Lower VO2 Research Articles

Increased myocardial stiffness as assessed by echocardiographic shear wave imaging is associated with Fontan circulatory failure

Abstract Background Diastolic dysfunction with elevated end-diastolic pressures is a key component of Fontan circulatory failure. However, conventional echocardiographic parameters of diastolic function do not correlate with invasive pressures in Fontan patients. Natural shear waves (SW) are emerging as a novel echocardiographic parameter of myocardial stiffness, a key determinant of diastolic function. Purpose We investigated the relationship between natural SW velocities and Fontan circulatory failure. Methods Fontan patients were prospectively recruited from a single center. They underwent a blood sampling for NT-proBNP and cardiopulmonary exercise testing on a supine bicycle combined with echocardiography and with peripheral venous pressure (PVP) measurement. PVP correlates with mean pulmonary arterial pressure in Fontan patients, and a PVP/cardiac output (CO) slope > 3 is associated with worse clinical status. In addition, high frame rate SW imaging was performed at rest in the parasternal long axis view. An anatomic M-mode was drawn along the ventricular septum, or if absent, in the corresponding anterior wall. In the color-coded M-mode maps for tissue acceleration, SW appear as tilted green bands after atrio-ventricular valve closure (AVVC), the slope of which represents their propagation velocity. A clinical diagnosis of Fontan circulatory failure was defined as one the following: dyspnea on exertion with NT-proBNP >300 ng/l, need for diuretics, a peak oxygen consumption (VO2) inferior to the lowest quartile according to age- and sex-adjusted Fontan norms, Fontan associated liver disease complicated by ascites or hepatocellular carcinoma, or protein losing enteropathy. Results Twenty-nine Fontan patients were included, of which 48.3% were female and 82.76% had a dominant left ventricle. The mean age was 33.7 ±8.6 years, the mean peak VO2 19.9 ± 5.9 ml/min/kg and the median NT-proBNP 225 ng/l (IQR 52-473.5). SW velocities increased with age (r = 0.63, p < 0.001) and time since Fontan palliation (r = 0.53, p = 0.005, Figure 1A). In addition, SW velocities significantly correlated with unfavorable clinical parameters: lower peak VO2 (r = -0.76, p < 0.001), elevated NT-proBNP (r = 0.53, p = 0.003) and an increased PVP/CO slope (r = 0.66, p < 0.001) (Figure 1 B-D). Of interest, SW velocities were significantly higher in patients with a clinical diagnosis of Fontan circulatory failure (mean 5.3 vs 7.4 m/sec, p = 0.003, Figure 2A). A cut-off value of 6.3 m/sec had a 90% sensitivity and 84% specificity to predict Fontan circulatory failure (AUC = 0.89; 95% CI [0.77 – 0.99], p = 0.001, Figure 2B). Conclusion Natural SW velocities after AVVC strongly correlated with parameters of Fontan circulatory failure. The preliminary results of this ongoing study highlight the potential of SW elastography in the assessment of patients with a Fontan circulation. Figure 1 Figure 2

Septum displacement implications in the limited cardiac reserve, RV to pc uncoupling and oxygen uptake during exercise in heart failure

Abstract Background Exertional dyspnea is crucial in heart failure (HF) and may be determined by an unfavorable dynamic of ventricular interaction. This concept has been poorly addressed over time and we hypothesized that a careful study of the interventricular septum adaptations during maximal exercise in HF might be implicated in the limited cardiac reserve, uncoupling of right ventricular (RV) to pulmonary circulation (Pc), both yielding to a limited O2 uptake. Aim To address the pathophysiology behind biventricular interaction during exercise in HF, studying the role of l septum displacement during exercise and how and whether it would affect peak exercise oxygen consumption (VO2 peak). Through a limited cardiac output (CO) increase and some degrees of RV to PC uncoupling assessed by TAPSE/PASP. Methods 22 HF underwent a combined cardiopulmonary exercise testing imaging (CPET imaging) with RV 3D-imaging analysis and were compared with a control population. 3D imaging of the RV chamber was examined off-line using the 4D RV TomTec software and obtained 3D mesh of the RV model using custom software to obtain the mean curvature value of IVS in 4 regions of: inflow tract (RVIT), outflow tract (RVOT), apical and body. We acquired measurements of curvature during end-diastole (ED) and at end systole (ES) phases and obtained a parametric curvature map. Results HF patients (mean age 72±12, 27% female) typically exhibited an abnormal septal curve, with a more leftward configuration either at rest and under exercise (rest =−0.01±0.007 at ED, and −0.01±0.009 at ES; peak exercise= −0.01±0.006 at ED, and −0.01±0.007 at ES) compared to controls (rest =−0.02±0.002 at ED, and −0.02±0.006 at ES; peak exercise −0.02±0.0.006 at ED, and −0.02±0.01 at ES, Figure). Notably, the degree of the IVS curvature was found to linearly correlate with an impaired gas exchange performance as showed by a lower peak VO2, a limited CO and impairment of TAPSE/PASP in HF (respectively, r=0.64, p<0.001, r=0.5, p<0.001, r=0.53, p<0.001 at ED during exercise; r=0.61, p<0.001 at ES during exercise; Figure). Conclusions In HF, the occurrence of right to left IVS displacement appears worth of investigation, tightly contributing to a reduced CO response, and RV-PA uncoupling during exercise. These findings clearly point to the utility of assessing how therapeutic strategies may modulate the negative septum displacement and overall cardiac mechanics. RV colorimetric curvature map Septal curvature correlations

Physiological differences in cardiopulmonary exercise testing between children and adults

Purpose: This study examines age- and sex-related physiological differences in cardiopulmonary exercise testing (CPET) between children and adults, focusing on ventilatory thresholds (VT) and oxygen uptake efficiency slope and plateau (OUES; OUEP). Methods: The cross-sectional analysis comprised 24 children (7–11 years), 20 moderately- trained (MTA) and 20 well-trained (WTA) adults (20–30 years). They performed a maximal CPET on a cycle ergometer, while respiratory responses were measured. Linear regression models analyzed differences by age and sex of the key outcome parameters VT1, VT2, OUES and OUEP. Results: Children exhibited higher absolute VO2 at VT1 (d=.66) and VT2 (d=.58) values than MTA but slightly lower VO2 at VT2 values compared to WTA (d=.35). Adults demonstrated higher OUES (MTA: d=.37; WTA: d=1.45) and OUEP (MTA: d=.81; WTA: d=.60) values than children. However, children had higher relative OUES when adjusted for body mass (OUESrel) (MTA: d=.1.80; WTA: d=.87). Males demonstrated higher values as females for VO2 at VT2 (d=.81), OUES (d=.79) and OUEP (d=.41), respectively. In contrast, females had higher VO2 at VT1 (d=.59) and VT2 (d=.44) relative to VO2peak as males. Conclusion: These findings suggest that compared to adults, children rely more on oxidative metabolism, reflected in higher ventilatory thresholds relative to their aerobic capacity. Absolute OUES and OUEP increased with age, but OUESrel values indicate that maturation influences efficiency more than body mass, reflecting underlying metabolic and physiological differences. These age- and sex-specific patterns highlight the need for further longitudinal research to clarify the roles of growth and training on these parameters.

A Study to Quantify the Exercise Stress in Terms of Oxygen Consumption and Anaerobic Threshold in Patients of Suspected Coronary Artery Disease during Conventional Treadmill Testing

ABSTRACT Background: Coronary artery disease (CAD) is one of the leading causes of mortality worldwide, and early detection is crucial for effective management. Exercise stress testing, particularly treadmill testing, is widely used to assess cardiovascular function, with oxygen consumption (VO2) and anaerobic threshold (AT) serving as key indicators of cardiovascular fitness and exertional capacity. The aim of this study is to quantify exercise stress using VO2 and AT in patients with suspected CAD during conventional treadmill testing. These parameters may provide additional insight into the severity of coronary artery blockages and help in predicting cardiovascular events. Objective: The objective of this study is to quantify the exercise stress in terms of oxygen consumption (VO2) and AT in patients with suspected CAD using conventional treadmill testing. Material and Method: The present study was conducted in the Department of Physiology at Jawaharlal Nehru Medical College Sawangi Meghe Wardha Maharashtra. The study included 100 patients with suspected CAD, aged 40 to 70 years. These patients presented with symptoms such as chest pain, breathlessness, or a family history of cardiovascular disease, prompting the need for exercise stress testing. A control group of 50 healthy individuals matched by age and sex was also included for comparison. Result: The study demonstrated that VO2 and AT levels significantly correlated with the presence and severity of CAD in patients. Patients with CAD exhibited lower VO2 levels and earlier onset of anaerobic threshold compared to the healthy control group. The results suggest that these parameters could be used as effective indicators in the early detection of CAD. Conclusion: The study highlights that measuring oxygen consumption and AT during treadmill testing can enhance the assessment of cardiovascular stress and provide valuable prognostic information in patients with suspected CAD.

MicroRNA signatures of VO 2 peak in older adult participants of the Study of Muscle, Mobility and Aging.

Peak oxygen consumption during exercise (VO 2 peak), is a direct measure of cardiorespiratory fitness (CF), a key indicator of physical function and overall health. However, the molecular changes that underpin VO 2 peak variation are not clear. Our objective is to understand the miRNA signatures that relate to VO 2 peak variation, which could provide insights to novel mechanisms that contribute to low VO 2 peak. We used small RNA sequencing to analyze serum samples from 72 participants (70-79 yrs old, 53% female) of the Study of Muscle, Mobility and Aging (SOMMA). We analyzed samples from individuals with low or high VO 2 peak (N=18/group) as well as samples from 36 randomly selected participants spanning the entire spectrum of VO 2 peak. We used LIMMA analysis package for regression analysis and to identify differentially expressed miRNAs. We used receiver operating characteristic curve analysis to evaluate the Area Under the Curve (AUC) and sensitivity and specificity rates. We identified 1,055 miRNAs expressed in all serum samples. Expression of 65 miRNAs differed between participants with low and high VO 2 peak (p < 0.05). After p-value adjustment, expression of 5 miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) remained significantly different (FDR = 0.05). The five miRNAs had AUC ranging from 0.77 to 0.84. The optimal sensitivity and specificity ranged from 70 to 80% and 80 to 90%, respectively. After adjustment for age and sex covariates, 46 miRNAs significantly correlated with VO 2 peak (p < 0.05) and miR-519a-3p remained significant based on adjusted of p-values. We identified a miRNA signature of VO 2 peak in older individuals that might provide insights to novel mechanisms that drive low VO 2 peak. Future studies will validate the findings in a larger, longitudinal study cohort.

Hepatic Steatosis and Fibrosis, Cardiorespiratory Fitness, and Metabolic Mediators in the Community.

Individuals with steatotic liver disease (SLD) are at high cardiovascular disease (CVD) risk, but approaches to characterise and mitigate this risk are limited. By investigating relations, and shared metabolic pathways, of hepatic steatosis/fibrosis and cardiorespiratory fitness (CRF), we sought to identify new avenues for CVD risk reduction in SLD. In Framingham Heart Study (FHS) participants (N = 2722, age 54 ± 9 years, 53% women), vibration-controlled transient elastography (VCTE) was performed between 2016-2019 to assess hepatic steatosis (continuous attenuation parameter [CAP]) and fibrosis (liver fibrosis measure [LSM]). Concurrently, participants underwent maximum effort cardiopulmonary exercise testing (CPET), and metabolomic profiling (201 circulating metabolites) was performed in a subsample (N = 1268). Mean BMI was 28.0 ± 5.3, 27% had hepatic steatosis, 7.6% had fibrosis, and peak oxygen uptake (VO2) was 26.2 ± 6.8 mL/kg/min in men and 20.7 ± 6.0 mL/kg/min in women (95% predicted overall). In linear models adjusted for cardiometabolic risk factors, greater CAP and LSM were associated with lower peak VO2 (p ≤ 0.002 for all), and the CAP association remained significant after BMI adjustment (p < 0.0001). We observed shared metabolic architecture of CAP, LSM, and peak VO2, with metabolites mediating up to 35% (for CAP) and 74% (for LSM) of the association with peak VO2. Metabolite mediators included amino acids and derivatives implicated in cardiometabolic risk and both protective and deleterious lipid species. Hepatic steatosis and fibrosis are associated with CRF impairment in the community, and these relations are partly mediated by pathways of altered lipid metabolism and general cardiometabolic risk.

Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study

ABSTRACTBackgroundPhysical activity is essential for maintaining muscle mitochondrial function and aerobic capacity. The molecular mechanisms underlying such protective effects are incompletely understood, in part because it is difficult to separate the effects of disease status and physical activity. We explored the association of human skeletal muscle transcriptomic with four measures of energetics and mitochondria oxidative capacity in healthy individuals.MethodsUsing RNA sequencing of vastus lateralis muscle biopsies from 82 GESTALT participants (52 males, aged 22–89 years), we explored gene and splicing variant expression profiles associated with self‐reported physical activity, peak oxygen consumption (VO2 peak), muscle oxidative capacity (kPCr) and mitochondrial respiration (Mit‐O2 flux). The effect of aging on gene expression was examined in participants with low and high VO2 peak.ResultsThe four measures of energetics were negative correlated with age and generally intercorrelated. We identified protein‐coding genes associated with four energetic measures adjusting for age, muscle fiber‐ratio, sex and batch effect. Mitochondrial pathways were overrepresented across all energetic variables, albeit with little overlap at the gene level. Alternative spliced transcript isoforms associated with energetics were primarily enriched for cytoplasmic ribonucleoprotein granules. The splicing pathway was up‐regulated with aging in low but not in high fitness participants, and transcript isoforms detected in the low fitness group pertain to processes such as cell cycle regulation, RNA/protein localization, nuclear transport and catabolism.ConclusionsA consistent mitochondrial signature emerged across all energetic measures. Alternative splicing was enhanced in older, low fitness participants supporting the energy‐splicing axis hypothesis. The identified splicing variants were enriched in pathways involving the accumulation of ribonucleoproteins in cytoplasmic granules, whose function remains unclear. Further research is needed to understand the function of these proteoforms in promoting adaptation to low energy availability.

Boys vs men differences in muscular fatigue, muscle and cerebral oxygenation during maximal effort isometric contractions: the effect of muscle blood flow restriction.

To examine whether the children's superiority, over adults, to resist fatigue during repeated maximal-efforts depends on their often-cited oxidative advantage, attributed to greater muscle blood flow and O2-delivery. We also investigated the mechanisms underlying child-adult differences in muscle-oxygenation (due to O2-supply or O2-utilization) and examined if there are age-differences in cerebral-oxygenation response (a brain-activation index). Eleven men (23.3 ± 1.8yrs) and eleven boys (11.6 ± 1.1yrs) performed 15 maximal-effort handgrips (3-s contraction/3-s rest) under two conditions: free-flow circulation (FF) and arterial-occlusion (OCC). Force, muscle-oxygenation (TSImuscle) and cerebral-oxygenation (oxyhemoglobin-O2Hbcerebral; total hemoglobin-tHbcerebral; deoxyhemoglobin-HHbcerebral) were assessed. In boys, force declined less (-26.3 ± 2.6 vs. -34.4 ± 2.4%) and at slower rate (-1.56 ± 0.16 vs. -2.24 ± 0.17%·rep-1) vs. men in FF (p < 0.01-0.05; d = 0.60-1.24). However, in OCC there were no age-differences in the magnitude (-38.3 ± 3.0 vs. -37.8 ± 3.0%) and rate (-2.44 ± 0.26 vs. -2.54 ± 0.26%·rep-1) of force decline. Boys compared to men, exhibited less TSImuscle decline in both protocols, and lower muscle VO2 (p < 0.05). Boys, also, presented a smaller O2Hbcerebral and tHbcerebral rise than men in FF; exercising with OCC increased the O2Hbcerebral and tHbcerebral response in boys. Using MVIC as a covariate in FF condition, abolished boys-men differences in force and TSImuscle decline and O2Hbcerebral rise. During repeated maximal-efforts: (i) blood flow is a significant contributor to children's superiority over adults to resist fatigue; (ii) age-difference in muscle hypoxia/deoxygenation is rather attributed to men's greater metabolic demand than to lower muscle-perfusion; and (iii) cerebral oxygenation/blood volume increase more in men than boys under free circulation, implying greater brain activation.

Abstract 4135001: Right Ventricular Function and Right Ventricular-Pulmonary Arterial Adaptations in Aging Older Adults

Background: Compared to our understanding of left ventricular (LV) dysfunction in cardiac aging, there is far less depiction of right heart function, especially right ventricular (RV) remodelling in response to pulmonary arterial (PA) changes with aging. Given the importance of cardio-respiratory function in declining aerobic capacity with age, identifying sensitive metrics of RV function would complete our understanding of RV and RV-PA conduit adaptations in aging. Methods: Community older adults without cardiovascular disease underwent prospective cardiac magnetic resonance (CMR) imaging that measured RV volumes (RV end-diastolic volume, EDV; end-systolic volume, ESV), RV function (RV ejection fraction, RVEF; RV global longitudinal strain, GLS) and RV-PA coupling (end-systolic elastance to arterial elastance, computed as ratio of LV stroke volume, SV to RVESV). A RV-PA coupling threshold of &gt;1.5 (based on prior literature) implies effective RV adaptation Aerobic capacity (VO 2 ) was calculated. Multivariable regression adjusted for significant covariates. Results: We studied 251 participants (54.5% female, 70.78±9.07 years) with normal LV and RV function (mean LVEF, 65.13±7.51 %, RVEF, 64.25±6.98 %). RV-PA threshold of &lt;1.5 defined poorer RV structure and function with lower RVEF (56.6 ± 3.95 vs. 67.5 ± 5.25, p &lt; 0.001), RVGLS (28.13± 4.55 vs. 32.8 ± 5.1, p = 0.0065) and higher RVEDV index (73.2 ± 15.15 vs. 63.34 ± 12.03, p &lt; 0.001), compared to those with RVPA &gt; 1.5. Predictors of better RVGLS were female sex (β=0.189, adj. p=0.019), independent of systolic and diastolic blood pressure while predictors of RVESV were female sex (β=-0.433, adj. p&lt;0.00), age (β=-0.195, adj. p&lt;0.001) and body mass index (β=0.264, adj. p&lt;0.001). Overall, women had better RVEF and RVGLS but lower RVSV and VO 2 (30.1±4,5 vs 37.7±5.1, ml/kg/min) compared to men (all p&lt;0.001) (Table 1). Lower VO 2 among women compared to men was accompanied by higher RV-PA (2.1±0.7 vs 1.8±0.7, p&lt;0.001). Female sex (β=0.233, 95% CI [0.158, 0.506, adj. p&lt;0.001) was independently associated with RV-PA coupling on multivariable analyses. Conclusions: Novel CMR-derived right heart parameters defined RV function and RV adaptations as depicted by RV-PA interactions in older adults. Superior RV functions and RV-PA coupling in women may represent hemodynamic adaptations in women, despite lower aerobic capacities.

Abstract 4122543: Can We Diagnose Ticagrelor-induced Dyspnea After Urgent Percutaneous Coronary Intervention with Cardiopulmonary Exercise Testing?

Background: Ticagrelor has been reported to cause shortness of breath (SOB) in 6 to 9 % of patients. Precise mechanisms are not enirely understood. We hypothesize that cardiopulmonary exercise testing (CPET) may be helpful in clinical assessment of patients reporting SOB on ticagrelor. Case presentation: 66-yo female with history of arterial hypertension, DM type 2 and prior MI presented with STEMI and successfully underwent urgent PCI of RCA and LAD. The patient received ticagrelor in loading dose followed by 90 mg b.i.d plus low-dose aspirin. Just after PCI she developed SOB with no evidence of acute cardiac or respiratory compromise. After discharge the patient continued to experience SOB impairing daily activities. In 6 months she was re-assessed. Clinical investigation (physical exam, blood tests, echo, CXR, spirometry) showed no abnormalities that could explain SOB. CPET despite good effort showed low VO 2 peak (7,8 ml*min/kg; 49% from predicted), undetectable anaerobic threshold (AT), severely impaired ventilatory efficacy (VE/VCO 2 =50,1) and marked hyperventilation (resting RER=1,0; PetCO 2 =18,0 mmHg at rest and 22,4 mmHg at peak load). Exercise EKG, blood pressure response, SpO 2 and breathing reserve were normal. Once the patient was switched from ticagrelor to clopidogrel she reported significant improvement. CPET one week after showed increase in VO 2 peak up to 12,5 ml/kg/min., AT of 11,1 ml*min/kg, better ventilatory efficacy (VE/VCO 2 =37,1) and less hyperventilation (PetCO 2 28,1 mmHg at rest and 28,8 mmHg at peak load). CPET performed one month later showed further improvement in VO 2 peak to 13,2 ml*min/kg, normal VE/VCO 2 and no signs of hyperventilation. Discussion: it is believed that ticagrelor-induced dyspnea can be driven by 2 potential mechanisms, first related to inhibition of adenosine reuptake, second - to sensory neuron P2Y12 inhibition. It occurs early after starting the medication and is not associated with structural cardiopulmonary abnormalities. Previous small data showed evidence of Cheyne-Stokes respiration during both night and day related to ticagrelor. Symptoms usually are dose-dependent and disappear after discontinuation of ticagrelor. In our case the patient demonstrated reversible hyperventilation and reduced exercise capacity associated with ticagrelor that was confirmed with CPET. Conclusion: CPET allows differentiating SOB in patients treated with ticagrelor. Further investigations are required to confirm this hypothesis.

Exercise gas exchange phenotyping according to body mass index: a population-based study in an apparently healthy population

Abstract Background Obesity is a widespread medical condition consisting in a BMI &amp;gt; 30 kg/m2. The link between BMI, exercise performance and cardiovascular risk is not well defined on large set of apparently healthy subjects. Aim In this population-based trial of apparently healthy individuals we aimed at defining the exercise gas exchange phenotype by cardiopulmonary exercise testing (CPET) according to BMI strata. Methods 932 subjects (54.7% females) presenting with none to five major cardiovascular risk factors (MCVRFs; hypertension, diabetes, tabagism, dyslipidaemia, BMI&amp;gt; 25), underwent CPET and were divided in 3 categories (normal weight; NW, overweight; OW and obese; Ob). Cohort analysis was carried out by dividing and analysing patients into groups based on BMI, sex, and number of MCVRFs. Peak VO2 was considered normal for a predicted value &amp;gt; 80%. Composite endpoint was defined as the combination of the following events: cardiovasular mortality, cardiovascular hospitalization, coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), percutaneous coronary intervention (PCI), TAVI (Transcatheter aortic valve implantation), cardiac surgery, acute pulmonary oedema or stroke/transient ischemic attack (TIA). Results the number of MCVRFs significantly increased (CI 95%, p-value 0,009) through BMI strata being in NW, OW and Ob 1.6, 2.7, 2.9 respectively. Peak VO2 significantly (CI 95%, p-value &amp;lt;0,001) decreased with rise in BMI (21.8ml/min/kg, 18.7 ml/min/kg, 15.5 ml/min/kg for NW, OW and Ob, respectively; p-value &amp;lt;0,001). A significant correlation between the increase in number of MCRVFs and the decrease in peak VO2 was documented for BMI&amp;lt;30 (-0.44 for NW and -0.30 for OW; p-value &amp;lt;0,001), whereas Ob exhibited the lowest mean peak VO2 which was unaffected by the increasing number of MCVRFs. (figure 1). HRR (Heart rate reserve) was significantly lower in Ob subjects compared to OW and NW (respectively 0.59, 0.68, 0.72 p-value &amp;lt;0,001). Regression models showed that neither risk factors nor CPET variables were predictive for composite endpoint in NW. Interestingly, peak VO2 (OR 0,93 [CI 0,86-0,99] p-value 0,039) and VE/VCO2 slope (OR 1,06 [CI 1,00-1,11] p-value 0,047) were predictive of composite endpoint just in OW with Ob subjects showing similar trend not reaching statistical power; Diabetes was predictive of composite endpoint in Ob cohort. KM curves reported higher event rates in OW subjects with higher VE/VCO2 slope and lower peak VO2. (figure 2) Conclusions As far as obesity is concerned, regardless of the number of MCVRFs, BMI is the single strong determinant of exercise performance and gas exchange phenotype. In OW and NW cohorts, the cumulative number of MCVRFs impacts on worse exercise performance and gas exchange inefficiency. Lower peak VO2 and higher VE/VCO2 slope are predictive of CV composite endpoint in OW and a similar trend was observed in Ob.BMI and peak VO2KM BMI 25-30

Myocardial determinants of Functional limitation in advanced Fabry cardiomyopathy

Abstract Background Cardiac involvement in Fabry Disease (FD) manifests as left ventricular hypertrophy (LVH) often complicated by myocardial fibrosis and/or inflammation. Both LVH and advanced tissue alterations can be non-invasively detected and quantified by cardiac magnetic resonance (CMR) with Late Gadolinium Enhancement (LGE). Impairment in functional capacity has been previously reported in FD patients. However, there is limited data regarding the determinants of myocardial alterations in exercise intolerance in FD. Methods Among 190 consecutive FD patients referred for CMR, 41 simultaneously performed a cardiopulmonary exercise test (CPET) to evaluate functional capacity. All patients underwent an extensive CMR protocol to provide a detailed evaluation of cardiac morphology and function, including multiparametric tissue characterization. CPET parameters were compared between patients with advanced Fabry cardiomyopathy (Group B), characterized by hypertrophy, inflammation, and fibrosis, and FD patients without irreversible cardiac damage (Group A). Results Group B patients were older compared to Group A (57.0 years vs 33.5 years, p&amp;lt;0.001), had a greater LVH (LVMI: 117 g/sqm vs 76.5 g/sqm, p&amp;lt;0.001; LVMWT 17 vs 10 mm, p&amp;lt;0.001). LV ejection fraction was preserved in both groups but Group B patients had a lower peak VO2 value compared to group A (17.8 ml/kg/min vs 21.9 ml/kg/min, p=0.025), a lower (but not significant) percent-predicted peak VO2. A negative linear correlation was identified between the LGE extension (expressed as % of LV mass) and peak VO2 (r=-0.553, p=0.014). This correlation remained consistent even after excluding patients under chronic beta-blocker therapy (r=-0.678, p=0.045). No significant correlation between LV mass and peak VO2 was found. Conclusions in patients with FD, the presence of advanced tissue alterations detected by LGE is associated with reduced functional capacity (low peak VO2) despite preserved LV ejection fraction, with a significant negative correlation.

Improving exercise cardiac reserve assessment using a novel cardiopulmonary and echocardiography testing protocol (CPET-ESE) based on individualised exercise intensity domains

Abstract Background Functional exercise stress echocardiography (ESE) is used to quantify changes in cardiac reserve and can improve early cardiac dysfunction diagnosis and follow-up.[1.2] Current ESE protocols do not account for individual variations in fitness and heart rate response, leading to difficulties in defining normal reference values.[2,3] Physiologically defined exercise intensity domains could be implemented as part of combined cardiopulmonary and ESE testing (CPET-ESE) to address this problem. Purpose We propose that using exercise intensity domains as part of CPET-ESE will result in cardiac reserve values not influenced by individual cardiorespiratory fitness or physical activity (PA) levels. We also hypothesise by matching work-rates and heart rates (HR), respectively, cardiac reserve will be higher in those exercising at the higher exercise intensity domain. Methods A total of 45 healthy adults (mean age 43.8 ± 14.2, range 18-65 y) underwent a CPET followed by a CPET-ESE consisting of two 6-minute stages: 1. Moderate intensity (MOD) at 90% of the work-rate at the gas exchange threshold (GET) and 2. High intensity (HIGH) at 40% of the difference between GET and peak. Global left ventricular and right ventricular free wall (LV and RV) longitudinal strain (Sl), RV fractional area change (RV-FAC), peak LV and RV TDI derived systolic (S’) and diastolic velocities (E’) were measured at each step, including rest. HIGH steps were matched 1-to-n with MOD steps from other participants based on work-rate and HR, respectively. Questionnaire derived PA was classified as low, moderate, and high active. Cardiorespiratory fitness was measured as peak oxygen uptake relative to body mass (mL·kg-1·min-1). Results After adjusting for age and sex, neither higher PA nor peak VO2 were associated with higher cardiac function parameters at either intensity (Table 1). Higher peak VO2 was associated with higher work-rate for HIGH only, while higher PA was associated with lower HR for MOD only (interaction term p&amp;lt;0.05). When paired by matching HR and work-rate, respectively, HIGH was associated with higher cardiac function parameters compared to MOD (all except for LV-S’ and RV-FAC when HR matched, Table 2), despite those matched from HIGH being older, less physically active and having lower peak VO2 (p&amp;lt;0.05 for all). Conclusions Current ESE protocols, which define submaximal exercise intensity using arbitrary work-rate or HR targets,[3] do not account for the complex differences in exercise response between healthy individuals. Cardiac function augmentation during exercise is likely a response to VO2 kinetics and this is not accurately described by either HR or work-rate alone. We derived normal reference values for cardiac reserve from implementing physiologically defined exercise intensity domains within the combined CPET-ESE testing frameworks. These values could be more appropriately used when comparing diverse clinical populations using CPET-ESE.

Coronary microvascular dysfunction as assessed by cardiac MRI and its association with aerobic exercise capacity in dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) has a poor prognosis. Aerobic exercise capacity (peak VO2) is an independent predictor of mortality but the central mechanisms contributing to exercise intolerance in DCM are unknown. Purpose To characterise myocardial perfusion reserve (MPR) and determine if cardiovascular magnetic resonance (CMR) measures of structure, function and microvascular function are associated with aerobic exercise capacity in DCM. Methods Single centre, prospective, case-control comparison of adults with DCM and matched controls. Adenosine-stress perfusion CMR to assess cardiac structure, function and quantitative perfusion, and cardiopulmonary exercise testing (CPET) to determine peak VO2, was performed. Controls were propensity matched based on age, sex, body mass index and diabetes status, and between group comparison was adjusted for other key clinical characteristics (CMR: ethnicity and systolic blood pressure; CPET: ethnicity, systolic blood pressure, smoking history and lung disease). Comparison of perfusion in segments with and without late gadolinium enhancement was performed using mixed effects linear regression taking into account individual patient segmental perfusion. Pre-specified multivariable linear regression, including key clinical and cardiac variables, was undertaken in patients with DCM to identify independent associations with percentage predicted peak VO2, which incorporates age, sex, height and weight. Results Sixty-six patients with DCM (median age 61 years, 71% male) were matched to 66 controls (median age 59 years, 71% male). The DCM group had greater left ventricular (LV) end-diastolic and end-systolic volumes, lower systolic and diastolic function, and had more focal and diffuse fibrosis compared to controls (Table 1). There was lower rest (0.58±0.14 versus 0.65±0.17 mL/min/g; P=0.033) and stress (1.53±0.49 versus 2.01±0.60 mL/g/min; P&amp;lt;0.001) myocardial blood flow, and lower MPR (2.69±0.84 versus 3.15±0.84 mL/g/min; P=0.002) in the DCM group. In DCM patients, mixed effects linear regression demonstrated lower rest (adjusted mean 0.54(95% CI 0.50-0.57) versus 0.58(0.55-0.62) mL/g/min; P&amp;lt;0.001) and stress MBF (1.38(1.25-1.51) versus 1.55(1.43-1.67) mL/g/min; P&amp;lt;0.001) in segments with LGE compared to segments without LGE, but there was no difference in MPR (2.71(2.47-2.96) versus 2.76(2.55-2.97) mL/g/min; P=0.496). DCM patients had markedly lower peak VO2 (19.8±5.5 versus 25.2±7.3 mL/kg/min; P&amp;lt;0.001). Multivariable linear regression demonstrated that LV ejection fraction, extracellular volume fraction and MPR, but not LV mass, were independently associated with percentage predicted peak VO2 in DCM (R squared=0.531, P&amp;lt;0.001; Table 2). Conclusions DCM patients have lower rest and stress myocardial blood flow and lower MPR compared to controls. In DCM, MPR, LV ejection fraction and fibrosis are independently associated with aerobic exercise capacity.

Interventricular abnormal septum displacement as contributory mechanism for impaired peak oxygen consumption and exercise cardiac output response in heart failure

Abstract Background In Heart failure (HF), the role of septum position and abnormal right ventricular (RV) geometry in determining exercise performance is unknown. Especially an abnormal interventricular septal (IVS) position is a well-known sign of RV pressure overload which affects left ventricular filling and output due to interdependence. Aim We postulated that an abnormal septum displacement during exercise and RV geometry alteration would affect peak exercise oxygen consumption (VO2) and cardiac output (CO) increase. Methods 17 HF patients with reduced ejection fraction (HFrEF) (mean age 71±12) underwent a cardiopulmonary exercise testing imaging (iCPET) with RV 3D-imaging analysis and were compared with a control population (mean age 67±14). 3D imaging of the RV chamber was examined off-line using the 4D RV TomTec software and obtained 3D mesh of the RV model using custom software to obtain the mean curvature value of IVS in 4 regions of: inflow tract (RVIT), outflow tract (RVOT), apical and body.We acquired measurements of curvature during end-diastole (ED) and at end systole (ES) phases and obtained a parametric curvature map. Results HF patients typically exhibited an abnormal of septal curve, with a more leftward configuration either at rest and under exercise (rest =−0.01±0.004 at ED, and −0.01±0.006 at ES; peak exercise= −0.01±0.004 at ED, and −0.01±0.004 at ES, Figure) compared to controls (rest=−0.02±0.003 at ED, and −0.02±0.005 at ES; peak exercise −0.02±0.008 at ED, and −0.03±0.006 at ES, Figure). Notably, the degree of the IVS curvature was found to linearly correlate with an impaired gas exchange performance as lower peak VO2 and a limited CO in HF (respectively r=0.62, p&amp;lt;0.001 and r=0.5, p&amp;lt;0.001 at ED during exercise; r=0.34, p&amp;lt;0.001 at ES during exercise, Figure). Conclusions In HF, the RV geometrical alterations reflected by an abnormal IVS displacement appear as novel contributory factors to a reduced exercise performance, impaired oxygen uptake and decreased CO.

Performance of an automated echocardiographic artificial intelligence model. to detect subclinical heart failure with preserved ejection fraction (HFpEF) in community-dwelling older adults

Abstract Background Heart failure (HF) with preserved Ejection Fraction (HFpEF) is common among older adults and associated with a high burden of morbidity and mortality. Early identification of subclinical HFpEF, defined by abnormalities in cardiac structure and function without symptoms of HF, can prompt early initiation of evidence-based therapies to prevent HFpEF. However, scalable strategies for the identification of subclinical HFpEF are lacking. Purpose To evaluate the performance of a validated, automated echocardiographic artificial Intelligence algorithm (Ultromics, UK) to identify subclinical HFpEF among community-dwelling individuals without HF. Methods The study included participants of the Dallas Hearts and Minds Study without HF who underwent cardiovascular phenotyping with resting and exercise echocardiography and maximal cardiopulmonary exercise testing. The resting apical 4C echocardiographic images were analyzed by the AI echo algorithm to identify the HFpEF phenotype (AI-HFpEF). Subclinical HFpEF was defined by E/e’ &amp;gt;14 and Peak exercise oxygen uptake (VO2peak) &amp;lt;25th percentile for the cohort. The performance of the AI algorithm to detect subclinical HFpEF was determined using the area under the receiver operating curve and decision curve analysis and was compared with the previously validated H2FpEF score. The association between the AI-HFpEF phenotype and the presence of subclinical HFpEF, VO2peak, exercise E/e’, left ventricular strain, and left atrial strain was assessed using multivariable-adjusted logistic and linear regression models. Results The study included 511 participants (mean age: 61 y, 57% women, mean VO2peak = 16.9 ml/kg/min). Using the AI echo algorithm, subclinical HFpEF was detected in 10% of participants (n=76), and 10% were non-diagnostic. The participants with (vs. without) AI-HFpEF phenotype were older and had a higher burden of CVD risk factors, left ventricular hypertrophy, and left atrial dilation. Subclinical HFpEF, as defined by the gold standard criteria, was present in 5.3% of participants. The AUROC for diagnosis of subclinical HFpEF using the AI-HFpEF algorithm was 0.85 vs. 0.78 by the H2FpEF score (see Figure). In the adjusted analysis, the AI-HFpEF phenotype was significantly associated with greater odds of subclinical HFpEF by exercise and echocardiographic phenotyping criteria, higher E/e’ with exercise, lower VO2 peak, and worse LV and LA strain (see Table). In decision curve analysis, the AI-HFpEF algorithm identified 23 additional cases of subclinical HFpEF per 1000 screened participants compared with the H2FpEF score. Conclusion The AI-HFpEF algorithm can reliably identify community-dwelling individuals with subclinical HFpEF characterized by diastolic dysfunction at rest or exercise and impaired exercise capacity. Future studies are needed to assess the utility of the AI-HFpEF algorithm in screening for subclinical HFpEF in health systems.

Survival in patients with chronic congestive heart failure and correlation of presence of risk factors and all-cause mortality

Abstract Background Right heart function is known to be an independent risk factor for early mortality in patients with acute and chronic heart failure (HF). The prognostic value of cardiopulmonary exercise testing (CPET) is established for risk stratification in patients with Heart Failure. Further, markers of inflammation may predict clinical outcomes. Purpose We performed a single-center retrospective analysis of a large single center cohort and assessed all-cause mortality. A simple score including presence of RVD, systemic inflammation and reduced O2 uptake was applied to all patients and a subgroup survival analysis was performed. Methods A total of 612 patients with HF across the whole spectrum of left ventricular ejection fraction (LVEF) were analyzed. We stratified patients according to RV function, peak relative oxygen consumption in ml/min/kg (VO2max) and CRP levels. Patients were classified as RV Dysfunction when a right ventricular dilation (RVEDD &amp;gt; 40 mm or RVOT &amp;gt; 30 MM) or decreased tricuspid annular systolic excursion (TAPSE &amp;lt; 17 mm) was seen in the echocardiography. All patients were followed up by phone or by hospital records if available. The primary end-point of all-cause mortality was assessed. Results For the primary analysis, 612 patients (mean age 59.8 ± 13.8 years, 71.41% male) were included. According to LVEF 248 (40.5%) patients had preserved LVEF (HFpEF), 82 (13.0%) had mid-range LVEF (HFmrEF) and 282 (46.0%) had reduced LVEF (HFrEF). HF etiology was in 27% ischemic. Mean BNP values were 514.1 ± 827.1 pg/l. Mean VO2max 15,9 ± 5,9 ml/min per kg. Patients were followed up for a median of 4.0 years (IQR: 3.4 - 4.9 years). Over this period, the primary end-point occurred in 17.6% of patients. 135 (22%) of patients had evidence of RV dysfunction, 26% had increased CRP-levels and 256 (41.8%) had a VO2max &amp;lt; 14 ml/min per kg. Patients with elevated CRP, VO2max &amp;lt; 14 ml/min/kg and RV-dysfunction showed worse survival according to the Kaplan-Meier-Estimate with a significant difference (Log Rank: Chi²: 1480, p = 0.013) compared to patients with only RV dysfunction low VO2 max or only increased CRP values. Conclusion A combined evaluation of systemic inflammation, cardiopulmonal exercise testing and right ventricular dysfunction is useful in predicting long-term outcomes of patients with HF. Patients with both risk factors show worse survival than patients with signs of inflammation or RV dysfunction only.Kaplan-Meier-Estimates

ASC speck serum concentrations, a component of sterile cellular inflammation, are associated with individual cardiopulmonary capacity.

Exercise-induced cellular stress and sterile inflammation are of increasing interest. ASC specks are a component of the intracellular NLRP3-inflammasome and can be released into the blood. For example, serum ASC specks are increased after marathon running. We therefore tested whether ASC specks are potentially associated with the individual response to physical training and cardiopulmonary capacity. We performed a prospective study in 45 healthy athletes. Blood samples were taken before and after cardiopulmonary exercise testing (CPET). ASC speck concentrations were quantitated using flow cytometry. Baseline ASC speck levels correlated with clinical parameters of body composition (height, weight, BMI) and parameters of cardiopulmonary performance (peak VO2, peak oxygen pulse, heart rate after exercise). Athletes with lowest baseline ASC speck concentrations have a significantly lower BMI (22.0 ± 1.8 vs. 24.9 ± 1.6kg/m2), higher heart rate at rest (72 ± 10 vs. 58 ± 10 beats/min), lower peak VO2 (2692 ± 629 vs. 3404 ± 747mL/min) and lower peak oxygen pulse (15.6 ± 3.4 vs. 20.7 ± 3.5mL/heart rate). Overall, ASC speck concentrations showed no significant change after CPET (7.0 ± 4.5 vs. 8.0 ± 5.4 ASC specks/µL, p = 0.3). However, subgroup analysis revealed a significant increase in circulating ASC specks in athletes with the lowest baseline values (2.37 ± 0.84 vs. 8.43 ± 7.52 ASC specks/µL, p < 0.05). Athletes with an increase in ASC speck concentrations in response to CPET had a lower peak oxygen pulse compared to those with a decrease (17.1 ± 4.2 vs. 19.8 ± 4.1, p < 0.05). Low ASC speck baseline values as well as an increase in response to exercise are associated with lower peak oxygen pulse in healthy athletes.

Sex Differences in Indicators of Mental and Cardiovascular Health in Cannabis-Using Undergraduates

This study investigated sex differences in indicators of mental health (anxiety, depression) and cardiovascular health (e.g., physical activity levels, heart rate, VO2 max) in a sample of cannabis-using undergraduates. The sample included 209 participants (65% female) who completed two daily diaries for 14 days on their mobile devices; half of whom ( n = 100) also wore a Fitbit Charge 4. Females (vs. males) reported significantly more psychological distress at baseline; greater use of cannabis to cope with symptoms of both physical and mental ill-health; and more risks to cardiovascular health. Discriminant function analysis revealed that the variables that significantly distinguished females from males were: 1. Lower VO2 max percentile; 2. Fewer “moderate-to-very active” minutes of physical activity; 3. Higher depression scores plus poorer perceptions of mental health and physical health. Findings from this study suggest that female emerging adults who use cannabis regularly may be uniquely vulnerable to cannabis-related risks.

Functional Capacity Assessment in Adults After Fontan Palliation: A Cardiopulmonary Exercise Test–Invasive Exercise Hemodynamics Correlation Study

While cardiopulmonary exercise testing (CPET) parameters have known prognostic value in adults post-Fontan, there is limited data correlating treadmill CPET with invasive exercise hemodynamics. Furthermore, the invasive hemodynamic underpinnings of exercise limitations have not been thoroughly investigated. This is retrospective analysis of 55 adults (≥18 years) post-Fontan who underwent treadmill CPET prior to invasive exercise hemodynamic testing via supine cycle protocol between November 2018 and April 2023. Median age was 32.2 (24.1; 37.2) years. Peak heart rate (HR) was 139.7±28.1 bpm and peak oxygen consumption (VO2) was 19.1±5.7 ml/kg/min (47.4±13.5% predicted). VO2/HR was directly related to exercise stroke volume index (Svi) (r=0.50; p=0.0002), while no association was seen with exercise arterio-mixed venous O2 content difference (r=0.14; p=0.32). Peak HR was inversely related to exercise pulmonary artery (PA) pressures (r=-0 61; p<0.0001) and PA wedge pressures (PAWP) (r=-0.61; p<0.0001). Moreover, % predicted VO2 was inversely related to exercise PA pressures (r=-0.50; p<0.0001) and PAWP (r=-0.55; p<0.0001). Peak VO2 ≤19.1 ml/kg/min had a sensitivity of 81% and specificity of 76% (AUC 0.82) for predicting a ΔPAWP/ΔQs ratio >2 mmHg/l/min and/or a ΔPA/ΔQp ratio >3 mmHg/l/min, while a predicted peak VO2 ≤48% had a sensitivity of 74% and specificity of 81% (AUC 0.79) for the same parameters. In summary, lower peak HR and lower peak VO2 were associated with higher exercise PAWP and PA pressure. Peak VO2 ≤48% predicted provided the optimal cut-off for predicting elevated indexed exercise PAWP or PA pressures, thus low peak VO2 should alert clinicians of abnormal underlying hemodynamics.