Author Archives: Paul Older

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.

Lean Mass Loss and Altered Muscular Aerobic Capacity after Bariatric Surgery.

Zhou N; Scoubeau C; Forton K; Loi P; Closset J; Deboeck G; Moraine JJ;
Klass M; Faoro V

Obesity Facts. 15(2):248-256, 2022.

INTRODUCTION: Patients undergoing weight loss surgery do not improve their
aerobic capacity or peak oxygen uptake (VO2peak) after bariatric surgery
and some still complain about asthenia and/or breathlessness. We
investigated the hypothesis that a post-surgery muscular limitation could
impact the ventilatory response to exercise by evaluating the post-surgery
changes in muscle mass, strength, and muscular aerobic capacity, measured
by the first ventilatory threshold (VT).

METHODS: Thirteen patients with obesity were referred to our university
exercise laboratory before and 6 months after bariatric surgery and were
matched by sex, age, and height to healthy subjects with normal weight.
All subjects underwent a clinical examination, blood sampling, and body
composition assessment by dual-energy X-ray absorptiometry, respiratory
and limb muscle strength assessments, and cardiopulmonary exercise testing
on a cyclo-ergometer.

RESULTS: Bariatric surgery resulted in a loss of 34% fat mass, 43%
visceral adipose tissue, and 12% lean mass (LM) (p < 0.001). Absolute
handgrip, quadriceps, or respiratory muscle strength remained unaffected,
while quadriceps/handgrip strength relative to LM increased (p < 0.05).
Absolute VO2peak or VO2peak/LM did not improve and the first VT was
decreased after surgery (1.4 +/- 0.3 vs. 1.1 +/- 0.4 L min-1, p < 0.05)
and correlated to the exercising LM (LM legs) (R = 0.84, p < 0.001).

CONCLUSIONS: Although bariatric surgery has numerous beneficial effects,
absolute VO2peak does not improve and the weight loss-induced LM reduction
is associated to an altered muscular aerobic capacity, as reflected by an
early VT triggering early exercise hyperventilation.

Ongoing Exercise Intolerance Following COVID-19: A Magnetic Resonance-Augmented Cardiopulmonary Exercise Test Study.

Brown JT; Saigal A; Karia N; Patel RK; Razvi Y; Constantinou N; Steeden
JA; Mandal S; Kotecha T; Fontana M; Goldring J; Muthurangu V; Knight DS

Journal of the American Heart Association. 11(9):e024207, 2022 May 03.

Background Ongoing exercise intolerance of unclear cause following
COVID-19 infection is well recognized but poorly understood. We
investigated exercise capacity in patients previously hospitalized with
COVID-19 with and without self-reported exercise intolerance using
magnetic resonance-augmented cardiopulmonary exercise testing.
Methods and Results Sixty subjects were enrolled in this single-center prospective
observational case-control study, split into 3 equally sized groups: 2
groups of age-, sex-, and comorbidity-matched previously hospitalized
patients following COVID-19 without clearly identifiable postviral
complications and with either self-reported reduced (COVIDreduced) or
fully recovered (COVIDnormal) exercise capacity; a group of age- and
sex-matched healthy controls. The COVID reduced group had the lowest peak
workload (79W [Interquartile range (IQR), 65-100] versus controls 104W
[IQR, 86-148]; P=0.01) and shortest exercise duration (13.3+/-2.8 minutes
versus controls 16.6+/-3.5 minutes; P=0.008), with no differences in these
parameters between COVIDnormal patients and controls. The COVIDreduced
group had: (1) the lowest peak indexed oxygen uptake (14.9 mL/minper kg
[IQR, 13.1-16.2]) versus controls (22.3 mL/min per kg [IQR, 16.9-27.6];
P=0.003) and COVIDnormal patients (19.1 mL/min per kg [IQR, 15.4-23.7];
P=0.04); (2) the lowest peak indexed cardiac output (4.7+/-1.2 L/min per
m2) versus controls (6.0+/-1.2 L/min per m2; P=0.004) and COVIDnormal
patients (5.7+/-1.5 L/min per m2; P=0.02), associated with lower indexed
stroke volume (SVi:COVIDreduced 39+/-10 mL/min per m2 versus COVIDnormal
43+/-7 mL/min per m2 versus controls 48+/-10 mL/min per m2; P=0.02). There
were no differences in peak tissue oxygen extraction or biventricular
ejection fractions between groups. There were no associations between
COVID-19 illness severity and peak magnetic resonance-augmented
cardiopulmonary exercise testing metrics. Peak indexed oxygen uptake,
indexed cardiac output, and indexed stroke volume all correlated with
duration from discharge to magnetic resonance-augmented cardiopulmonary
exercise testing (P<0.05).
Conclusions Magnetic resonance-augmented
cardiopulmonary exercise testing suggests failure to augment stroke volume
as a potential mechanism of exercise intolerance in previously
hospitalized patients with COVID-19. This is unrelated to disease severity
and, reassuringly, improves with time from acute illness.

Rheumatoid arthritis T cell and muscle oxidative metabolism associate with exercise-induced changes in cardiorespiratory fitness.

Andonian BJ; Koss A; Koves TR; Hauser ER; Hubal MJ; Pober DM; Lord JM;MacIver NJ; St Clair EW; Muoio DM;
Kraus WE; Bartlett DB;Huffman KM;

Scientific reports [Sci Rep] 2022 May 06; Vol. 12 (1), pp. 7450.
Date of Electronic Publication: 2022 May 06.

Rheumatoid arthritis (RA) T cells drive autoimmune features via metabolic reprogramming that reduces oxidative metabolism. Exercise training improves cardiorespiratory fitness (i.e., systemic oxidative metabolism) and thus may impact RA T cell oxidative metabolic function. In this pilot study of RA participants, we took advantage of heterogeneous responses to a high-intensity interval training (HIIT) exercise program to identify relationships between improvements in cardiorespiratory fitness with changes in peripheral T cell and skeletal muscle oxidative metabolism. In 12 previously sedentary persons with seropositive RA, maximal cardiopulmonary exercise tests, fasting blood, and vastus lateralis biopsies were obtained before and after 10 weeks of HIIT. Following HIIT, improvements in RA cardiorespiratory fitness were associated with changes in RA CD4 + T cell basal and maximal respiration and skeletal muscle carnitine acetyltransferase (CrAT) enzyme activity. Further, changes in CD4 + T cell respiration were associated with changes in naïve CD4 + CCR7 + CD45RA + T cells, muscle CrAT, and muscle medium-chain acylcarnitines and fat oxidation gene expression profiles. In summary, modulation of cardiorespiratory fitness and molecular markers of skeletal muscle oxidative metabolism during exercise training paralleled changes in T cell metabolism. Exercise training that improves RA cardiorespiratory fitness may therefore be valuable in managing pathologically related immune and muscle dysfunction.

Trends of glucose, lactate and ketones during anaerobic and aerobic exercise in subjects with type 1 diabetes: The ACTION-1 Study.

De Ridder F; Ledeganck KJ; De Winter B; Braspenning R; Delbeke D; Renard E; Pozzilli P; Pieralice S; Vissers D;
De Block C;

Diabetes/metabolism research and reviews [Diabetes Metab Res Rev] 2022 May 09, pp. e3537.
Date of Electronic Publication: 2022 May 09.

Background: Exercise is part of type 1 diabetes (T1D) management due to its cardiovascular and metabolic benefits. However, despite using continuous glucose monitoring, many patients are reluctant to exercise because of fear for hypoglycaemia.
Aims: We assessed trends in glucose, lactate and ketones during anaerobic and aerobic exercise in people with T1D and compared incremental area under the curve (AUC) between both exercises.
Methods: Twenty-one men with T1D (median [IQR]: age 29 years [28-38], BMI 24.4 kg/m 2 [22.3-24.9], HbA1c 7.2% [6.7-7.8]), completed a cardiopulmonary exercise test (CPET) and a 60-minute aerobic exercise (AEX) at 60% VO 2 peak on an ergometer bicycle within a 6-week period. Subjects consumed a standardised breakfast (6 kcal/kg, 20.2g CHO/100ml) before exercise without pre-meal insulin and basal insulin for pump users.
Results: During CPET, glucose levels increased, peaking at 331mg/dL [257-392] 1-3h after exercise and reaching a nadir 6h after exercise at 176mg/dL [118-217]. Lactate levels peaked at 6.0mmol/L [5.0-6.6] (max 12.5mmol/L). During AEX, glucose levels also increased, peaking at 305mg/dL [245-336] 80 min after exercise and reaching a nadir 6h after exercise at 211mg/dL [116-222]. Lactate levels rose quickly to a median of 4.3mmol/L [2.7-6.7] after 10 min. Ketone levels were low during both tests (median ≤0.2mmol/L). Lactate, but not glucose or ketone AUC, was significantly higher in CPET compared to AEX (p=0.04).
Conclusions: Omitting pre-meal insulin and also basal insulin in pump users, did prevent hypoglycaemia but induced hyperglycaemia due to a too high carbohydrate ingestion. No ketosis was recorded during or after the exercises.

The effect of breathing an oxygen-enriched mixture on tissue saturation in obese women.

Zawada AE; Juchacz A; Palutka R; Zaleśna K; Drużdż A; Dobrowolska A;Domaszewska K;

Advances in clinical and experimental medicine : official organ Wroclaw Medical University [Adv Clin Exp Med] 2022 May 11. Date of Electronic Publication: 2022 May 11.

Background: Physical activity undertaken in the treatment process additionally increases the oxygen demand of the working muscles. It seems interesting to see whether a delivery of an enriched respiratory mixture can have an impact on lower acidification of working muscles and oxygenation of tissues.
Objectives: To assess tissue saturation and the level of acidification at rest and during exercise while breathing atmospheric air or an oxygen-enriched mixture.
Material and Methods: Tissue saturation and lactate concentration at rest and during exercise were assessed in 18 females with an average body mass index (BMI) of 42 kg/m2. The study regimen was as follows: day 1 – cardiopulmonary exercise testing (CPET) – determination of the threshold load; day 2 – 20 min of physical effort on a cycloergometer (threshold load, breathing atmospheric air); day 3 – 20 min of physical effort on a cycloergometer (threshold load, breathing mixture enriched with oxygen). Saturation measurements were performed in 3 places on the patient’s body by measuring absorbance via near-infrared spectroscopy (NIRS).
Results: A significant decrease in heart rate (HR) at rest was found when using the oxygen-enriched air mixture (Z = 2.1339, p = 0.0328 (effect size (ES) = 0.478)). During the exercise, a significant decrease in saturation was shown only for the midpoint of the quadriceps muscles (Z = 2.1572, p = 0.309 (ES = 0.600)). Medium effect sizes were shown by the difference in resting and exercising lactate concentration change between the experimental models studied (Z = 2.5041, p = 0.0122 (ES = 0.707)). In the experimental models studied, different medium effect sizes were demonstrated in the resting and exercising lactate concentration change.
Conclusions: Oxygen-enriched air mixture contributes to reducing hypoxia in working muscles of obese people. Oxygen supplementation can result in higher physical fitness levels. The implementation of oxygen-enriched air mixture is a promising therapeutic strategy for obese patients who exhibit high lactate concentrations after exercise.

Determinants of exercise capacity in children and adolescents with severe therapy-resistant asthma.

Schindel CS; Schiwe D; Heinzmann-Filho JP; Gheller MF; Campos NE; Pitrez PM; Donadio MVF

Journal of Asthma. 59(1):115-125, 2022 01.

OBJECTIVE: To evaluate the exercise capacity of children and adolescents
with severe therapy resistant asthma (STRA) aiming to identify its main

METHODS: Cross-sectional study including individuals aged 6-18 years with
a diagnosis of STRA. Clinical (age and gender), anthropometric (weight,
height and body mass index) and disease control data were collected. Lung
function (spirometry), cardiopulmonary exercise testing (CPET) and
exercise-induced bronchoconstriction (EIB) test were performed.

RESULTS: Twenty-four patients aged 11.5 +/- 2.6 years were included. The
mean forced expiratory volume in one second (FEV1) was 91.3 +/- 9.2%. EIB
occurred in 54.2% of patients. In CPET, the peak oxygen uptake (VO2peak)
was 34.1 +/- 7.8 mL kg-1 min-1. A significant correlation between
ventilatory reserve and FEV1 (r = 0.57; p = 0.003) was found. Similarly,
there was a significant correlation between CPET and percent of FEV1 fall
in the EIB test for both VE/VO2 (r = 0.47; p = 0.02) and VE/VCO2 (r =
0.46; p = 0.02). Patients with FEV1<80% had lower ventilatory reserve (p =
0.009). In addition, resting heart rate correlated with VO2peak (r=-0.40;
p = 0.04), VE/VO2 (r = 0.46; p = 0.02) and VE/VCO2 (r = 0.48; p = 0.01).

CONCLUSIONS: Exercise capacity is impaired in approximately 30% of
children and adolescents with STRA. The results indicate that different
aspects of aerobic fitness are influenced by distinct determinants,
including lung function and EIB.