Cardiopulmonary exercise testing and heart failure: a tale born from oxygen uptake.

Since 50 years, cardiopulmonary exercise testing (CPET) plays a central role in heart failure (HF) assessment. Oxygen uptake (VO2) is one of the main HF prognostic indicators, then paralleled by ventilation to carbon dioxide (VE/VCO2) relationship slope. Also anaerobic threshold retains a strong prognostic power in severe HF, especially if expressed as a percent of maximal VO2 predicted value. Moving beyond its absolute value, a modern approach is to consider the percentage of predicted value for peak VO2 and VE/VCO2 slope, thus allowing a better comparison between genders, ages, and races. Several VO2 equations have been adopted to predict peak VO2, built considering different populations. A step forward was made possible by the introduction of reliable non-invasive methods able to calculate cardiac output during exercise: the inert gas rebreathing method and the thoracic electrical bioimpedance. These techniques made possible to calculate the artero-venous oxygen content differences (ΔC(a-v)O2), a value related to haemoglobin concentration, pO2, muscle perfusion, and oxygen extraction. The role of haemoglobin, frequently neglected, is however essential being anaemia a frequent HF comorbidity. Finally, peak VO2 is traditionally obtained in a laboratory setting while performing a standardized physical effort. Recently, different wearable ergo-spirometers have been developed to allow an accurate metabolic data collection during different activities that better reproduce HF patients' everyday life. The evaluation of exercise performance is now part of the holistic approach to the HF syndrome, with the inclusion of CPET data into multiparametric prognostic scores, such as the MECKI score.

Why Levosimendan Improves the Clinical Condition of Patients With Advanced Heart Failure: A Holistic Approach.

BACKGROUND: In advanced heart failure (HF), levosimendan increases peak oxygen uptake (VO2). We investigated whether peak VO2 increase is linked to cardiovascular, respiratory, or muscular performance changes. METHODS AND RESULTS: Twenty patients hospitalized for advanced HF underwent, before and shortly after levosimendan infusion, 2 different cardiopulmonary exercise tests: (a) a personalized ramp protocol with repeated arterial blood gas analysis and standard spirometry including alveolar-capillary gas diffusion measurements at rest and at peak exercise, and (b) a step incremental workload cardiopulmonary exercise testing with continuous near-infrared spectroscopy analysis and cardiac output assessment by bioelectrical impedance analysis.Levosimendan significantly decreased natriuretic peptides, improved peak VO2 (11.3 [interquartile range 10.1-12.8] to 12.6 [10.2-14.4] mL/kg/min, P < .01) and decreased minute ventilation to carbon dioxide production relationship slope (47.7 ± 10.7 to 43.4 ± 8.1, P < .01). In parallel, spirometry showed only a minor increase in forced expiratory volume, whereas the peak exercise dead space ventilation was unchanged. However, during exercise, a smaller edema formation was observed after levosimendan infusion, as inferable from the changes in diffusion components, that is, the membrane diffusion and capillary volume. The end-tidal pressure of CO2 during the isocapnic buffering period increased after levosimendan (from 28 ± 3 mm Hg to 31 ± 2 mm Hg, P < .01). During exercise, cardiac output increased in parallel with VO2. After levosimendan, the total and oxygenated tissue hemoglobin, but not deoxygenated hemoglobin, increased in all exercise phases. CONCLUSIONS: In advanced HF, levosimendan increases peak VO2, decreases the formation of exercise-induced lung edema, increases ventilation efficiency owing to a decrease of reflex hyperventilation, and increases cardiac output and muscular oxygen delivery and extraction.

Technology and technique for left ventricular assist device optimization: A Bi-Tech solution.

BACKGROUND: We investigated the synergistic effect of the new cone-bearing design of Jarvik 2000 (Jarvik Heart Inc., NY) together with a minimally-invasive approach to outcomes of LVAD patients. METHODS: We retrospectively reviewed all patients from 5 institutions involved in the Jarvik 2000 Italian Registry, from October 2008 to October 2016. Patients were divided into three groups according to pump design and implantation technique: pin-bearing design and conventional approach (Group 1); cone-bearing and conventional approach (Group 2); cone-bearing and minimally-invasive implantation (Group 3). RESULTS: A total of 150 adult patients with end-stage heart failure were enrolled: 26 subjects in Group 1, 74 in Group 2, and 50 in Group 3. Nineteen patients (73%) in Group 1, 51 (69%) in Group 2, and 36 (72%) in Group 3 were discharged. During follow-up, 22 patients underwent transplantation, while in 3 patients the LVAD was explanted. The overall 1-year survival was 58 ± 10%, 64 ± 6%, and 74% ± 7% in Groups 1, 2, and 3, respectively (p = 0.034). The competing-risks-adjusted cumulative incidence rate for adverse events was 42.1 [27-62.7] per 100 patient-years in Group 1, 35.4 [25.3-48.2] in Group 2, and 22.1 [12.4-36.4] in Group 3 (p = 0.046 for Group 1 vs. 3). CONCLUSIONS: The association of the modern cone-bearing configuration of Jarvik 2000 and minimally invasive surgery improved survival and minimized the risk for cardiovascular events, as a result of combining technology and technique.

ACE-Inhibition Benefit on Lung Function in Heart Failure is Modulated by ACE Insertion/Deletion Polymorphism.

PURPOSE: The benefit of angiotensin converting enzyme (ACE) inhibition in chronic heart failure (HF) is partially due to its effects on pulmonary function and particularly on lung diffusion, the latter being counteracted by acetylsalicylic acid (ASA). Tissue ACE activity is largely determined by an insertion/deletion (I/D) polymorphism resulting in three possible genotypes (DD, ID and II). It is not clear if ACE inhibitor therapy could exert different effects in these genotypes. The aim of the study was to understand whether I/D polymorphism interferes with ACE inhibitor's protection of the lungs in HF during acute fluid overload. METHODS: 100 HF patients (left ventricular ejection fraction ≤40 %) in stable clinical conditions, treated with enalapril but without ASA performed pulmonary function tests including lung diffusion (DLco) and its subcomponents, membrane diffusion (Dm) and capillary volume (Vcap), and a cardiopulmonary exercise test before and immediately after rapid infusion of 500 cc saline. RESULTS: ACE I/D genotype prevalence was: DD = 28, ID =55 and II = 17 cases. No significant differences in major pulmonary function and exercise parameters were observed before saline infusion among ACE genotypes. After fluid challenge, DD patients presented a higher DLco and Dm reduction than ID and II (DLco -2.3 ± 1.3 vs. -0.8 ± 1.9 and -0.6 ± 1 mL/mmHg/min, p < 0.0001 and p < 0.01; Dm -7 ± 5 vs. -3.2 ± 7.4 and -1.3 ± 5 mL/mmHg/min, p < 0.05, respectively) and a higher increase in VE/VCO2 slope than II (1.8 ± 1.9 vs. -0.8 ± 2.3, p = 0.01). CONCLUSIONS: ACE DD genotype is associated with higher vulnerability of the alveolar-capillary membrane to acute fluid overload in HF patients treated with ACE inhibitors.

The effects of anesthesia, muscle paralysis, and ventilation on the lung evaluated by lung diffusion for carbon monoxide and pulmonary surfactant protein B.

BACKGROUND: An increased alveolar-arterial oxygen tension difference is frequent in anesthetized patients. In this study, we evaluated the effect on the lung of anesthesia, muscle paralysis, and a brief course of mechanical ventilation. METHODS: Lung diffusion for carbon monoxide (DLCO), including pulmonary capillary blood volume (Vc) and conductance of the alveolar-capillary membrane (DM), and pulmonary surfactant protein type B (a marker of alveolar damage) were measured in 45 patients without pulmonary disease undergoing extrathoracic surgery. RESULTS: Anesthesia, muscle paralysis, and mechanical ventilation led to impairment of gas exchange, with a reduction of DLCO values immediately after anesthetic induction due to a concomitant reduction of both DM and Vc. While changes in DM were due to the reduction of lung volume, changes in Vc were not limited to volume loss, since the Vc/alveolar volume ratio decreased significantly. Although DLCO and its components decreased immediately after induction, none of the values decreased further at 1 and 3 hours. Surfactant protein type B, however, was unchanged immediately after anesthesia but increased at 1 hour after induction and further increased after 3 hours of anesthesia. The level of alveolar damage correlated with the reduction of lung perfusion and lung dynamic strain (i.e., ratio between tidal volume and end-expiratory lung volume). CONCLUSIONS: A brief course of anesthesia and controlled ventilation leads to: (1) alveolar damage, which is correlated with lung strain and perfusion, and (2) impaired gas exchange mainly due to volume loss but also to reduced aerated lung perfusion.

Acetazolamide and inhaled carbon dioxide reduce periodic breathing during exercise in patients with chronic heart failure.

BACKGROUND: Periodic breathing (PB) during sleep and exercise in heart failure (HF) is related to respiratory acid-base status, CO2 chemosensitivity, and temporal dynamics of CO2 and O2 sensing. We studied inhaled CO2 and acetazolamide to alter these factors and reduce PB. METHODS AND RESULTS: We measured expired and arterial gases and PB amplitude and duration in 20 HF patients during exercise before and after acetazolamide given acutely (500 mg intravenously) and prolonged (24 hours, 2 g orally), and we performed overnight polysomnography. We studied CO2 inhalation (1%-2%) during constant workload exercise. PB disappeared in 19/20 and 2/7 patients during 2% and 1% CO2. No changes in cardiorespiratory parameters were observed after acute acetazolamide. With prolonged acetazolamide at rest: ventilation +2.04 ± 4.0 L/min (P = .001), tidal volume +0.11 ± 1.13 L (P = .003), respiratory rate +1.24 ± 4.63 breaths/min (NS), end-tidal PO2 +4.62 ± 2.43 mm Hg (P = .001), and end-tidal PCO2 -2.59 ± 9.7 mm Hg (P < .001). At maximum exercise: Watts -10% (P < .02), VO2 -61 ± 109 mL/min (P = .04) and VCO2 101 ± 151 mL/min (P < .02). Among 20 patients, PB disappeared in 1 and 7 subjects after acute and prolonged acetazolamide, respectively. PB was present 80% ± 26, 65% ± 28, and 43% ± 39 of exercise time before and after acute and prolonged acetazolamide, respectively. Overnight apnea/hypopnea index decreased from 30.8 ± 83.8 to 21.1 ± 16.9 (P = .003). CONCLUSIONS: In HF, inhaled CO2 and acetazolamide reduce exercise PB with additional benefits of acetazolamide on sleep PB.

Deceived by the Fick principle: blood flow distribution in heart failure.

AIMS: The Fick principle states that oxygen uptake (V̇O2) is cardiac output (Qc)*arterial-venous O2 content difference [ΔC(a-v)O2]. Blood flow distribution is hidden in Fick principle and its relevance during exercise in heart failure (HF) is undefined.To highlight the role of blood flow distribution, we evaluated peak-exercise V̇O2, Qc and ΔC(a-v)O2, before and after HF therapeutic interventions. METHODS: Symptoms-limited cardiopulmonary exercise tests with Qc measurement (inert-gas-rebreathing) was performed in 234 HF patients before and 6 months after successful exercise training, cardiac-resynchronization therapy or percutaneous-edge-to-edge mitral valve repair. RESULTS: Considering all tests (n=468) a direct correlation between peakV̇O2 and peakQc (R2=0.47) and workload (R2=0.70) were observed. Patients were grouped according to treatment efficacy in group 1 (peakV̇O2 increase >10%, n=93), group 2 (peakV̇O2 change between 0 and 10%, n=60) and group 3 (reduction in peakV̇O2, n=81). Post-treatment peakV̇O2 changes poorly correlated with peakQc and peakΔC(a-v)O2 changes. Differently, post-procedures peakQc vs. peakΔC(a-v)O2 changes showed a close negative correlation (R2=0.46), becoming stronger grouping patients according to peakV̇O2 improvement (R2=0.64, 0.79 and 0.58 in group 1, 2 and 3, respectively). In 76% of patients peakQc and ΔC(a-v)O2 changes diverged regardless of treatment. CONCLUSION: The bulk of these data suggests that blood flow distribution plays a pivotal role on peakV̇O2 determination regardless of HF treatment strategies. Accordingly, for assessing HF treatment efficacy on exercise performance the sole peakV̇O2 may be deceptive and the combination of V̇O2, Qc and ΔC(a-v)O2, must be considered.

This study aimed to understand how oxygen uptake during exercise is affected by heart failure therapeutic intervention. We evaluated 234 heart failure patients before and after treatments such as exercise training, cardiac resynchronization therapy, or mitral valve repair, finding that changes in oxygen uptake were poorly correlated with changes in cardiac output and oxygen content difference between arteries and veins. However, we observed a strong negative correlation between changes in cardiac output and oxygen content difference, especially in patients with significant improvement in oxygen uptake. This suggests that blood flow distribution is crucial for oxygen uptake during exercise, regardless of treatment. Therefore, relying solely on oxygen uptake may not accurately assess treatment effectiveness, and considering a combination of oxygen uptake, cardiac output, and oxygen content difference is important. Oxygen uptake during exercise was strongly related to cardiac output and workload.Changes in cardiac output and oxygen content difference were closely related after treatments, especially in patients with significant improvement in oxygen uptake.

Exercise oscillatory ventilation: the past, present, and future.

Exercise oscillatory ventilation (EOV) is a fascinating event that can be appreciated in the cardiopulmonary exercise test and is characterized by a cyclic fluctuation of minute ventilation, tidal volume, oxygen uptake, carbon dioxide production, and end-tidal pressure for oxygen and carbon dioxide. Its mechanisms stem from a dysregulation of the normal control feedback of ventilation involving one or more of its components, namely, chemoreflex delay, chemoreflex gain, plant delay, and plant gain. In this review, we intend to breakdown therapeutic targets according to pathophysiology and revise the prognostic value of exercise oscillatory ventilation in the setting of heart failure and other diagnoses.

Determinants of exercise performance in heart failure patients with extremely reduced cardiac output and left ventricular assist device.

The evaluation of exercise capacity and cardiac output (QC) is fundamental in the management of patients with advanced heart failure (AdHF). QC and peak oxygen uptake (VO2) have a pivotal role in the prognostic stratification and in the definition of therapeutic interventions, including medical therapies and devices, but also specific treatments such as heart transplantation and left ventricular assist device (LVAD) implantation. Due to the intertwined relationship between exercise capacity and daily activities, exercise intolerance dramatically has impact on the quality of life of patients. It is a multifactorial process that includes alterations in central and peripheral haemodynamic regulation, anaemia and iron deficiency, pulmonary congestion, pulmonary hypertension, and peripheral O2 extraction. This paper aims to review the pathophysiological background of exercise limitations in HF patients and to examine the complex physiology of exercise in LVAD recipients, analysing the interactions between the cardiopulmonary system, the musculoskeletal system, the autonomic nervous system, and the pump. We performed a literature review to highlight the current knowledge on this topic and possible interventions that can be implemented to increase exercise capacity in AdHF patients-including administration of levosimendan, rehabilitation, and the intriguing field of LVAD speed changes. The present paper confirms the role of CPET in the follow-up of this peculiar population and the impact of exercise capacity on the quality of life of AdHF patients.

Beyond VO2: the complex cardiopulmonary exercise test.

Cardiopulmonary exercise test (CPET) is a valuable diagnostic tool with a specific application in heart failure (HF) thanks to the strong prognostic value of its parameters. The most important value provided by CPET is the peak oxygen uptake (peak VO2), the maximum rate of oxygen consumption attainable during physical exertion. According to the Fick principle, VO2 equals cardiac output (Qc) times the arteriovenous content difference [C(a-v)O2], where Ca is the arterial oxygen and Cv is the mixed venous oxygen content, respectively; therefore, VO2 can be reduced both by impaired O2 delivery (reduced Qc) or extraction (reduced arteriovenous O2 content). However, standard CPET is not capable of discriminating between these different impairments, leading to the need for 'complex' CPET technologies. Among non-invasive methods for Qc measurement during CPET, inert gas rebreathing and thoracic impedance cardiography are the most used techniques, both validated in healthy subjects and patients with HF, at rest and during exercise. On the other hand, the non-invasive assessment of peripheral muscle perfusion is possible with the application of near-infrared spectroscopy, capable of measuring tissue oxygenation. Measuring Qc allows, by having haemoglobin values available, to discriminate how much any VO2 deficit depends on the muscle, anaemia or heart.

The importance of re-evaluating the risk score in heart failure patients: An analysis from the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score database.

BACKGROUND: The role of risk scores in heart failure (HF) management has been highlighted by international guidelines. In contrast with HF, which is intrinsically a dynamic and unstable syndrome, all its prognostic studies have been based on a single evaluation. We investigated whether time-related changes of a well-recognized risk score, the MECKI score, added prognostic value. MECKI score is based on peak VO2, VE/VCO2 slope, Na+, LVEF, MDRD and Hb. METHODS: A multi-centre retrospective study was conducted involving 660 patients who performed MECKI re-evaluation at least 6 months apart. Based on the difference between II and I evaluation of MECKI values (MECKI II - MECKI I = ∆ MECKI) the study population was divided in 2 groups: those presenting a score reduction (∆ MECKI <0, i.e. clinical improvement), vs. patients presenting an increase (∆ MECKI >0, clinical deterioration). RESULTS: The prognostic value of MECKI score is confirmed also when re-assessed during follow-up. The group with improved MECKI (366 patients) showed a better prognosis compared to patients with worsened MECKI (294 patients) (p < 0.0001). At 1st evaluation, the two groups differentiated by LVEF, VE/VCO2 slope and blood Na+ concentration, while at 2nd evaluation they differentiated in all 6 parameters considered in the score. The patients who improved MECKI score, improved in all components of the score but hemoglobin, while patients who worsened the score, worsened all parameters. CONCLUSIONS: This study shows that re-assessment of MECKI score identifies HF subjects at higher risk and that score improvement or deterioration regards several MECKI score generating parameters confirming the holistic background of HF.

International validation of the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score in heart failure.

AIMS: Current European heart failure (HF) guidelines suggest the use of risk score: among them, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score has demonstrated to be one of the most accurate. However, the risk scores are still poorly implemented in clinical practice, also due to the lack of strong evidence regarding their external validation in different populations. Thus, the current study was designed as an external validation test of the MECKI score in an international multicentre setting. METHODS AND RESULTS: The study cohort consisted of patients diagnosed with HF with reduced ejection fraction (HFrEF) across international centres (not Italian), retrospectively recruited. Collected data included demographics, HF aetiology, laboratory testing, electrocardiogram (ECG), echocardiographic findings, and cardiopulmonary exercise testing (CPET) results as described in the original MECKI score publication. A total of 1042 patients across 8 international centres (7 European and 1 Asian) were included and followed up from 1998 till 2019. Patients were divided according to the calculated MECKI scores into three subgroups: (i) MECKI score <10%, (ii) 10-20%, and (iii) ≥ 20%. Survival analysis comparison among the three MECKI score subgroups showed a worse prognosis in patients with higher MECKI score value: median event-free survival times were 4396 days for MECKI score <10%, 3457 days for 10-20%, and 1022 days for ≥20% (P < 0.0001). Receiver operating characteristic (ROC) curves and area under the ROC curves (AUC) were like those reported in the original internal validation studies. CONCLUSION: In patients diagnosed with HFrEF, the power of the MECKI score was confirmed in terms of prognosis and risk stratification, supporting its implementation as advised by the HF guidelines.

In patients diagnosed with heart failure with reduced ejection fraction, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) risk score underwent an external validation. The MECKI score prognostic power was confirmed in a large population of patients from Europe and Asia. These data support MECKI score implementation, as advised by the 2021 European heart failure guidelines.

Heart failure patients with improved ejection fraction: Insights from the MECKI score database.

AIMS: Improvement of left ventricular ejection fraction is a major goal of heart failure (HF) treatment. However, data on clinical characteristics, exercise performance and prognosis in HF patients who improved ejection fraction (HFimpEF) are scarce. The study aimed to determine whether HFimpEF patients have a distinct clinical phenotype, biology and prognosis than HF patients with persistently reduced ejection fraction (pHFrEF). METHODS AND RESULTS: A total of 7948 patients enrolled in the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score database were evaluated (median follow-up of 1490 days). We analysed clinical, laboratory, electrocardiographic, echocardiographic, exercise, and survival data from HFimpEF (n = 1504) and pHFrEF (n = 6017) patients. The primary endpoint of the study was the composite of cardiovascular death, left ventricular assist device implantation, and urgent heart transplantation. HFimpEF patients had lower HF severity: left ventricular ejection fraction 44.0 [41.0-47.0] versus 29.7 [24.1-34.5]%, B-type natriuretic peptide 122 [65-296] versus 373 [152-888] pg/ml, haemoglobin 13.5 [12.2-14.6] versus 13.7 [12.5-14.7] g/dl, renal function by the Modification of Diet in Renal Disease equation 72.0 [56.7-89.3] versus 70.4 [54.5-85.3] ml/min, peak oxygen uptake 62.2 [50.7-74.1] versus 52.6 [41.8-64.3]% predicted, minute ventilation-to-carbon dioxide output slope 30.0 [26.9-34.4] versus 32.1 [28.0-38.0] in HFimpEF and pHFrEF, respectively (p < 0.001 for all). Cardiovascular mortality rates were 26.6 and 46.9 per 1000 person-years for HFimpEF and pHFrEF, respectively (p < 0.001). Kaplan-Meier analysis showed that HFimpEF had better a long-term prognosis compared with pHFrEF patients. After adjustment for variables differentiating HFimpEF from pHFrEF, except echocardiographic parameters, the Kaplan-Meier curves showed the same prognosis. CONCLUSIONS: Heart failure with improved ejection fraction represents a peculiar group of HF patients whose clinical, laboratory, electrocardiographic, echocardiographic, and exercise characteristics parallel the recovery of systolic function. Nonetheless, these patients remain at risk for adverse outcome.

Marginal donors and organ shortness: concomitant surgical procedures during heart transplantation: a literature review.

Heart transplantation represents the gold standard for end-stage heart failure. However, due to the increasing demand and the shortage of available organs, donor supply remains the main limitation. Marginal donor hearts in high-risk candidates who do not meet standard listing criteria are the only alternative when life expectancy is limited, but their use is still debated. Surgical correction of detected coronary lesions or valvular heart defects allows further enlargement of the number of available organs. In this article, we offer a literature review on this topic and report two marginal donor hearts with angiography evidence of coronary stenosis and preserved ventricular function, which underwent concomitant myocardial revascularization during heart implantation.

Week to week variability of pulmonary capillary blood volume and alveolar membrane diffusing capacity in patients with heart failure.

BACKGROUND: Alveolar-capillary membrane diffusing capacity for carbon monoxide (DMCO) and pulmonary capillary volume (Vcap) can be estimated by the multi-step Roughton and Foster (RF, original method from 1957) or the single-step NO-CO double diffusion technique (developed in the 1980s). The latter method implies inherent assumptions. We sought to determine which combination of the alveolar membrane diffusing capacity for nitric oxide (DMNO) to DMCO ratio, an specific conductance of the blood for NO (θNO) and CO (θCO) gave the lowest week-to-week variability in patients with heart failure. METHODS: 44 heart failure patients underwent DMCO and Vcap measurements on three occasions over a ten-week period using both RF and double dilution NO-CO techniques. RESULTS: When using the double diffusing method and applying θNO = infinity, the smallest week-to-week coefficient of variation for DMCO was 10 %. Conversely, the RF method derived DMCO had a much greater week-to-week variability (2x higher coefficient of variation) than the DMCO derived via the NO-CO double dilution technique. The DMCO derived from the double diffusion technique most closely matched the DMCO from the RF method when θNO = infinity and DMCO = DLNO/2.42. The Vcap measured week-to-week was unreliable regardless of the method or constants used. CONCLUSIONS: In heart failure patients, the week-to-week DMCO variability was lowest when using the single-step NO-CO technique. DMCO obtained from double diffusion most closely matched the RF DMCO when DMCO/2.42 and θNO = infinity. Vcap estimation was unreliable with either method.

Successful Open Chest Epicardial Ablation for Refractory Ventricular Tachycardia in an LVAD Recipient.

A patient with history of dilated cardiomyopathy, a cardiac resynchronization therapy defibrillator, and endocardial ablation presented for refractory ventricular tachycardia 3 years after implantation of a Jarvik 2000 left ventricular assist device (Jarvik Heart, Inc., New York, New York). Open-chest epicardial ablation safely and effectively terminated the arrhythmia, without ventricular tachycardia recurrence at 9-month follow-up and in the absence of complications during the hospital stay. (Level of Difficulty: Advanced.).

Minute ventilation/carbon dioxide production in chronic heart failure.

In chronic heart failure, minute ventilation (V'E) for a given carbon dioxide production (V'CO2 ) might be abnormally high during exercise due to increased dead space ventilation, lung stiffness, chemo- and metaboreflex sensitivity, early metabolic acidosis and abnormal pulmonary haemodynamics. The V'E versus V'CO2 relationship, analysed either as ratio or as slope, enables us to evaluate the causes and entity of the V'E/perfusion mismatch. Moreover, the V'E axis intercept, i.e. when V'CO2 is extrapolated to 0, embeds information on exercise-induced dead space changes, while the analysis of end-tidal and arterial CO2 pressures provides knowledge about reflex activities. The V'E versus V'CO2 relationship has a relevant prognostic power either alone or, better, when included within prognostic scores. The V'E versus V'CO2 slope is reported as an absolute number with a recognised cut-off prognostic value of 35, except for specific diseases such as hypertrophic cardiomyopathy and idiopathic cardiomyopathy, where a lower cut-off has been suggested. However, nowadays, it is more appropriate to report V'E versus V'CO2 slope as percentage of the predicted value, due to age and gender interferences. Relevant attention is needed in V'E versus V'CO2 analysis in the presence of heart failure comorbidities. Finally, V'E versus V'CO2 abnormalities are relevant targets for treatment in heart failure.

Effects of beta-blockers on ventilation efficiency in heart failure.

BACKGROUND: Hyperventilation and consequent reduction of ventilation (VE) efficiency are frequently observed during exercise in heart failure (HF) patients, resulting in an increased slope of VE/carbon dioxide (VE/Vco(2)) relationship. The latter is an independent predictor of HF prognosis. beta-Blockers improve the prognosis of HF patients. We evaluated the effect on the efficiency of VE of a beta(1)-beta(2) unselective (carvedilol) versus a beta(1) selective (bisoprolol) beta-blocker. METHODS: We analyzed consecutive maximal cardiopulmonary exercise tests performed on 572 clinically stable HF patients (New York Heart Association class I-III, left ventricle ejection fraction < or =50%) categorized in 3 groups: 81 were not treated with beta-blocker, 304 were treated with carvedilol, and 187 were treated with bisoprolol. Clinical conditions were similar. RESULTS: The VE/Vco(2) slope was lower in carvedilol- compared with bisoprolol-treated patients (29.7 +/- 0.4 vs 31.6 +/- 0.5, P = .023, peak oxygen consumption adjusted) and with patients not receiving beta-blockers (31.6 +/- 0.7, P = .036). Maximum end-tidal CO(2) pressure during the isocapnic buffering period was higher in patients treated with carvedilol (39.0 +/- 0.3 mm Hg) than with bisoprolol (37.2 +/- 0.4 mm Hg, P < .001) and in patients not receiving beta-blockers (37.2 +/- 0.5 mm Hg, P = .001). CONCLUSIONS: Reduction of hyperventilation, with improvement of VE efficiency during exercise (reduction of VE/Vco(2) slope and increase of maximum end-tidal CO(2) pressure), is specific to carvedilol (beta(1)-beta(2) unselective blocker) and not to bisoprolol (beta(1)-selective blocker).

Relationship of resting hemoglobin concentration to peak oxygen uptake in heart failure patients.

Anemia is frequent in chronic heart failure (HF). To calculate what change in peak oxygen uptake ( VO(2)) should be expected in the event of changes in hemoglobin concentration, we studied the correlation between peak VO(2) and hemoglobin concentration in a large HF population. We carried out retrospective analysis of all cardiopulmonary exercise tests (CPET) performed in our HF Clinic between June 2001 and March 2009 in HF patients who had a resting hemoglobin concentration measurement taken within 7 days of the CPET. We collected 967 CPETs, 704 tests were considered maximal and analyzed. We identified 181 patients (26%) as anemic. Peak VO(2) was lower (P < 0.001) in anemic patients (971 +/- 23 ml/min) compared with nonanemic (1243 +/- 18 ml/min). The slope of the VO(2) vs. hemoglobin ratio was 109 ml/min/g/dl at peak exercise. This correlation remained significant also when several confounding variables were analyzed by multivariate analysis. As an average, each gram of hemoglobin accounts, at peak exercise, for 109 ml/min change in VO(2) which is equivalent to 0.97 ml/min/kg. Therefore, in HF patients anemia treatment should increase VO(2) by 109 ml/min for each g/dl of hemoglobin increase.

Roles of periodic breathing and isocapnic buffering period during exercise in heart failure.

In heart failure, exercise - induced periodic breathing and end tidal carbon dioxide pressure value during the isocapnic buffering period are two features identified at cardiopulmonary exercise testing strictly related to sympathetic activation. In the present review we analysed the physiology behind periodic breathing and the isocapnic buffering period and present the relevant prognostic value of both periodic breathing and the presence/absence of the identifiable isocapnic buffering period.