Phillip Joseph

This study demonstrates a clinically significant association between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and angina with nonobstructive coronary arteries (ANOCA), with 18% of patients with coronary function testing-confirmed ANOCA meeting diagnostic criteria for ME/CFS. Invasive cardiopulmonary exercise testing (iCPET) in patients with concurrent ME/CFS and ANOCA reveals a primary peripheral, not cardiac, limitation to exercise. These findings highlight the complementary roles of coronary function testing and iCPET for hemodynamic phenotyping in this underrecognized patient population.

Pulmonary hypertension (PH) is defined by elevated mean pulmonary arterial pressure (mPAP). Pulmonary vascular resistance (PVR) and SvO ₂ (mixed venous oxygenation), measured by right heart catheterization (RHC), are key determinants of disease severity and prognosis. The right‐to‐left ventricular (RV/LV) blood‐pool T2 ratio (T2 _RV/LV ) by MRI has been proposed as a surrogate of RV–LV blood oxygenation differences and SvO ₂ . Therefore, we analyzed 31 consecutive patients with PH (precapillary = 13, postcapillary = 6, combined = 12) compared to data from four patients with no PH and 21 healthy subjects. All subjects underwent 1.5 T MRI with cine for RV/LV and atrial volumes and T2 mapping. Blood T2 _RV/LV was measured on mid‐ventricular short‐axis images. Hemodynamic data (including mPAP, PVR, pulmonary arterial wedge pressure (PAWP) and oxygen saturations) were obtained from recent (within 1.5 months) RHC. We found that the T2 _RV/LV was significantly lower in PH patients than in healthy controls (0.76 ± 0.09 vs. 0.91 ± 0.05; p < 0.001) and correlated with pulmonary artery oxygen saturations (SvO ₂ ) ( r = 0.77; p < 0.001). It also correlated with PVR ( ρ = −0.74; p < 0.001), mPAP ( r = –0.54; p < 0.001), RVEF ( r  = –0.61; p < 0.001). In multivariable analysis, T2 _RV/LV independently predicted mPAP ( p < 0.001; R ² = 0.64 with LA volume index and RVEF) and PVR ( p < 0.001; R ² = 0.63 with RVEF). Inter‐ and intra‐observer variability for T2 _RV/LV was excellent ( R = 0.96–0.97). In conclusion, blood T2 _RV/LV independently predicts invasive hemodynamic indices and is a non‐invasive biomarker of SvO ₂ , which might enable noninvasive risk stratification and treatment monitoring in PH.

Impaired PS _Max is associated with worse RV systolic function and outcomes in PAH when compared with conventional 2-D metrics of RV systolic function, while ϴ _Max is progressively oriented longitudinally in PAH patients with RH failure compared to those without RH failure, potentially reflecting an echocardiographic representation of maladaptive RV myofiber reorientation. PS _Max and ϴ _Max represent a powerful and concise way to describe RV systolic function that may prove useful in the care of PAH patients.

Pulmonary arterial hypertension (PAH) is a rare, progressive disease of the pulmonary vasculature that is associated with pulmonary vascular remodeling and right heart failure. While there have been recent advances both in understanding pathobiology and in diagnosis and therapeutic options, PAH remains a disease with significant delays in diagnosis and high morbidity and mortality. Information from invasive cardiopulmonary exercise testing (iCPET) presents an important opportunity to evaluate the dynamic interactions within and between the right heart circulatory system and the skeletal muscle during different loading conditions to enhance early diagnosis, phenotype disease subtypes, and personalize treatment in PAH given the shortcomings of contemporary diagnostic and therapeutic approaches. The purpose of this review is to present the current applications of iCPET in PAH and to discuss future applications of the testing methodology.

Data from invasive CPET (iCPET) revealed long COVID patients have impaired systemic oxygen extraction (EO₂), suggesting impaired mitochondrial ATP production. However, it remains uncertain whether the initial severity of SARS‐CoV‐2 infection has implications on EO₂ and exercise capacity (VO₂) nor has there been assessment of anerobic ATP generation in long COVID patients. iCPET was performed on 47 long COVID patients (i.e., full cohort; n = 8 with severe SARS‐CoV‐2 infection). In a subset of patients (i.e., metabolomic cohort; n = 26) metabolomics on venous and arterial blood samples during iCPET was performed. In the full cohort, long COVID patients exhibited reduced peak EO₂ with reduced peak VO₂ (90 ± 17% predicted) relative to cardiac output (118 ± 23% predicted). Peak VO₂ [88% predicted (IQR 81% ‐ 108%) vs. 70% predicted (IQR 64% ‐ 89%); p = 0.02] and EO₂ [0.59(IQR 0.53–0.62) vs. 0.53(IQR 0.50–0.48); p = 0.01) were lower in severe versus mild infection. In the metabolomic cohort, 12 metabolites were significantly consumed, and 41 metabolites were significantly released (p‐values < 0.05). Quantitative metabolomics demonstrated significant increases in inosine and succinate arteriovenous gradients during exercise. Peak VO₂ was significantly correlated with peak venous succinate (r = 0.68; p = 0.0008) and peak venous lactate (r = 0.49; p = 0.0004). Peak EO₂ and consequently peak VO₂ impact long COVID patients in a severity dependent manner. Exercise intolerance associated with long COVID is defined by impaired aerobic and anaerobic energy production. Peak venous succinate may serve as a potential biomarker in long COVID.

ObjectivesTo report a case-control study of new-onset small fiber neuropathy (SFN) after COVID-19 with invasive cardiopulmonary exercise testing (iCPET). SFN is a critical objective finding in long COVID and amenable to treatment.MethodsA retrospective ...

Background: Post-acute sequelae of COVID-19 (PASC) affect a significant proportion of patients who have previously contracted SARS-CoV-2, with exertional intolerance being a prominent symptom. This study aimed to characterise the invasive haemodynamic abnormalities of PASC-related exertional intolerance using invasive cardiopulmonary exercise testing (iCPET).Study design and intervention: 55 patients were recruited from the Yale Post-COVID-19 Recovery Program, with most experiencing mild acute illness. Supine right heart catheterisation and iCPET were performed on all participants.Main results: The majority (75%) of PASC patients exhibited impaired peak systemic oxygen extraction (pEO₂) during iCPET in conjunction with supranormal cardiac output (CO) (i.e., PASC alone group). On average, the PASC alone group exhibited a “normal” peak exercise capacity,V′O₂(89±18% predicted). ∼25% of patients had evidence of central cardiopulmonary pathology (i.e., 12 with resting and exercise heart failure with preserved ejection fraction (HFpEF) and two with exercise pulmonary hypertension (PH)). PASC patients with HFpEF (i.e., PASC HFpEF group) exhibited similarly impaired pEO₂with well compensated PH (i.e., peakV′O₂and CO >80% respectively) despite aberrant central cardiopulmonary exercise haemodynamics. PASC patients with HFpEF also exhibited increased body mass index of 39±7 kg·m⁻². To examine the relative contribution of obesity to exertional impairment in PASC HFpEF, a control group comprising obese non-PASC group (n=61) derived from a historical iCPET cohort was used. The non-PASC obese patients with preserved peakV′O₂(>80% predicted) exhibited a normal peak pulmonary artery wedge pressure (17±14versus25±6 mmHg; p=0.03) with similar maximal voluntary ventilation (90±12versus86±10% predicted; p=0.53) compared to PASC HFpEF patients. Impaired pEO₂was not significantly different between PASC patients who underwent supervised rehabilitation and those who did not (p=0.19).Conclusions: This study highlights the importance of considering impaired pEO₂in PASC patients with persistent exertional intolerance unexplained by conventional investigative testing. Results of the current study also highlight the prevalence of a distinct high output HFpEF phenotype in PASC with a primary peripheral limitation to exercise.

Approximately 50% of patients who recover from the acute SARS‐CoV‐2 experience Post Acute Sequelae of SARS‐CoV‐2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO₂) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO₂ remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO₂peak‐mild) and severely reduced (EO₂peak‐severe) EO₂ groups according to the median peak EO₂ value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO₂; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO₂ (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO₂ (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO₂peak‐mild exhibited greater DO₂ compared to those with EO₂peak‐severe [42.9 (34.2–41.2) vs. 32.1 (26.8–38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO₂peak‐severe group were involved in inflammatory and fibrotic processes. In the EO₂peak‐mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio‐pulmonary physiologic response. PASC patients with EO₂peak‐severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO₂peak‐mild group, there is enhanced expression of proteins involved in oxidative phosphorylation‐mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.