Novak P;  Brigham and Women’s Hospital, Boston, Massachusetts, USA
Systrom DM; Witte A; Marciano SP; Felsenstein D; Milunsky JM;
Milunsky A; Krier J; Fishman MC

PLoS ONE [Electronic Resource]. 21(1):e0341278, 2026.

INTRODUCTION: Long COVID and myalgic encephalomyelitis/chronic fatigue
syndrome (ME/CFS) are relatively common and disabling multisystem
disorders that share overlapping features, including post-infectious onset
and similar clinical manifestations such as brain fog, fatigue, muscle
pain, and dysautonomia with orthostatic intolerance. These similarities
suggest that Long COVID and ME/CFS may share common pathophysiological
mechanisms, though the underlying mechanisms remain poorly understood,
partly due to the difficulty in quantifying many of the symptoms.

MATERIALS AND METHODS: This retrospective study evaluated Long COVID and
pre-COVID ME/CFS patients who completed autonomic testing between 2018 and
2023 at the Brigham and Women’s Faulkner Hospital Autonomic Laboratory.
The evaluations included autonomic tests (Valsalva maneuver, deep
breathing, tilt-table test, and sudomotor function) with capnography and
transcranial Doppler monitoring of cerebral blood flow velocity (CBFv) in
the middle cerebral artery, neuropathic assessment through skin biopsies
for small fiber neuropathy (SFN), invasive cardiopulmonary exercise
testing (ICPET), and laboratory analyses covering metabolic, inflammatory,
autoimmune, and hormonal profiles.

RESULTS: A total of 143 Long COVID and 170 ME/CFS patients were analyzed
and compared to 73 healthy controls and 290 patients with hypermobile
Ehlers-Danlos syndrome (hEDS). Tests revealed extensive similarities
between Long COVID and ME/CFS, including reduced orthostatic CBFv (92%/88%
in Long COVID/ME/CFS), mild-to-moderate widespread autonomic failure
(95%/89%), presence of SFN (67%/53%), postural tachycardia syndrome (POTS)
(22%/19%), neurogenic orthostatic hypotension (15%/15%) and preload
failure (96%/92%, assessed in 25/66 Long COVID/ME/CFS). Patients with hEDS
exhibited more severe peripheral neurodegeneration compared to the other
groups. Laboratory tests did not distinguish between the conditions.

CONCLUSION: Both Long COVID and ME/CFS demonstrate dysregulation in
cerebrovascular blood flow, autonomic reflexes, and small fiber
neuropathy, suggesting that these conditions may share a common underlying
pathophysiology. However, differing distributions of findings in patients
with hEDS raise the question of whether these conditions represent
distinct but overlapping syndromes or reflect a shared underlying pathway.
Further research is required to clarify the relationship between these
conditions and the potential underlying pathophysiological mechanisms.

Suzuki T; Department of Cardiology, Yokohama City University Graduate School of Medicine.
Iwahashi N; Abe T; Komura N; Abe M; Konishi M; Otsuka F; SuganoT; Ishigami T; Hibi K

Circulation Journal. 90(2):228-231, 2026 Jan 23.
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BACKGROUND: Passive leg lifting (PLL) may serve as a simple alternative to
simulate exercise stress.

METHODS AND RESULTS: We evaluated 33 patients with PH who underwent
PLL-RHC and exercise right heart catheterization (RHC); 25 patients were
classified as having PLL-induced PH (LIPH), demonstrating significant
increases in mean pulmonary arterial pressure (mPAP) and mPAP-cardiac
output slopes. Strong correlations were observed between PLL-RHC and
exercise RHC measurements.

CONCLUSIONS: PLL-RHC may represent a simple method for detecting EIPH.

Sato T; Department of Physical Therapy, Fukushima Medical University, Fukushima City, Japan.
Sagawa S; Kataoka D; Igarashi M; Ishibashi R; Endo Y; Tsubaki A; Tamiya H; Morishita S

Advances in Experimental Medicine & Biology. 1498:271-275, 2026.
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PURPOSE: We aimed to clarify the compensatory changes in oxygenation in
non-active versus active muscles during incremental exercise.

METHODS: Fifteen male volunteers (age, 21.1 +/- 0.5 years) underwent
cardiopulmonary exercise testing (CPET) using a cycle ergometer ramp
protocol, while maintaining the left upper extremity in a drooping
position. We continuously recorded oxygenated hemoglobin (O2Hb),
deoxygenated hemoglobin (HHb), total hemoglobin (THb), and tissue oxygen
saturation (StO2) in the left vastus lateralis (active muscle) and triceps
brachii (non-active muscle), as well as cardiopulmonary parameters, during
the test.

RESULTS: There were significant interactions between time and muscles for
all changes in O2Hb (p < 0.001), HHb (p < 0.001), THb (p < 0.001), and
StO2 (p < 0.001). In the non-active muscle, O2Hb and StO2 remained higher
than at rest until the 40% point of the test, unlike in the active muscle.
HHb increased from the 80% point in the non-active muscle, but it
increased immediately after the start of the test in the active muscle.
THb showed no significant change in the non-active muscle, but it
continued to increase immediately after the start of the test in the
active muscle.

CONCLUSION: During CPET, O2Hb and StO2 in the non-active muscle remained
higher in the low- to moderate-intensity phases than in the rest phase and
decreased in the high-intensity phase, unlike in the active muscle.

Van Hooren B; Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht, the Netherlands.
Souren T; Miqueu F; Bongers BC

Scandinavian Journal of Medicine & Science in Sports. 36(1):e70184, 2026 Jan.

The validity and between-day reliability of cardiopulmonary exercise
testing (CPET) systems remain largely unexplored. We therefore evaluate
the validity and between-day technological and biological reliability of
five popular CPET systems for assessing respiratory variables, substrate
use, and energy expenditure during simulated and real human exercise. The
following systems were assessed: Vyntus CPX, Oxycon Pro, VO2 Master, KORR,
and Calibre. A metabolic simulator was used to simulate breath-by-breath
gas exchange. The values measured by each system (minute ventilation (VE),
breathing frequency (BF), oxygen uptake (VO2), carbon dioxide production
(VCO2), respiratory exchange ratio (RER), energy from carbohydrates and
fats, and total energy expenditure) were compared to the simulated values
to assess the validity. Six well-trained participants cycled 5% below
their first ventilatory threshold on 2 days to verify the validity in
human exercise. Between-session reliability was assessed in both the
simulation and human experiments to determine technological and biological
variability. Absolute percentage errors during the simulations ranged from
0.69% to 5.56% for VE, 0.92% to 1.44% for BF, 3.12% to 7.86% for VO2,
4.07% to 12.1% for VCO2, 1.21% to 6.94% for RER, 2.83% to 48.8% for Kcal
from carbohydrates, 14.1% to 50.3% for Kcal from fats, and 4.21% to 6.98%
for total energy expenditure. Between-session variability during
simulation (i.e., technological variability) ranged from 0.46% to 3.15%
for VO2 and 0.71% to 4.99% for VCO2. The error and between-day variability
of the error for respiratory gas variables, substrate, and energy use
differed substantially between systems. Biological and technological VO2
and VCO2 variability, respectively, accounted for ~60%-70% and 40%-30% of
the variability in repeated human testing.

Abbasi A;  Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA, USA.
Hansen N; Palade J; Paredes D; Meechoovet B; Van Keuren-Jensen
K; Pirrotte P; Stringer WW

Scientific Reports. 16(1):3469, 2026 Jan 26.
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Headings placed by Dr Paul Older not the authors

Background The Persistence of SARS-CoV-2 in tissues has been proposed as a driver of
prolonged symptoms in long COVID. Pulmonary rehabilitation with exercise
training is a well-established intervention for improving symptoms,
functional capacity, and inflammation in chronic cardiorespiratory
diseases. To investigate whether long COVID is associated with persistent
viral or immune-related signals, we analyzed the long RNA profile of
circulating extracellular vesicles (EVs) to determine the presence of
virus-related transcripts and assess changes in response to exercise
training.
Methods Fourteen adults with long COVID participated in this
single-center pilot clinical trial and completed a 10-week aerobic
exercise training program (twenty 1.5 h sessions). Serum-derived EV RNA
profiles were analyzed via sequencing at rest (T0) and peak
cardiopulmonary exercise testing (T1), before (V2) and after (V24)
exercise training.
Results Differentially expressed genes (DEGs) were identified
(q < 0.05), and pathway activation analysis was performed. Serum EVs
carried diverse RNA species, including protein-coding RNAs, long
non-coding RNAs, short non-coding RNAs, and pseudogenes, with no
virus-related RNAs detected. No significant DEGs were identified at rest
between pre- and post-training, nor in response to acute exercise at
pre-training. However, following training, 53 DEGs were found at peak
exercise (V24T1) compared to rest (V24T0), including three upregulated
genes (ANK3, FTO, FCN1) and 50 downregulated genes (TOP 5: MYL9, NRGN,
H2AC6, MAP3K7CL, B2M). These genes were primarily involved in inflammation
and metabolism. Pathway analysis revealed significant regulation of 100
pathways at post-training compared to pre training, predominantly
inactivated, including pathways involved in inflammation (STAT3 signaling)
and metabolism (O-linked glycosylation).
Conclusions Acute exercise and exercise
training modulated EV-associated gene expression in long COVID, primarily
through transcriptional downregulation. Suppression of inflammation- and
immune-related genes post-training highlights potential molecular
mechanisms underlying symptom improvement and identifies candidate
biomarkers of recovery biology in long COVID. Importantly, while exercise
training did not substantially alter EV RNA content at rest, it enhanced
the body’s ability to mount a dynamic EV-mediated molecular response
during exertion, reflecting improved physiological adaptability.

Jiang Y;  School of Medicine, Tongji University, Shanghai, 200065, China.
Shen T; Shi C; Li D; Zhan M; Li G; Qian L; Huang Q; Zheng L;
CheL; Wang L; Shen Y

BMC Cardiovascular Disorders. 26(1):91, 2025 Dec 27.
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BACKGROUND: Acute coronary syndrome (ACS) is a major global health burden
with a high risk of adverse outcomes. Existing predictive models (e.g.,
GRACE) primarily rely on static indicators and focus on short-term
prognosis, limiting their ability to comprehensively assess patient status
and predict long-term mortality. To address the need for improved
long-term risk prediction in this specific patient subgroup, this study
developed and validated a long-term mortality prediction model for ACS
patients incorporating cardiopulmonary exercise testing (CPET) and other
clinical indicators.

METHODS: This retrospective cohort study included ACS patients treated at
Tongji Hospital from January 1, 2007, to December 31, 2018. Demographic
data, medical histories, CPET indicators, laboratory indicators, and other
baseline data were collected, and all-cause mortality was followed up
until June 30, 2023. All data sets were randomly divided into derivation
and validation cohorts in a ratio of 7/3. Least absolute shrinkage and
selection operator regression and Cox multivariate analysis were used to
identify independent risk factors and a risk prediction model was
established using nomograms.

RESULTS: A total of 299 patients were included in this cohort (211 in the
derivation cohort and 88 in the validation cohort), with an average age of
57.00 years, including 280 males (93.6%). The median follow-up time was
3821 days, and 46 cases (15.4%) reached the study endpoint. The derivation
cohort identified four independent predictive factors: age, blood urea
nitrogen (BUN), ejection fraction (EF), and heart rate reserve (HRR), and
a Nomogram scoring model was constructed based on these factors. The model
demonstrated good discrimination in the derivation cohort (C-index: 0.83)
but this decreased in the validation cohort (C-index: 0.72), suggesting
potential overfitting. Time-dependent calibration analysis showed poor
agreement at 5 years in the validation cohort (R2 = 0.1819), but improved
at 10 years (Slope = 0.8006, R2 = 0.5575) and 15 years (R2 = 0.5638). The
model’s applicability is strictly limited to the studied population: a
predominantly male, lower-risk subset of ACS survivors capable of
completing CPET.

CONCLUSIONS: A model based on four readily available variables-age, BUN,
EF, and the key CPET parameter, HRR-may have utility for predicting
long-term all-cause mortality. This model provides a preliminary tool for
the long-term management of a specific subpopulation of acute coronary
syndrome (ACS) survivors, namely a predominantly male, lower-risk cohort
with the capacity to complete CPET. Further external validation in similar
populations is required before prospective clinical application.

Berger L;  Institute of Aerospace Medicine, Cologne, GERMANY
Mulder E; Zange J; Frings-Meuthen P; Frett T; Simon P; Hoenemann
JN; Poczatek MJ; Laurie SS; Huang AS; Macias BR; Jordan J; Tank J;
Rittweger J; Schmitz MT; Pesta D

Medicine & Science in Sports & Exercise. 57(12):2887-2901, 2025 Dec 01.
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PURPOSE: During spaceflight, countermeasures are crucial to counteract
cardiorespiratory and musculoskeletal deconditioning, similar to effects
seen after prolonged immobilization. Within a bed rest study simulating
the effects of microgravity, we investigated the effectiveness of
submaximal aerobic exercise and postexercise venoconstrictive thigh cuffs
(VTC) for maintaining cardiorespiratory fitness and muscle function.

METHODS: Twenty-four males and females were randomly allocated to a
countermeasure ( n = 12, age = 34 +/- 9 yr, body mass index = 22.9 +/- 2.9
kg.m -2 ) or control group ( n = 12, age = 35 +/- 8 yr, body mass index =
23.3 +/- 2.0 kg.m -2 ). Participants underwent 30 d of strict 6degree
head-down tilt (HDT) bed rest. Six days per week, the countermeasure group
completed 60 min of submaximal cycling in HDT position, followed by 6 h of
VTC (50 +/- 5 mm Hg). The control group maintained HDT bed rest without
any countermeasure. Cardiorespiratory fitness and muscle strength were
assessed before and after bed rest via cardiopulmonary exercise testing
and isokinetic dynamometry, respectively.

RESULTS: Peak oxygen uptake was maintained in the countermeasure group
(-106 +/- 148 mL.min -1 ) compared with the control group (-607 +/- 343
mL.min -1 ; P < 0.001). The countermeasure also mitigated the decrease in
plasma volume (countermeasure: -147 +/- 95 mL vs control: -286 +/- 153 mL;
P = 0.014), peak estimated stroke volume (countermeasure: -6 +/- 5 mL vs
control: -21 +/- 13 mL; P < 0.001), and cardiac output (countermeasure:
-0.7 +/- 0.9 L.min -1 vs control: -3.8 +/- 2.1 L.min -1 ; P < 0.001). Both
groups showed reductions in fat-free mass and muscle strength after bed
rest.

CONCLUSIONS: Submaximal exercise with subsequent VTC preserves
cardiorespiratory fitness during bed rest, likely by maintaining peak
stroke volume and cardiac output. However, this countermeasure did not
prevent declines of fat-free mass and muscle strength.

Sabino-Carvalho JL; Department of VA Health Care System, Decatur, GA.
Li S; Mekonnen E; Mammino K; Nocera JR; Park J

Medicine & Science in Sports & Exercise. 57(12):2621-2629, 2025 Dec 01.
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PURPOSE: Parasympathetic reactivation is essential for the rapid decrease
in heart rate following exercise and delayed heart rate recovery (HRR)
post-exercise is linked to poor clinical outcomes. Chronic kidney disease
(CKD) is associated with autonomic dysfunction including reduced
parasympathetic activity. Exercise training may improve parasympathetic
reactivation. Therefore, this study aimed to test whether CKD patients
experience delayed HRR due to impaired vagal reactivation and if 12 wk of
aerobic exercise can improve HRR.

METHODS: Twenty-seven CKD patients (stages III and IV, estimated
glomerular filtration rate 15-59 mL.min -1 .1.73 m -2 ) and 18 age-matched
controls underwent cardiopulmonary exercise testing. HRR was assessed
through heart rate decay (HRR60s) and heart rate variability (HRV) during
the first 60 s of recovery. Recovery kinetics were modeled to calculate
the time constant ( tau ). CKD patients were then randomly assigned to
aerobic exercise or non-aerobic stretching interventions for 12 wk (3 d.wk
-1 ), and cardiopulmonary exercise testing was repeated post-intervention.

RESULTS: CKD patients exhibited significantly blunted HRR60s
(DELTAHRR60s: -11 +/- 4 vs -17 +/- 6 bpm, P = 0.001) and a longer recovery
time constant ( tau : 142 +/- 33 vs 116 +/- 21 s, P = 0.004) compared with
controls. HRV indices increased less post-exercise in CKD patients
compared with controls (DELTARMSSD: 0.3 +/- 1 vs 1.6 +/- 1 ms, P = 0.001).
Twelve weeks of aerobic exercise did not improve HRR60s (DELTAHRR60s: pre
-12 +/- 4 bpm vs post -12 +/- 7 bpm, P = 0.971) or HRV indices (all P >
0.108).

CONCLUSIONS: CKD patients have decreased HRR post-exercise due to
impaired cardiac vagal reactivation. Twelve weeks of aerobic exercise
training did not improve cardiac vagal reactivation. Future studies should
explore different exercise modalities and manipulate training variables
such as intensity, volume, and frequency to assess their potential impact
on cardiac vagal reactivation in patients with CKD.

Belanger N; Department of Cardiology  Gutenberg-University Mainz,  Mainz, Germany.
Zeid S; Velmeden D; Schulz A; Koeck T; Rausch F; Foos B; Kazemi-Asrar F; Lackner KJ;
Gori T; Munzel T; Prochaska JH; Simon P; Wild PS

Cardiovascular Diabetology. 25(1):26, 2026 Jan 08.
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BACKGROUND: Cardiac autonomic dysfunction plays a pivotal role in the
heart failure syndrome. Metabolic dysregulation affects both autonomic
function and heart failure, but these relationships remain incompletely
understood. This study aimed at investigating the role of glucose and
insulin metabolism for parasympathetic reactivation.

METHODS: Data from the MyoVasc study (NCT04064450), a prospective heart
failure cohort study, were analyzed. Participants underwent a highly
standardized 5-hour examination, including venous blood sampling. To
assess the impact of glucose and insulin metabolism (HbA1c, HOMA-IR, and
C-peptide) on parasympathetic reactivation as reflected by heart rate
recovery 60 s (HRR60) after cardiopulmonary exercise testing,
multivariable linear regression models with adjustment for sex, age,
clinical profile (cardiovascular risk factors and comorbidities) and
medication were calculated in cross-sectional and longitudinal settings.
Additional adjustment for complementary glucose or insulin status was
performed to assess the dependency of each other. Analyses were carried
out in symptomatic heart failure and across the spectrum of glucose
metabolism dysfunction.

RESULTS: The analysis sample included 1,588 individuals (median age 64.0
years [IQR 55.0;72.0]; 33% women) in a fasting state. Symptomatic heart
failure was present in 43.7% of the subjects. Median HRR60 was 21.0 beats
per minute (IQR 14.0;28.0). In multivariable regression analysis with
adjustment for age, sex, clinical profile, and medication, both HbA1c
([Formula: see text]per SD -0.074, 95% CI [- 0.122;-0.026], P = 0.003) and
HOMA-IR ([Formula: see text]per SD -0.113 [- 0.165;-0.062], P < 0.0001)
predicted HRR60. Additional adjustment for both glucose and insulin
status, respectively, demonstrated that HOMA-IR ([Formula: see text]per SD
-0.097 [- 0.155;-0.040], P < 0.0001), but not HbA1c ([Formula: see
text]per SD -0.030 [- 0.084;0.025], P = 0.28), was independently related
to HRR60. This finding was confirmed in subgroups with heart failure and
type 2 diabetes. In all analyses, C-peptide was related to HRR60
independently of HbA1c with higher effect estimates than HOMA-IR
([Formula: see text]per SD -0.171 [- 0.225;-0.117], P < 0.0001). Finally,
higher HbA1c ([Formula: see text]per SD -0.094, [- 0.171;-0.017], P =
0.017) and C-peptide ([Formula: see text]per SD -0.076, [- 0.159;0.007], P
= 0.075) were more strongly associated with a lower HRR60 after two years
of follow-up.

CONCLUSIONS: This study demonstrates the relevance of insulin status for
vagal activity of cardiac autonomic function, particularly in heart
failure. The pathophysiological implications underlying the relationship
between insulin status and parasympathetic activity merit further
mechanistic exploration.

Timóteo AT, Department of Cardiology, Santa Marta Hospital,  Lisbon, Portugal
Rosa SA, Branco LM, Galrinho A, Rio PS, Thomas B, Ferreira RC

Int J Cardiovasc Imaging. 2026 Jan 27. doi: 10.1007/s10554-026-03635-7. Online ahead of print.

Right ventricular (RV) to pulmonary arterial (PA) uncoupling measures RV exhaustion. There is limited evidence regarding the association between RV to PA coupling and hypertrophic cardiomyopathy (HCM). Evaluate RV to PA uncoupling in patients with HCM. Prospective cohort study in 62 patients with HCM without obstructive epicardial coronary disease. Echocardiography was used to assess RV to PA coupling as the ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP). Coronary flow reserve in the left anterior descending artery (CVFR_LAD) was a surrogate marker for coronary microvascular dysfunction. Cardiopulmonary exercise testing (CPET) and cardiac magnetic resonance (CMR) were also performed. Mean age was 55 (15) years, 65% males. Mean TAPSE/PASP was 0.56 (0.23). The independent predictors of RV to PA coupling were age (β: - 0.184), left atrial volume index (β: - 0.641), CFVR_LAD (β: 0.183) and the extent of LGE in the LV (β: - 0.262). 43.5% showed reduced exercise tolerance. Independent predictors of peak VO2 were male gender (β: 0.349), age (β: - 0.286), global radial strain (β: 0.249) and TAPSE/PASP (β: 0.253). TAPSE/PASP showed a modest predictive accuracy for peak VO2 < 20 ml/Kg/min (AUC 0.671, p = 0.022), with the best cut-off set at 0.60 mm/mmHg (sensitivity 85% and specificity 47%). A TAPSE / PASP ≤ 0.60 mm/mmHg was present in 66% of patients. In patients with HCM, both coronary microvascular dysfunction and fibrosis are associated with RV to PA coupling, which is a determinant of exercise tolerance.