due LV filling pressure with consequent stimulation of vagal irritant receptors have been implicated [73]. Collectively, all these mechanisms seem to interact in determining a complex pathophysiological picture [5] that has a clinical presentation worthy of special attention and tight clinical monitoring. Because of the wide variability in EOV pattern presentations, such as variable frequency, length and amplitude of the oscillations and persistence or disappearance at early/intermediate exercise duration, different EOV classificatory criteria have been proposed [67, 68]. Recent statements have harmonized and simplified the evidence in a broad definition, i.e., the occurrence

Fig. 4 Examples of different EOV patterns with high frequency/amplitude and low length (a), moderate frequency, high amplitude and length (b) and very low frequency, very high amplitude/length (c)

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oscillations invariably emerged as strong and independent prognosticators of outcome [63, 67, 68, 74, 75]. When EOV is present along with other ventilatory abnormalities, especially an increased VE/VCO2 slope, the risk for adverse cardiac event is particularly high [74]. Interestingly, in one study EOV was a strong predictor of sudden cardiac death [69•]. We recently proposed a score system classification based on a combined analysis of the three more studied and most prognostic CPET-derived variables, EOV, VE/VCO2 slope and peak VO2. The analysis performed in 685 patients provided EOV once again as the strongest CPET-derived variable predictor and a multiple level of risk was obtained based on the corresponding level of VE inefficiency and VO2 impairment levels by the VC and Weber classification, respectively. EOV as a Target of Therapy The increased interest for EOV clinical and prognostic significance has stimulated a recent search for potential treatments and modalities to reverse or modulate the oscillatory pattern [72, 76•, 77]. In an ancillary trial performed in a small number of patients with severe HF, Ribeiro and co-workers [65] reported the effectiveness of an inodilator, milrinone, in blunting EOV. In a study from our group [77], we addressed the hypothesis that sildenafil might be effective in modulating the EOV cycle length and amplitude with average changes observed. A beneficial activity was similarly demonstrated and reproduced by Murphy et al. [72] who interestingly showed that improvements in cycle length and amplitude were related to changes in cardiac index. Finally, exercise aerobic training favourably impacted the cyclic oscillation in VE along with improving ventilation efficiency [76•].

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References Papers of particular interest, published recently, have been highlighted as: • Of importance

1. 2.

3.

4.•

5. 6.

7.

8.

9.

10.•

Conclusions HF is a complex syndrome characterized by cardiac dysfunction and impaired regulatory function of multiple organ systems. Exercise limitation is a typical manifestation that is accompanied by dyspnoea and ventilation inefficiency. Characterization of abnormalities in exercise ventilation and their full assessment in clinical daily practice may help clinicians to better define clinical condition and risk stratification.

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13. Compliance with Ethics Guidelines 14. Conflict of Interest Marco Guazzi declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Weber KT, Janicki JS. Cardiopulmonary exercise testing for evaluation of chronic cardiac failure. Am J Cardiol. 1985;55(2):22A–31A. Tumminello G, Lancellotti P, Lempereur M, D'Orio V, Pierard LA. Determinants of pulmonary artery hypertension at rest and during exercise in patients with heart failure. Eur Heart J. 2007;28(5):569–74. Guazzi M, Adams V, Conraads V, Halle M, Mezzani A, Vanhees L, et al. EACPR/AHA Scientific Statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation. 2012;126(18):2261–74. Arena R, Myers J, Guazzi M. The clinical and research applications of aerobic capacity and ventilatory efficiency in heart failure: an evidence-based review. Heart Fail Rev. 2008;13(2):245–69. Interesting review that comprehensively analyzes pathophysiology and prognostic relevance of an impaired ventilatory efficiency during exercise. Guazzi M. Treating exercise oscillatory ventilation in heart failure: the detail that may matter. Eur Respir J. 2012;40(5):1075–7. Chua TP, Clark AL, Amadi AA, Coats AJS. Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1996;27(3):650–7. Robbins M, Francis G, Pashkow FJ, Snader CE, Hoercher K, Young JB, et al. Ventilatory and heart rate responses to exercise Better predictors of heart failure mortality than peak oxygen consumption. Circulation. 1999;100(24):2411–7. Ponikowski P, Francis DP, Piepoli MF, Davies LC, Chua TP, Davos CH, et al. Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance - Marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis. Circulation. 2001;103(7):967–72. Guazzi M, Reina G, Tumminello G, Guazzi MD. Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure. Eur Heart J. 2005;26(5):472–80. Arena R, Myers J, Abella J, Peberdy MA, Bensimhon D, Chase P, et al. Development of a ventilatory classification system in patients with heart failure. Circulation. 2007;115(18):2410–7. Landmark study proposing a new objective classification of dyspnea sensation and prognosis in chronic heart failure by stratifying according to different categories of VE/VCO2 slope response. 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(10):1883–90. Maeder MT, Thompson BR, Htun N, Kaye DM. Hemodynamic determinants of the abnormal cardiopulmonary exercise response in heart failure with preserved left ventricular ejection fraction. J Card Fail. 2012;18(9):702–10. Wasserman K, Zhang YY, Gitt A, Belardinelli R, Koike A, Lubarsky L, et al. Lung function and exercise gas exchange in chronic heart failure. Circulation. 1997;96(7):2221–7. Gitt AK, Wasserman K, Kilkowski C, Kleemann T, Kilkowski A, Bangert M, et al. Exercise anaerobic threshold and Ventilatory efficiency identify heart failure patients for high risk of early death. Circulation. 2002;106(24):3079–84. Agostoni P, Corra U, Cattadori G, Veglia F, Battaia E, La Gioia R, et al. Prognostic value of indeterminable anaerobic threshold in heart failure. Circ Heart Fail. 2013;6(5):977–87.

86 16.

Agostoni P, Emdin M, Corra U, Veglia F, Magri D, Tedesco CC, et al. Permanent atrial fibrillation affects exercise capacity in chronic heart failure patients. Eur Heart J. 2008;29(19):2367–72. 17. Guazzi M. Letter by Guazzi regarding article "Sleep and exertional periodic breathing in chronic heart failure: prognostic importance and interdependence". Circulation. 2006;114(3):e53. author reply e4. 18. Ingle L, Goode K, Carroll S, Sloan R, Boyes C, Cleland JG, et al. Prognostic value of the VE/VCO2 slope calculated from different time intervals in patients with suspected heart failure. Int J Cardiol. 2007;118(3):350–5. 19. Arena R, Humphrey R, Peberdy MA. Prognostic ability of VE/ VCO2 slope calculations using different exercise test time intervals in subjects with heart failure. Eur J Cardiovasc Prev Rehabil : Off J Eur Soc Cardiol Work Groups Epidemiol Prev Card Rehabil Exerc Physiol. 2003;10(6):463–8. 20. Myers J, Salleh A, Buchanan N, Smith D, Neutel J, Bowes E, et al. Ventilatory mechanisms of exercise intolerance in chronic heartfailure. Am Heart J. 1992;124(3):710–9. 21. Reindl I, Wernecke KD, Opitz C, Wensel R, Konig D, Dengler T, et al. Impaired ventilatory efficiency in chronic heart failure: possible role of pulmonary vasoconstriction. Am Heart J. 1998;136(5): 778–85. 22. Lewis GD, Shah RV, Pappagianopolas PP, Systrom DM, Semigran MJ. Determinants of ventilatory efficiency in heart failure: the role of right ventricular performance and pulmonary vascular tone. Circ Heart Fail. 2008;1(4):227–33. 23. Wada O, Asanoi H, Miyagi K, Ishizaka S, Kameyama T, Seto H, et al. Importance of abnormal lung perfusion in excessive exercise ventilation in chronic heart-failure. Am Heart J. 1993;125(3):790–8. 24. Wensel R, Georgiadou P, Francis DP, Bayne S, Scott AC, GenthZotz S, et al. Differential contribution of dead space ventilation and low arterial pCO(2) to exercise hyperpnea in patients with chronic heart-failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 2004;93(3):318–23. 25. Lewis GD, Murphy RM, Shah RV, Pappagianopoulos PP, Malhotra R, Bloch KD, et al. Pulmonary vascular response patterns during exercise in left ventricular systolic dysfunction predict exercise capacity and outcomes. Circ Heart Fail. 2011;4(3):276–85. 26. Guazzi M, Cahalin LP, Arena R. Cardiopulmonary exercise testing as a diagnostic tool for the detection of left-sided pulmonary hypertension in heart failure. J Card Fail. 2013;19(7):461–7. 27. Guazzi M, Reina G, Tumminello G, Guazzi MD. Alveolar-capillary membrane conductance is the best pulmonary function correlate of exercise ventilation efficiency in heart failure patients. Eur J Heart Fail. 2005;7(6):1017–22. 28. Wilson JR, Ferraro N, Weber KT. Respiratory gas analysis during exercise as a noninvasive measure of lactate concentration in chronic congestive heart failure. Am J Cardiol. 1983;51(10):1639–43. 29. Hachamovitch R, Brown HV, Rubin SA. Respiratory and circulatory analysis of CO2 output during exercise in chronic heart failure. Circulation. 1991;84(2):605–12. 30. Perego GB, Marenzi GC, Guazzi M, Sganzerla P, Assanelli E, Palermo P, et al. Contribution of PO2, P50, and Hb to changes in arteriovenous O2 content during exercise in heart failure. J Appl Physiol. 1996;80(2):623–31. 31. Ponikowski PP, Chua TP, Francis DP, Capucci A, Coats AJS, Piepoli MF. Muscle ergoreceptor overactivity reflects deterioration in clinical status and cardiorespiratory reflex control in chronic heart failure. Circulation. 2001;104(19):2324–30. 32. Scott AC, Wensel R, Davos CH, Georgiadou P, Kemp M, Hooper J, et al. Skeletal muscle reflex in heart failure patients - Role of hydrogen. Circulation. 2003;107(2):300–6. 33. Tomita T, Takaki H, Hara Y, Sakamaki F, Satoh T, Takagi S, et al. Attenuation of hypercapnic carbon dioxide chemosensitivity after postinfarction exercise training: possible contribution to the improvement in exercise hyperventilation. Heart. 2003;89(4):404–10.

Curr Heart Fail Rep (2014) 11:80–87 34.

35.

36.

37.

38.

39.

40.

41.

42.•

43.

44.

45.

46. 47.

48.

49.

50.

51.

Ciarka A, Cuylits N, Vachiery JL, Lamotte M, Degaute JP, Naeije R, et al. Increased peripheral chemoreceptors sensitivity and exercise ventilation in heart transplant recipients. Circulation. 2006;113(2):252–7. Piepoli M, Clark AL, Volterrani M, Adamopoulos S, Sleight P, Coats AJS. Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure - Effects of physical training. Circulation. 1996;93(5):940–52. Rosen SD, Murphy K, Leff AP, Cunningham V, Wise RJS, Adams L, et al. Is central nervous system processing altered in patients with heart failure? Eur Heart J. 2004;25(11):952–62. O'Donnell CP, Tankersley CG, Polotsky VP, Schwartz AR, Smith PL. Leptin, obesity, and respiratory function. Respir Physiol. 2000;119(2-3):163–70. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds Jr LH, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation. 1991;83(3):778–86. Forman DE, Guazzi M, Myers J, Chase P, Bensimhon D, Cahalin LP, et al. Ventilatory power: a novel index that enhances prognostic assessment of patients with heart failure. Circ Heart Fail. 2012;5(5):621–6. Ferreira AM, Tabet JY, Frankenstein L, Metra M, Mendes M, Zugck C, et al. Ventilatory efficiency and the selection of patients for heart transplantation. Circ Heart Fail. 2010;3(3):378–86. Wessler BS, Kramer DG, Kelly JL, Trikalinos TA, Kent DM, Konstam MA, et al. Drug and device effects on peak oxygen consumption, 6-minute walk distance, and natriuretic peptides as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction. Circ Heart Fail. 2011;4(5):578–88. Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol. 2004;44:2339–48. First demonstration that acute PDE5 inhibition with sildenafil acutely improves gas diffusion and exercise VE/VCO2 slope. Agostoni P, Guazzi M, Bussotti M, De Vita S, Palermo P. Carvedilol reduces the inappropriate increase of ventilation during exercise in heart failure patients. Chest. 2002;122(6):2062–7. Guazzi M, Agostoni PG. Monitoring gas exchange during a constant work rate exercise in patients with left ventricular dysfunction treated with carvedilol. Am J Cardiol. 2000;85(5):660. Butland RJ, Pang JA, Geddes DM. The selectivity of the betaadrenoceptor for ventilation in man. Br J Clin Pharmacol. 1982;14(5):707–11. Clark AL, Cleland JG. Beta-blockers, exercise, and ventilation in chronic heart failure. J Card Fail. 2005;11(5):340–2. Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, et al. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007;116(14):1555–62. Guazzi M, Vicenzi M, Arena R, Guazzi MD. PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebocontrolled study. Circ Heart Fail. 2011;4(1):8–17. Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol. 2007;50:2136–44. Wong AK, Symon R, AlZadjali MA, Ang DS, Ogston S, Choy A, et al. The effect of metformin on insulin resistance and exercise parameters in patients with heart failure. Eur J Heart Fail. 2012;14(11):1303–10. Jaussaud J, Blanc P, Derval N, Bordachar P, Courregelongue M, Roudaut R, et al. Ventilatory response and peak circulatory power:

Curr Heart Fail Rep (2014) 11:80–87

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

new functional markers of response after cardiac resynchronization therapy. Arch Cardiovasc Dis. 2010;103(3):184–91. Guazzi M, Reina G, Tumminello G, Guazzi MD. Improvement of alveolar-capillary membrane diffusing capacity with exercise training in chronic heart failure. J Appl Physiol. 2004;97(5):1866–73. Arzt M, Schulz M, Wensel R, Montalvan S, Blumberg FC, Riegger GAJ, et al. Nocturnal continuous positive airway pressure improves ventilatory efficiency during exercise in patients with chronic heart failure. Chest. 2005;127(3):794–802. Naughton MT, Liu PP, Benard DC, Goldstein RS, Bradley TD. Treatment of congestive-heart-failure and cheyne-stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med. 1995;151(1):92–7. Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F, Bradley TD. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med. 1995;152(2):473–9. Belardinelli R, Georgiou D, Purcaro A. Low dose dobutamine echocardiography predicts improvement in functional capacity after exercise training in patients with ischemic cardiomyopathy: prognostic implication. J Am Coll Cardiol. 1998;31(5):1027–34. Davey P, Meyer T, Coats A, Adamopoulos S, Casadei B, Conway J, et al. Ventilation in chronic heart-failure - effects of physical-trainig. Br Heart J. 1992;68(5):473–7. Adamopoulos S, Coats AJS, Brunotte F, Arnolda L, Meyer T, Thompson CH, et al. Physical-training improves skeletal-muscle metabolism in patients with chronic heart-failure. J Am Coll Cardiol. 1993;21(5):1101–6. Piepoli MF, Ponikowski PP, Volterrani M, Francis D, Coats AJ. Aetiology and pathophysiological implications of oscillatory ventilation at rest and during exercise in chronic heart failure. Do Cheyne and Stokes have an important message for modern-day patients with heart failure? Eur Heart J. 1999;20(13):946–53. Corra U, Pistono M, Mezzani A, Braghiroli A, Giordano A, Lanfranchi P, et al. Sleep and exertional periodic breathing in chronic heart failure - Prognostic importance and interdependence. Circulation. 2006;113(1):44–50. Sun XG, Hansen JE, Beshai JF, Wasserman K. Oscillatory breathing and exercise gas exchange abnormalities prognosticate early mortality and morbidity in heart failure. J Am Coll Cardiol. 2010;55(17):1814–23. Guazzi M, Myers J, Peberdy MA, Bensimhon D, Chase P, Arena R. Exercise oscillatory breathing in diastolic heart failure: prevalence and prognostic insights. Eur Heart J. 2008;29(22):2751–9. Guazzi M, Boracchi P, Labate V, Arena R, Reina G. Exercise oscillatory breathing and NT-proBNP levels in stable heart failure provide the strongest prediction of cardiac outcome when combining biomarkers with cardiopulmonary exercise testing. J Card Fail. 2012;18(4):313–20. Kremser CB, O'Toole MF, Leff AR. Oscillatory hyperventilation in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy. Am J Cardiol. 1987;59(8):900–5. Ribeiro JP, Knutzen A, Rocco MB, Hartley LH, Colucci WS. Periodic breathing during exercise in severe heart failure.

87

66.

67.

68.

69.•

70.

71.

72.

73.

74.

75.

76.•

77.

Reversal with milrinone or cardiac transplantation. Chest. 1987;92(3):555–6. Bendov I, Sietsema KE, Casaburi R, Wasserman K. Evidence that circulatory oscillations accompany ventilatory oscillations during exercise in patients with heart-failure. Am Rev Respir Dis. 1992;145(4):776–81. Leite JJ, Mansur AJ, de Freitas HFG, Chizola PR, Bocchi EA, Terra M, et al. Periodic breathing during incremental exercise predicts mortality in patients with chronic heart failure evaluated for cardiac transplantation. J Am Coll Cardiol. 2003;41(12):2175–81. Corra U, Giordano A, Bosimini E, Mezzani A, Piepoli M, Coats AJ, et al. Oscillatory ventilation during exercise in patients with chronic heart failure: clinical correlates and prognostic implications. Chest. 2002;121(5):1572–80. Guazzi M, Raimondo R, Vicenzi M, Arena R, Proserpio C, Sarzi Braga S, et al. Exercise oscillatory ventilation may predict sudden cardiac death in heart failure patients. J Am Coll Cardiol. 2007;50(4):299–308. Unique study that addresses the potential of CPX-derived variables to predict cardiac sudden death and identification of EOV as the only variable capable to discriminate it. Yajima T, Koike A, Sugimoto K, Miyahara Y, Marumo F, Hiroe M. Mechanism of periodic breathing in patients with cardiovascular disease. Chest. 1994;106(1):142–6. Ponikowski P, Anker SD, Chua TP, Francis D, Banasiak W, PooleWilson PA, et al. Oscillatory breathing patterns during wakefulness in patients with chronic heart failure - Clinical implications and role of augmented peripheral chemosensitivity. Circulation. 1999;100(24):2418–24. Murphy RM, Shah RV, Malhotra R, Pappagianopoulos PP, Hough SS, Systrom DM, et al. Exercise oscillatory ventilation in systolic heart failure: an indicator of impaired hemodynamic response to exercise. Circulation. 2011;124(13):1442–51. Olson TP, Frantz RP, Snyder EM, O'Malley KA, Beck KC, Johnson BD. Effects of acute changes in pulmonary wedge pressure on periodic breathing at rest in heart failure patients. Am Heart J. 2007;153(1):104. e1-7. Guazzi M, Arena R, Ascione A, Piepoli M, Guazzi MD. Gruppo Studio Fisiologia dE. Exercise oscillatory breathing and increased ventilation to carbon dioxide production slope in heart failure: an unfavorable combination with high prognostic value. Am Heart J. 2007;153(5):859–67. Cahalin LP, Chase P, Arena R, Myers J, Bensimhon D, Peberdy MA, et al. A meta-analysis of the prognostic significance of cardiopulmonary exercise testing in patients with heart failure. Heart Fail Rev. 2013;18(1):79–94. Zurek M, Corra U, Piepoli MF, Binder RK, Saner H, Schmid JP. Exercise training reverses exertional oscillatory ventilation in heart failure patients. Eur Respir J Off J Eur Soc Clin Respir Physiol. 2012;40(5):1238–44. Remarkable demonstration that beneficial effects of aerobic exercise training extend to EOV modulation and reversal. Guazzi M, Vicenzi M, Arena R. Phosphodiesterase 5 inhibition with sildenafil reverses exercise oscillatory breathing in chronic heart failure: a long-term cardiopulmonary exercise testing placebo-controlled study. Eur J Heart Fail. 2012;14(1):82–90.