Author Archives: Paul Older

Prognostic value of 6-min walk test compared to cardiopulmonary exercise test in patients with severe heart failure.

Corrà U; Giordano A; Marcassa C; Gambarin FI; Gnemmi M; Pistono M;

Journal of cardiovascular medicine (Hagerstown, Md.) [J Cardiovasc Med (Hagerstown)] 2022 Jun 01; Vol. 23 (6),
pp. 379-386.

Aims: The 6-min walk test (6MWT) and cardiopulmonary exercise test (CPET) are both predictive in heart failure (HFrEF). Although 6MWT substitutes for CPET in HFrEF patients, as submaximal testing may be preferable, its prognostic superiority still needs to be verified, particularly in regard to beta blockers (BBs). We aimed to compare the prognostic role of CPET and 6MWT and investigate whether BB therapy influences the predictive value.
Methods: This is a single-center, retrospective study. Advanced HFrEF patients were followed up for 3 years: events were cardiovascular death or urgent heart transplantation. We analyzed the predictive capacity of CPET and 6MWT in patients, and subdivided according to use of BBs.
Results: In a group of 251 HFrEF patients, we found a correlation between meters and peak VO2 (r2 = 0.94). Over the 3-year follow-up, 74 events were recorded. Both CPET and 6MWT variables were correlated with outcome at univariate analysis (meter and VE/VCO2 slope, peak VO2, VO2 at ventilatory anaerobic threshold, percentage predicted of peak VO2), but only percentage predicted of peak VO2 (pppVO2) was an independent predictor. In 103 HFrEF patients on BBs (23 nonsurvivors), neither pppVO2 nor meter were predictive, while in 148 patients not treated with BB (51 with events) pppVO2 was selected as an independent prognostic parameter (P = 0.001).
Conclusions: 6MWT is a valid alternative to CPET, although the percentage of predicted of peak VO2 emerged as the strongest predictor. Nonetheless, our results suggest that both functional derived parameters are not predictive among those patients treated with BBs. Further studies are necessary to confirm these findings.


Magr D; Piepoli M; Gallo G; Corr U; Metra M; Paolillo S; Filardi PP; Maruotti A; Assunta.; Salvioni E; Mapelli M; Vignati C; Senni M; Limongelli G; Lagioia R; Scrutinio D; Emdin M; Passino C; Parati G; Sinagra G; Correale M; Badagliacca R; Sciomer S; Di Lenarda A; Agostoni P;

European journal of preventive cardiology [Eur J Prev Cardiol] 2022 May 17.
Date of Electronic Publication: 2022 May 17.

Background: Predicting maximal heart rate (MHR) in heart failure and reduced ejection fraction (HFrEF) still remains a major concern. In such a context, the Keteyian equation is the only one derived in a HFrEF cohort on optimized β-blockers treatment. Therefore, using the Metabolic Exercise combined with Cardiac and Kidney Indexes (MECKI) dataset, we looked for a possible MHR equation, for an external validation of Keteyien formula and, contextually, for accuracy of the historical MHR formulas and their relationship with the HR measured at the anaerobic threshold (AT).
Methods and Results: Data from 3,487 HFrEF outpatients on optimized β-blockers treatment from the MECKI dataset were analyzed. Besides excluding all possible confounders, the new equation was derived by using HR data coming from maximal cardiopulmonary exercise test (CPET).The simplified derived equation was [109 – (0.5*age) + (0.5*HR rest) + (0.2*LVEF) – (5 if haemoglobin < 11 g/dL)]. The R2 and the SEE were 0.24 and 17.5 beats·min-1 with a MAPE = 11.9%. The Keteyian equation had a slightly higher mean absolute percentage error (MAPE = 12.3%). Conversely the Fox and Tanaka equations showed extremely higher MAPE values. The range 75-80% of MHR according to the new and the Keteyian equations was the most accurate in identifying the HR at the AT (MAPEs 11.3% to 11.6%).
Conclusions: The derived equation to estimate the MHR in HFrEF patients, by accounting also for the systolic dysfunction degree and anemia, improved slightly the Keteyian formula. Both formulas might be helpful in identifying the true maximal effort during an exercise test and the intensity domain during a rehabilitation program.

The double anaerobic threshold in heart failure: MECKI score database overview.

Rovai S; Zaffalon D; Cittar M; Felli LF; Salvioni E; Galotta A; Mattavelli I; Carriere C; Mapelli M; Merlo M; Vignati C; Sinagra G; Agostoni P;

ESC heart failure [ESC Heart Fail] 2022 May 17.
Date of Electronic Publication: 2022 May 17.

Aims: In heart failure (HF), anaerobic threshold (AT) may be indeterminable but its value held a relevant prognostic role. AT is evaluated joining three methods: V-slope, ventilatory equivalent, and end-tidal methods. The possible non-concordance between the V-slope (met AT) and the other two methods (vent AT) has been highlighted in healthy individuals and named double threshold (DT).
Methods and Results: We reanalysed 1075 cardiopulmonary exercise tests of HF patients recruited in the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score database. We identified DT in 43% of cases. Met AT precedes vent AT being met-ventΔVO 2 221 (interquartile range: 129-319) mL/min. Peak VO 2 , 1307 ± 485 vs. 1343 ± 446 mL/min (63 ± 17 vs. 63 ± 17 percentage of predicted), was similar between DT+ and DT- patients. Differently, DT+ showed a lower ventilatory vs. carbon dioxide production (VE/VCO 2 ) slope (29.6 ± 6.1 vs. 31.0 ± 6.3), a lower peak exercise end-tidal oxygen tension (PetO 2 ) 115.3 (111.5-118.9) vs. 116.4 (112.4-120.2) mmHg, and a higher carbon dioxide tension (PetCO 2 ) 34.2 (30.9-37.1) vs. 32.4 (28.7-35.5) mmHg. Vent AT showed a significant higher VO 2 , 957 ± 318 vs. 719 ± 252 mL/min, VCO 2 , 939 ± 319 vs. 627 ± 226 mL/min, ventilation, 31.0 ± 8.3 vs. 22.5 ± 6.3 L/min, respiratory exchange ratio, 0.98 ± 0.08 vs. 0.87 ± 0.07, PetO 2 , 108 (104-112) vs. 105 (101-109) mmHg, PetCO 2 , 37 (34-40) vs. 36 (33-39) mmHg, and VE/VO 2 ratio, 33.5 ± 6.7 vs. 32.6 ± 6.9, but lower VE/VCO 2 ratio, 33 (30-37) vs. 36 (32-41), compared with met AT. At 2 year survival by Kaplan-Meier analysis, even adjusted for confounders, DT resulted not associated with survival.
Conclusions: Double threshold is frequently observed in HF patients. DT+ is associated to a decreased ventilatory response during exercise.

A case report of profound atrioventricular block in an endurance athlete: how far do you go?

Abela M; Bonello J; Sammut MA;

European heart journal. Case reports [Eur Heart J Case Rep] 2022 May 02; Vol. 6 (5), pp. ytac190.
Date of Electronic Publication: 2022 May 02 (Print Publication: 2022).

Background: Athletes presenting with 1st-degree atrioventricular block (AVB) on 12-lead electrocardiogram (ECG) may present a diagnostic conundrum, especially when significantly prolonged and associated with higher degrees of block. A pragmatic stepwise approach to the evaluation of these patients is, therefore, crucial.
Case Summary: A 19-year-old waterpolo player was referred for assessment of a 1st-degree heart block and one isolated episode of syncope. All other cardiac investigations were within normal limits except for a 24-h ambulatory ECG which showed Mobitz 1 AVB and episodes of 2:1 block occurring in the context of Wenchebach. An electrophysiological study (EPS) was performed which effectively excluded infranodal conductive tissue disease, confirming physiological intranodal block.
Discussion: The increase in vagal tone is one of the physiological adaptations to an increased demand in cardiac output in athletes, which explains the presence of 1st-degree AVB in up to 7.5% of athletes. The presence of 2:1 AVB on 24 h ECG raises doubts whether the 1st-degree AVB on resting ECG is pathological or physiological, especially considering this particular patient had suffered an episode of syncope. When this diagnostic uncertainty persists despite non-invasive investigations, including cardiopulmonary exercise testing, invasive EPS may be required to assess the refractoriness of the AV node and at what level within the cardiac conductive system block occurs. The electrophysiological study can effectively rule out infranodal disease by confirming physiological intranodal block using incremental atrial pacing.

Exercise Capacity in Children and Adolescents With Congenital Heart Disease: A Systematic Review and Meta-Analysis.

Villaseca-Rojas Y; Varela-Melo J; Torres-Castro R; Vasconcello-Castillo L; Mazzucco G; Vilaró J; Blanco I;

Frontiers in cardiovascular medicine [Front Cardiovasc Med] 2022 May 04; Vol. 9, pp. 874700.
Date of Electronic Publication: 2022 May 04 (Print Publication: 2022).

Background: Congenital heart disease (CHD) entails structural defects in the morphogenesis of the heart or its main vessels. Analyzing exercise capacity of children and adolescents with CHD is important to improve their functional condition and quality of life, since it can allow timely intervention on poor prognostic factors associated with higher risk of morbidity and mortality.
Objective: To describe exercise capacity in children and adolescents with CHD compared with healthy controls.
Methods: A systematic review was carried out. Randomized clinical trials and observational studies were included assessing exercise capacity through direct and indirect methods in children and adolescents between 5 and 17 years-old. A sensitive analysis was performed including studies with CHD repaired participants. Additionally, it was sub-analyzed by age range (< and ≥ 12 years old). Two independent reviewers analyzed the studies, extracted the data, and assessed the quality of the evidence.
Results: 5619 articles were found and 21 were considered for the review. Eighteen articles used the direct exercise capacity measurement method by cardiopulmonary exercise test (CPET). The CHD group showed significant differences in peak oxygen consumption (VO 2 peak) with a value of -7.9 ml/Kg/min (95% CI: -9.9, -5.9, p = 0.00001), maximum workload (Wmax) -41.5 (95% CI: -57.9, -25.1 watts, p = 0.00001), ventilatory equivalent (VE/VCO 2) slope 2.6 (95% CI: 0.3, 4.8), oxygen pulse (O 2 pulse)-2.4 ml/beat (95% CI: -3.7, -1.1, p = 0.0003), and maximum heart rate (HRmax) -15 bpm (95% CI: -18, -12 bpm, p = 0.00001), compared with healthy controls. Adolescents (≥ 12 yrs) with CHD had a greater reduction in VO 2 peak (-10.0 ml/Kg/min (95% CI: -12.0, -5.3), p < 0.00001), Wmax (-45.5 watts (95% CI: -54.4, -36.7), p < 0.00001) and HRmax (-21 bpm (95% CI: -28, -14), p <0.00001).
Conclusion: Suffering CHD in childhood and adolescence is associated with lower exercise capacity as shown by worse VO 2 peak, Wmax, VE/VCO 2 slope, O 2 pulse, and HRmax compared with matched healthy controls. The reduction in exercise capacity was greater in adolescents.

The effect of medium-term recovery status after COVID-19 illness on cardiopulmonary exercise capacity in a physically active adult population.

Ladlow P; O’Sullivan O; Bennett AN; Barker-Davies R; Houston A; Chamley R; May S; Mills D; Dewson D;
Rogers-Smith K; Ward C; TayloJ;Mulae J; Naylor J; Nicol ED; Holdsworth DA;

Journal of applied physiology (Bethesda, Md. : 1985) [J Appl Physiol (1985)] 2022 May 19.
Date of Electronic Publication: 2022 May 19.

Background: A failure to fully recover following coronavirus disease 2019 (COVID-19) may have a profound impact on high functioning populations ranging from front-line emergency services to professional or amateur/recreational athletes.
Aim: To describe the medium-term cardiopulmonary exercise profiles of individuals with ‘persistent symptoms’ and individuals who feel ‘recovered’ after hospitalization or mild-moderate community infection following COVID-19 to an age, sex and job-role matched control group.
Methods: 113 participants underwent cardiopulmonary functional tests at a mean 159±7 days (~5 months) following acute illness; 27 hospitalized with persistent symptoms (hospitalized-symptomatic), 8 hospitalized and now recovered (hospitalized-recovered); 34 community managed with persistent symptoms (community-symptomatic); 18 community managed and now recovered (community-recovered), and 26 controls.
Results: Hospitalized groups had the least favorable body composition (body mass, body mass index and waist circumference) compared to controls. Hospitalized-symptomatic and community-symptomatic individuals had a lower oxygen uptake (V̇O 2 ) at peak exercise (hospitalized-symptomatic, 29.9±5.0ml/kg/min; community-symptomatic, 34.4±7.2ml/kg/min; vs. control 43.9±3.1ml/kg/min, both p<0.001). Hospitalized-symptomatic individuals had a steeper V̇E/V̇CO 2 slope (lower ventilatory efficiency) (30.5±5.3 vs. 25.5±2.6, p=0.003) vs. controls. Hospitalized-recovered had a significantly lower oxygen uptake at peak (32.6±6.6ml/kg/min vs. 43.9 ±13.1ml/kg/min, p=0.015) compared to controls. No significant differences were reported between community-recovered individuals and controls in any cardiopulmonary parameter.
Conclusion: Medium term findings suggest community-recovered individuals did not differ in cardiopulmonary fitness from physically active healthy controls. This suggests their readiness to return to higher levels of physical activity. However, the hospitalized-recovered group and both groups with persistent symptoms had enduring functional limitations, warranting further monitoring, rehabilitation and recovery.

Tricuspid regurgitation management: a systematic review of clinical practice guidelines and recommendations.

Ricci F; Bufano G; Galusko V; Sekar B; Benedetto U; Awad WI; Di Mauro M;
Gallina S; Ionescu A; Badano L; Khanji MY

European Heart Journal Quality of Care & Clinical Outcomes. 8(3):238-248,
2022 May 05.

Tricuspid regurgitation (TR) is a highly prevalent condition and an
independent risk factor for adverse outcomes. Multiple clinical guidelines
exist for the diagnosis and management of TR, but the recommendations may
sometimes vary. We systematically reviewed high-quality guidelines with a
specific focus on areas of agreement, disagreement, and gaps in evidence.
We searched MEDLINE and EMBASE (1 January 2011 to 30 August 2021), the
Guidelines International Network International, Guideline Library,
National Guideline Clearinghouse, National Library for Health Guidelines
Finder, Canadian Medical Association Clinical Practice Guidelines
Infobase, Google Scholar, and websites of relevant organizations for
contemporary guidelines that were rigorously developed (as assessed by the
Appraisal of Guidelines for Research and Evaluation II tool). Three
guidelines were finally retained. There was consensus on a TR grading
system, recognition of isolated functional TR associated with atrial
fibrillation, and indications for valve surgery in symptomatic vs.
asymptomatic patients, primary vs. secondary TR, and isolated TR forms.
Discrepancies exist in the role of biomarkers, complementary multimodality
imaging, exercise echocardiography, and cardiopulmonary exercise testing
for risk stratification and clinical decision-making of progressive TR and
asymptomatic severe TR, management of atrial functional TR, and choice of
transcatheter tricuspid valve intervention (TTVI). Risk-based thresholds
for quantitative TR grading, robust risk score models for TR surgery,
surveillance intervals, population-based screening programmes, TTVI
indications, and consensus on endpoint definitions are lacking.

Characterization of hemodynamic and metabolic abnormalities in the heart failure spectrum: the role of combined cardiopulmonary and exercise echocardiography stress test. [Review]

Pugliese NR; DE Biase N; Balletti A; Filidei F; Pieroni A; D’Angelo G;
Armenia S; Mazzola M; Gargani L; Del Punta L; Asomov M; Cerri E; Franzoni F;
Nesti L; Mengozzi A; Paneni F; Masi S

Minerva Cardiology and Angiology. 70(3):370-384, 2022 Jun.

Heart failure (HF) is a complex clinical syndrome characterized by
different etiologies and a broad spectrum of cardiac structural and
functional abnormalities. Current guidelines suggest a classification
based on left ventricular ejection fraction (LVEF), distinguishing HF with
reduced (HFrEF) from preserved (HFpEF) LVEF. HF should also be thought of
as a continuous range of conditions, from asymptomatic stages to
clinically manifest syndrome. The transition from one stage to the next is
associated with a worse prognosis. While the rate of HF-related
hospitalization is similar in HFrEF and HFpEF once clinical manifestations
occur, accurate knowledge of the steps and risk factors leading to HF
progression is still lacking, especially in HFpEF. Precise hemodynamic and
metabolic characterization of patients with or at risk of HF may help
identify different disease trajectories and risk factors, with the
potential to identify specific treatment targets that might offset the
slippery slope towards overt clinical manifestations. Exercise can unravel
early metabolic and hemodynamic alterations that might be silent at rest,
potentially leading to improved risk stratification and more effective
treatment strategies. Cardiopulmonary exercise testing (CPET) offers
valuable aid to investigate functional alterations in subjects with or at
risk of HF, while echocardiography can assess cardiac structure and
function objectively, both at rest and during exercise (exercise stress
echocardiography [ESE]). The purpose of this narrative review was to
summarize the potential advantages of using an integrated CPET-ESE
evaluation in the characterization of both subjects at risk of developing
HF and patients with stable HF.

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

Apostolo A; Vignati C; Della Rocca M; De Martino F; Berna G; Campodonico
J; Contini M; Muratori M; Palermo P; Mapelli M; Alimento M; Pezzuto B;
Agostoni P

Journal of Cardiac Failure. 28(3):509-514, 2022 03.

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

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.

Preoperative physical performance as predictor of postoperative outcomes in patients aged 65 and older scheduled for major abdominal cancer surgery: A systematic review.

Argillander TE; Heil TC; Melis RJF; van Duijvendijk P; Klaase JM;
van Munster BC

BACKGROUND: Abdominal cancer surgery is associated with considerable
morbidity in older patients. Assessment of preoperative physical status is
therefore essential. The aim of this review was to describe and compare
the objective physical tests that are currently used in abdominal cancer
surgery in the older patient population with regard to postoperative

METHODS: Medline, Embase, CINAHL and Web of Science were searched until
31 December 2020. Non-interventional cohort studies were eligible if they
included patients >=65 years undergoing abdominal cancer surgery, reported
results on objective preoperative physical assessment such as
Cardiopulmonary Exercise Testing (CPET), field walk tests or muscle
strength, and on postoperative outcomes.

RESULTS: 23 publications were included (10 CPET, 13 non-CPET including
Timed Up & Go, grip strength, 6-minute walking test (6MWT) and incremental
shuttle walk test (ISWT)). Meta-analysis was precluded due to
heterogeneity between study cohorts, different cut-off points, and
inconsistent reporting of outcomes. In CPET studies, ventilatory anaerobic
threshold and minute ventilation/carbon dioxide production gradient were
associated with adverse outcomes. ISWT and 6MWT predicted outcomes in two
studies. Tests addressing muscle strength and function were of limited
value. No study compared different physical tests.

DISCUSSION: CPET has the ability to predict adverse postoperative
outcomes, but it is time-consuming and requires expert assessment. ISWT or
6MWT might be a feasible alternative to estimate aerobic capacity. Muscle
strength and function tests currently have limited value in risk
prediction. Future research should compare the predictive value of
different physical instruments with regard to postoperative outcomes in
older surgical patients.