Systolic Reserve Research Articles

Left atrial function during exercise stress echocardiography as a sign of paroxysmal/persistent atrial fibrillation

ObjectiveAtrial cardiomyopathy is closely associated with atrial fibrillation (AF), and some patients exhibit no dysfunction at rest but demonstrate evident changes in left atrial (LA) function and LA volume during exercise. This study aimed to identify distinguishing signs during exercise stress echocardiography (ESE) among patients in sinus rhythm (SR), with and without history of paroxysmal/persistent AF (PAF).MethodsA prospective cohort of 1055 patients in SR was enrolled across 12 centers. The main study cohort was divided into two groups: the modeling group (n = 513) and the verification group (n = 542). All patients underwent ESE, which included B-lines, LA volume index (LAVi), and LA strain of the reservoir phase (LASr).ResultsAge, resting and stress LAVi and LASr, and B-lines were identified as a combination of detectors for PAF in both groups. In the entire cohort, aside from resting and stress LAVi and LASr, additional parameters differentiating PAF and non-PAF patients were the presence of systemic hypertension, exercise E/e’ > 7, worse right ventricle (RV) contraction during exercise (∆ tricuspid annular plane systolic excursion < 5 mm), a lower left ventricular contractile reserve (< 1.6), and a reduced chronotropic reserve (heart rate reserve < 1.64). The composite score, summing all 9 items, yielded a score of > 4 as the best sensitivity (79%) and specificity (65%).ConclusionESE can complement rest echocardiography in the identification of previous PAF in patients with SR through the evaluation of LA functional reservoir and volume reserve, LV chronotropic, diastolic, and systolic reserve, and RV contractile reserve.Graphical A scoring system predicting the probability of PAF. The score was computed using the cutoff values as in the illustration. The score >4 demonstrated a sensitivity of 79% and a specificity of 65% of PAF.

Impaired Left Atrial Reserve Function in Heart Failure With Preserved Ejection Fraction.

Left atrial (LA) dysfunction is common in heart failure (HF) with preserved ejection fraction. However, data on the pathophysiologic impacts of impaired LA functional reserve remained limited. We sought to determine the association of abnormal LA dynamics during exercise with cardiovascular reserve, exercise capacity, and clinical outcomes. Patients with HF with preserved ejection fraction (n=231) and controls without HF (n=219) underwent exercise stress echocardiography with simultaneous expired gas analysis. LA function was assessed at rest and during exercise using speckle-tracking echocardiography. Patients with HF with preserved ejection fraction demonstrated less increase in LA reservoir and booster pump strain during exercise than those in controls. The degree of LA dilation was more closely related to exercise LA reservoir strain than to resting LA strain (Meng test, P=0.002). The presence of impaired LA reservoir strain during exercise was associated with poorer biventricular systolic reserve and cardiac output augmentation, more severe right ventricular-pulmonary artery uncoupling, and lower peak oxygen consumption. Patients with a lower exercise LA reservoir strain had a 2.7-fold increased risk of HF events (hazard ratio, 2.66 [95% CI, 1.32-5.38]; P=0.006). Among patients with follow-up echocardiography, initiation of guideline-directed medical therapy or atrial fibrillation ablation showed significant improvements in LA reservoir (P<0.001 and P=0.022) and booster pump strain (P=0.011 and 0.028) at rest and during exercise, respectively. Impaired LA reservoir function during exercise in HF with preserved ejection fraction is associated with biventricular reserve limitations, exercise intolerance, and increased risks of HF events.

Abstract 15158: Prognostic Impact of Right Ventricular-Pulmonary Arterial Coupling Ratio in Patients Undergoing Transcatheter Aortic Valve Replacement

Introduction: Right ventricular (RV) dysfunction is known as an important prognostic factor in heart failure. As reduced RV systolic reserve, RV contractility no longer increases against afterload, resulting in lower ratios of RV function to pulmonary artery (PA) pressure, known as RV-PA coupling ratios. Hypothesis: The assessment of RV-PA coupling ratios provides prognostic information for patients undergoing transcatheter aortic valve replacement (TAVR). Methods and Results: A total of 540 patients with TAVR (age, 84 ± 6 years; 186 men, 354 women) were included in this study. The RV-PA coupling ratio was calculated by dividing the tricuspid annular plane systolic excursion (TAPSE) by the PA systolic pressure (PASP) using transthoracic echocardiography before TAVR. Based on the median TAPSE/PASP (0.584 mm/mmHg), the patients were divided into two groups. Kaplan-Meier analysis demonstrated a higher incidence of adverse cardiac events (cardiac death and heart failure hospitalization) in the group with a low TAPSE/PASP ratio (log-rank test, P &lt;0.001). In multivariate Cox regression analysis, TAPSE/PASP was identified as an independent prognostic parameter (adjusted hazard ratio, 0.259; P = 0.028), whereas neither TAPSE alone nor PASP alone demonstrated any significant prognostic value. Conclusion: The RV-PA coupling ratio serves as a prognostic predictor for adverse cardiac events in patients undergoing TAVR.

Abnormal left ventricular systolic reserve function detected by treadmill exercise stress echocardiography in asymptomatic type 2 diabetes

AimsSubclinical left ventricular (LV) dysfunction may occur in T2DM patients at the early asymptomatic stage, and LV reserve function is a sensitive index to detect subtle LV dysfunction. The purpose of our study is (1) to assess the LV reserve function using treadmill exercise stress echocardiography (ESE) in asymptomatic type 2 diabetes mellitus (T2DM) patients; (2) to explore the link of serum biological parameters and LV reserve function.MethodsThis study included 84 patients with asymptomatic T2DM from September 2021 to July 2022 and 41 sex- and age-matched healthy controls during the corresponding period. All subjects completed treadmill ESE, LV systolic function-related parameters such as global longitudinal strain (GLS) and systolic strain rate (SRs), as well as diastolic function-related parameters such as E wave (E), early diastolic velocity (e′), E/e′ ratio, early diastolic SR (SRe), and late diastolic SR (SRa) were compared at rest and immediately after exercise. The difference between LV functional parameters after treadmill exercise and its corresponding resting value was used to compute LV reserve function. In addition, the associations of LV reserve function and serum biological parameters were analyzed.ResultsPatients with T2DM did not significantly vary from the controls in terms of alterations in LV diastolic reserve measures, the changes of LVGLS and SRs (ΔGLS: 2.19 ± 2.72% vs. 4.13 ± 2.79%, P &amp;lt; 0.001 and ΔSRs:0.78 ± 0.33 s−1 vs. 1.02 ± 0.28 s−1, P &amp;lt; 0.001) in the T2DM group were both lower than those in the control group. Glycated hemoglobin (HbA1c), N-terminal pro-brain natriuretic peptide (NTproBNP), waist circumference, and high-sensitive C-reactive protein (hsCRP) were identified as independent predictors of LV systolic reserve by stepwise multiple linear regression analysis.ConclusionLV systolic reserve function, as measured by pre- and post-exercise differences in GLS and SRs were significantly impaired in patients with asymptomatic T2DM, whereas diastolic reserve remained normal during exercise and was comparable to that of the control group. This was different from previous findings. High levels of HbA1c, NTproBNP, hsCRP, and increasing waist circumference were independent predictors of LV systolic reserve.

Distinct effects of type 2 diabetes and obesity on cardiopulmonary performance.

Effort intolerance is frequent in patients with overweight/obesity and/or type 2 diabetes (T2D) free from cardiac and respiratory disease. We sought to quantify the independent effects of T2D and body mass index (BMI) on cardiopulmonary capacity and gain insights on the possible pathophysiology by case-control and regression analyses. Patients at high/moderate cardiovascular risk, with or without T2D, underwent spirometry and combined echocardiography-cardiopulmonary exercise test as part of their clinical workup. Subjects with evidence of cardiopulmonary disease were excluded. The effects of T2D and obesity were estimated by multivariable models accounting for known/potential confounders and the major pathophysiological determinants of oxygen uptake at peak exercise (VO2peak ) normalized for fat-free mass (FFM). In total, 109 patients with T2D and 97 controls were included in the analysis. The two groups had similar demographic and anthropometric characteristics except for higher BMI in T2D (28.6 ± 4.6 vs. 26.3 ± 4.4 kg/m2 , p = .0003) but comparable FFM. Patients with T2D achieved lower VO2peak than controls (18.5 ± 4.4 vs. 21.7 ± 8.3 ml/min/kg, p = .0006). Subclinical cardiovascular dysfunctions were observed in T2D: concentric left ventricular remodelling, autonomic dysfunction, systolic dysfunction and reduced systolic reserve. After accounting for confounders and major determinants of VO2peakFFM , T2D still displayed reduced VO2peak by 1.0 (-1.7/-0.3) ml/min/kgFFM , p = .0089, while the effect of BMI [-0.2 (-0.3/0.1) ml/min/kgFFM , p = .06 per unit increase], was largely explained by a combination of chronotropic incompetence, reduced peripheral oxygen extraction, impaired systolic reserve and ventilatory (in)efficiency. T2D is an independent negative determinant of VO2peak whose effect is additive to other pathophysiological determinants of oxygen uptake, including BMI.

P446 INDEPENDENT EFFECTS OF TYPE 2 DIABETES AND OBESITY ON CARDIOPULMONARY PERFORMANCE IN SUBJECTS AT HIGH CARDIOVASCULAR RISK

Abstract Background Both obesity and type 2 diabetes (T2D) are associated with effort intolerance and heart failure. Since the two conditions often coexist and overlap, their distinct effect on cardiopulmonary performance remains to be elucidated. Methods Patients at high cardiovascular risk, free from any clinical or instrumental evidence of heart disease, with a wide range of body mass index (BMI) values, and with or without T2D underwent combined echocardiography–cardiopulmonary exercise test (eCPET). Patients were divided in T2D and controls, as well as in lean (BMI &amp;lt;25 kg/m2), overweight (BMI 25 – 30 kg/m2), and obese (BMI &amp;gt;30 kg/m2). Results A total of 206 patients was analyzed, divided in 109 patients with T2D and 97 controls. Increased BMI is associated with multiple cardiovascular dysfunctions including chronotropic insufficiency, subclinical systolic dysfunction (reduced global longitudinal strain, GLS), and impaired systolic reserve, achieving significantly lower oxygen uptake and workload. Obesity is associated with reduced lung volumes and mild ventilatory alterations at peak exercise, irrespective of diabetes. T2D patients showed more frequent LV concentric remodeling, worse systolic and diastolic performance at rest with diminished ameliorations during exercise, and worse sympatho–vagal balance as expressed by the higher prevalence of chronotropic insufficiency and delayed heart rate recovery. Nonetheless, when divided in BMI subclasses, the differences between T2D and controls were only evident among lean subjects. In fact, while no difference between T2D and controls was evident among overweight and obese patients, lean individuals with T2D display worse cardiopulmonary performance than lean controls, achieving lower workload and lower VO2peak, revealing systolic dysfunction (lower GLS) and higher LV filling pressures (E/e’). Unlike glycated hemoglobin, strong linear relationships were proven between fat mass and oxygen uptake, workload, systolic, and diastolic indices. Conclusions T2D affects LV dimensions and geometry, systo–diastolic functions, autonomic balance, cardiopulmonary capacity, and exercise tolerance, independently of the presence of obesity. Nonetheless, increased BMI is an even more powerful independent negative determinant of systolic function, autonomic balance, and effort tolerance. These early alterations might partly explain the increased risk of developing heart failure associated with diabetes and obesity.

VEGF-B hypertrophy predisposes to transition from diastolic to systolic heart failure in hypertensive rats.

Cardiac energy metabolism is centrally involved in heart failure (HF), although the direction of the metabolic alterations is complex and likely dependent on the particular stage of HF progression. Vascular endothelial growth factor B (VEGF-B) has been shown to modulate metabolic processes and to induce physiological cardiac hypertrophy; thus, it could be cardioprotective in the failing myocardium. This study investigates the role of VEGF-B in cardiac proteomic and metabolic adaptation in HF during aldosterone and high-salt hypertensive challenges. Male rats overexpressing the cardiac-specific VEGF-B transgene (VEGF-B TG) were treated for 3 or 6 weeks with deoxycorticosterone-acetate combined with a high-salt (HS) diet (DOCA + HS) to induce hypertension and cardiac damage. Extensive longitudinal echocardiographic studies of HF progression were conducted, starting at baseline. Sham-treated rats served as controls. To evaluate the metabolic alterations associated with HF, cardiac proteomics by mass spectrometry was performed. Hypertrophic non-treated VEGF-B TG hearts demonstrated high oxygen and adenosine triphosphate (ATP) demand with early onset of diastolic dysfunction. Administration of DOCA + HS to VEGF-B TG rats for 6 weeks amplified the progression from cardiac hypertrophy to HF, with a drastic drop in heart ATP concentration. Dobutamine stress echocardiographic analyses uncovered a significantly impaired systolic reserve. Mechanistically, the hallmark of the failing TG heart was an abnormal energy metabolism with decreased mitochondrial ATP, preceding the attenuated cardiac performance and leading to systolic HF. This study shows that the VEGF-B TG accelerates metabolic maladaptation which precedes structural cardiomyopathy in experimental hypertension and ultimately leads to systolic HF.

HFpEF animal models display differences in myofibril mechanics.

Heart Failure with preserved Ejection Fraction (HFpEF) is a complex, multi-organ disease historically defined by cardiac aberrations including diastolic dysfunction with normal resting systolic function and depressed systolic reserve, hypertrophy, and impaired relaxation. Though diastolic dysfunction is a hallmark of HFpEF, it is unknown whether organ-level deficiencies in relaxation persist down to the myofibrils, the contractile organelles within cells. Here, we performed mechanics analysis on cardiac myofibrils from three common HFpEF animal models to assess potential differences in myofibrillar force and relaxation kinetics, independent of higher-order deficits associated with the disease. The Göttingen minipig (GM) HFpEF model recapitulates the spectrum of human HFpEF multiorgan pathophysiology, including severe diastolic dysfunction, myocardial hypertrophy, fibrosis, and pulmonary and systemic hypertension. We found that GM-HFpEF myofibrils produced significantly less maximal force versus controls, with no change in either the slow or fast relaxation phases. Therefore, impaired myofibril relaxation likely does not contribute to the diastolic dysfunction in this model. Another model assessed was the Zucker spontaneously hypertensive heart failure F1 (ZSF1) rat, which exhibits elevated E/e′, insulin resistance, elevated end-diastolic pressure, and preserved ejection fraction. Our preliminary data indicate that ZSF1 myofibrils produce normal maximal force, but have a slower initial rate of relaxation compared to controls. These data suggest that impaired myofibril relaxation may contribute to diastolic dysfunction in the ZSF1 model. Moreover, the distinct responses of myofibrils from these models appear to recapitulate cell-level behavior in human cardiomyocytes isolated from patients with different HFpEF subphenotypes. Therefore, certain animal models may mimic unique HFpEF characteristics at the cellular and/or myofibril levels and be better-suited for investigating specific aspects of this extremely complex syndrome, and aid in the design of effective pharmacological or device-based treatments.

Assessing systolic and diastolic reserves in male and female mice.

Cardiac reserve is a widely used health indicator and prognostic tool. Although it is well established how to assess cardiac reserve clinically, in preclinical models, it is more challenging lacking standardization. Furthermore, although cardiac reserve incorporates both systolic (i.e., contractile reserve) and diastolic (i.e., relaxation reserve) components of the cardiac cycle, less focus has been placed on diastolic reserve. The aim of our study was to determine which technique (i.e., echocardiography, invasive hemodynamic, and Langendorff) and corresponding parameters can be used to assess the systolic and diastolic reserves in preclinical models. Healthy adult male and female CD-1 mice were administered dobutamine and evaluated by echocardiography and invasive hemodynamic, or Langendorff to establish systolic and diastolic reserves. Here, we show that systolic reserve can be assessed using all techniques in vivo and in vitro. Yet, the current indices available are ineffective at capturing diastolic reserve of healthy mice in vivo. When assessing systolic reserve, sex affects the dose response of several commonly used echocardiography parameters [i.e., fractional shortening (FS), ejection fraction (EF)]. Taken together, this study improves our understanding of how sex impacts the interpretation assessment of cardiac reserve and establishes for the first time that in healthy adult mice, the diastolic reserve cannot be assessed by currently established methods in vivo.NEW & NOTEWORTHY Cardiac reserve is a globally used health indicator and prognostic tool that is used by clinicians and preclinical scientists. In physiology, we have a long-standing appreciation of how to assess systolic reserve but lack insight into sex differences and have no frame of reference for measuring diastolic reserve to certainty across cardiac techniques or the influence of sex. Here, we show that the primary means for assessing diastolic reserve is incorrect. Furthermore, we provided proof and clarity on how to correctly measure systolic and diastolic reserve capacities. We also highlight the imperative of sex differences to the measures of both systolic and diastolic reserves using several techniques (i.e., echocardiography, invasive hemodynamics, and Langendorff) in mice.

Clinical parameters and cardiovascular risk factors related to heart failure with preserved ejection fraction: a comparative analysis between HFA-PEFF and H2FPEF Scores

Abstract Background Heart failure with preserved ejection fraction (HFpEF) diagnosis remains challenging, since several mechanisms (diastolic and systolic reserve abnormalities, chronotropic incompetence, ventricular or vascular stiffening, atrial dysfunction, pulmonary hypertension, impaired vasodilation, endothelial dysfunction, energetic abnormalities and autonomic dysfunction) play different roles in HFpEF development. European Society of Cardiology HF guidelines recently suggested a stepwise non-invasive diagnostic approach consisting of three steps: the first is clinical, the second includes echocardiographic and laboratory data (natriuretic peptides), named HFA-PEEF score, and finally, in case of inconclusive findings, diastolic stress echocardiography is recommended. On the other hand, in United States, another multiparametric score, named H2FPEF, has been proposed for HFpEF diagnosis, and including, in addition to echocardiographic parameters, also clinical data; thereby more applicable in the outpatient clinical arena. Purpose Whether there is a clinical overlap between the two scores (HFA-PEEF and H2FPEF) as well as whether the addition of clinical data to the HFA-PEEF could improve its ability to identify different HFpEF phenotypes is still an open issue and these were the aims of our study. Methods HFA-PEEF and H2FPEF scores were systematically applied on 1,156 consecutive subjects with preserved ejection fraction who undergone cardiovascular evaluation at the Cardiovascular Prevention Center of Fondazione Don Gnocchi &amp; University of Parma. All subjects underwent cardiovascular risk assessment followed by echocardiography and cardiopulmonary exercise testing; due to the outpatient (non-acute) setting of the evaluation, natriuretic peptides assay was not performed. Clinical data and cardiovascular risk factors data were compared between different groups of HFpEF risk. Results According to H2FPEF score, low risk (&amp;lt;40%) of HFpEF was found in 659 (57%), moderate in 300 (26%) and high (&amp;gt;75%) in 197 (17%); according to HFA-PEEF score, 675 (58%) had 0 or 1 point, 253 (22%) had 2 points and 230 (20%) had 3 or 4 points (moderate-to-high risk). Patients with higher HFA-PEEF score were older (p&amp;lt;0.001), had higher prevalence of HTN (p&amp;lt;0.001), diabetes (p&amp;lt;0.001), obesity (p&amp;lt;0.001), sedentary lifestyle (p&amp;lt;0.001), AF (p&amp;lt;0.001) and CCS (p&amp;lt;0.001) (figure 1). More specifically, AF was associated to a 6.3-fold higher risk (p&amp;lt;0.001) of high (3–4) HFA-PEEF Score, age &amp;gt;75 years to a 4.6-fold higher risk, HTN to a 3.6-fold higher risk (p&amp;lt;0.001), CCS to a 3.3-fold higher risk (p&amp;lt;0.001), obesity to a 2.2-fold higher risk (p&amp;lt;0.001), diabetes to a 1.9-fold higher risk (p&amp;lt;0.001) and sedentary to a 1.7-fold higher risk (p=0.001). Conclusions Although HFA-PEEF score does not include clinical data, patients with older age, atrial fibrillation, hypertension, hypertensive heart, diabetes, sedentary lifestyle and chronic coronary syndrome show a higher ESC risk of HFpEF. Funding Acknowledgement Type of funding sources: None.

Cardiopulmonary response to exercise and heart failure with preserved ejection fraction risk: a comparative analysis of HFA-PEFF and H2FPEF scores

Abstract Background Exercise intolerance evaluation in Heart failure with preserved ejection fraction (HFpEF) remains challenging, since several mechanisms (diastolic and systolic reserve abnormalities, low chronotropic reserve (CR), ventricular or vascular stiffening, atrial dysfunction, pulmonary hypertension, endothelial dysfunction, energetic abnormalities and autonomic dysfunction) play different roles. European Society of Cardiology HF guidelines recently suggested a stepwise non-invasive HFpEF diagnostic approach consisting of three steps: clinical, echocardiographic and laboratory data (natriuretic peptides), named HFA-PEEF Score, and finally, in case of inconclusive findings, diastolic stress echocardiography data. Cardiopulmonary exercise testing (CPET) may represent a promising further non-invasive diagnostic tool in HFpEF evaluation since allow to assess the presence of reduced functional capacity as well as to differentiate between cardiovascular, ventilatory or peripheral causes. Purpose Whether increased risk of HFpEF is associated with different and specific cardiopulmonary responses to exercise is still an open issue and this was the aim of our study. Methods 1.156 consecutive subjects with preserved ejection fraction undergoing cardiovascular evaluation at the Cardiovascular Prevention Center of Fondazione Don Gnocchi &amp; University of Parma were enrolled. All subjects underwent cardiovascular evaluation and echocardiography, HFA-PEEF and H2FPEF Score assessment and cardiopulmonary exercise testing. Different cardiopulmonary response to exercise were compared between different groups of HFpEF risk. Results According to HFA-PEEF Score, 675 (58%) had 0 or 1 point, 253 (22%) had 2 points and 230 (20%) had 3 or 4 points (moderate-to-high risk). Patients with both higher HFA-PEEF and H2FPEF Score showed lower functional capacity, expressed as low peak V02 (p&amp;lt;0.001) associated with lower oxygen pulse (V02/HR) (p&amp;lt;0.001), cardiac output (CO) at peak (p&amp;lt;0.001), CR (p&amp;lt;0.001), ventilatory efficiency (expressed as VE/VC02 slope) (p&amp;lt;0.001) and oxygen uptake extraction (OUES) (p&amp;lt;0.001). Moreover, higher H2FPEF Score patients showed lower stroke volume (SV) at peak (p&amp;lt;0.001), while high HFA-PEEF score was not associated to SV at peak (Table 1 and Figure 1). More specifically, the presence of reduced cardiovascular efficiency (V02/Watt Slope &amp;lt;7) was associated to a 2.2-fold higher risk of HFpEF (p=0.003), impaired ventilator efficiency (VE/VCO2 Slope &amp;gt;35) to a 2.4-fold higher risk (p&amp;lt;0.001), reduced CR (&amp;lt;70%) 4.3-fold higher risk (p&amp;lt;0.001). Conclusions Different degrees HFpEF risk, estimated using both HFA-PEEF and H2FPEF score, are associated with different cardiopulmonary responses to exercise. High HFpEF risk patients show low functional capacity, cardiovascular and ventilator efficiency due to lower cardiac output at peak, despite preserved ejection fraction, associated to lower chronotropic response to exercise. Funding Acknowledgement Type of funding sources: None.

Epicardial adipose tissue thickness is associated with reduced peak oxygen consumption and systolic reserve in patients with type 2 diabetes and normal heart function.

To investigate the impact of epicardial adipose tissue (EAT) thickness on cardiopulmonary performance in patients with type 2 diabetes (T2D) and normal heart function. We analysed EAT thickness in subjects with T2D and normal biventricular systo-diastolic functions undergoing a maximal cardiopulmonary exercise test combined with stress echocardiography, speckle tracking and pulmonary function assessment, as well as serum N-terminal pro B-type natriuretic peptide (NT-proBNP). In the 72 subjects enrolled, those with EAT thickness above the median (> 5 mm) showed higher body fat mass, smaller indexed left ventricular dimensions and marginally reduced diastolic function variables at rest. Higher EAT thickness was associated with lower peak oxygen uptake (VO2peak 17.1 ± 3.6 vs. 21.0 ± 5.7ml/min/kg, P=.001), reduced systolic reserve (ΔS' 4.6 ± 1.6 vs. 5.8 ± 2.5m/s, P=.02) and higher natriuretic peptides (NT-proBNP 64 [29-165] vs. 31 [26-139] pg/ml, P=.04), as well as chronotropic insufficiency and impaired heart rate recovery. Ventilatory variables and peripheral oxygen extraction were not different between groups. EAT was independently associated with VO2peak and linearly and negatively correlated with peak heart rate, heart rate recovery, workload, VO2 at the anaerobic threshold and at peak, and cardiac power output, and was directly correlated with natriuretic peptides. Higher EAT thickness in T2D is associated with worse cardiopulmonary performance and multiple traits of subclinical cardiac systolic dysfunction.

Pulmonary hypertension during exercise underlies unexplained exertional dyspnoea in patients with Type 2 diabetes.

To compare the cardiac function and pulmonary vascular function during exercise between dyspnoeic and non-dyspnoeic patients with Type 2 diabetes mellitus (T2DM). Forty-seven T2DM patients with unexplained dyspnoea and 50 asymptomatic T2DM patients underwent exercise echocardiography combined with ergospirometry. Left ventricular (LV) function [stroke volume, cardiac output (CO), LV ejection fraction, systolic annular velocity (s')], estimated LV filling pressures (E/e'), mean pulmonary arterial pressures (mPAPs) and mPAP/COslope were assessed at rest, low- and high-intensity exercise with colloid contrast. Groups had similar patient characteristics, glycemic control, stroke volume, CO, LV ejection fraction, and E/e' (P > 0.05). The dyspnoeic group had significantly lower systolic LV reserve at peak exercise (s') (P = 0.021) with a significant interaction effect (P < 0.001). The dyspnoeic group also had significantly higher mPAP and mPAP/CO at rest and exercise (P < 0.001) with significant interaction for mPAP (P < 0.009) and insignificant for mPAP/CO (P = 0.385). There was no significant difference in mPAP/COslope between groups (P = 0.706). However, about 61% of dyspnoeic vs. 30% of non-dyspnoeic group had mPAP/COslope > 3 (P = 0.009). The mPAP/COslope negatively predicted V̇O2peak in dyspneic group (β = -1.86, 95% CI: -2.75, -0.98; multivariate model R2:0.54). Pulmonary hypertension and less LV systolic reserve detected by exercise echocardiography with colloid contrast underlie unexplained exertional dyspnoea and reduced exercise capacity in T2DM.

Reduction in myocardial function and oxygen consumption after chemoradiotherapy in patients with esophageal cancer

Background Chemoradiotherapy (CRT) may induce myocardial dysfunction, congestive heart failure, and impaired physical performance in patients with esophageal cancer (EC). We aimed to investigate left ventricular (LV) function at rest and during stress, using echocardiography (echo) and a cardiopulmonary exercise (CPX) test both before and immediately after completing CRT. Material and methods Consecutive EC patients referred for curative treatment were enrolled. Patients attended either definitive CRT or neoadjuvant CRT with subsequent surgery. The evaluation included cardiac biomarkers, electrocardiogram, echo, and CPX test. The primary endpoint was changes in left ventricular (LV) global longitudinal strain (GLS) at rest. Secondary endpoints were LV ejection fraction (LVEF), LV diastolic function, LVEF and GLS at peak exercise, and maximal oxygen consumption (VO2max). The trial was registered with ClinicalTrials.gov (NCT03619317). Results Among 47 patients enrolled (94% male; median age 67 years, range 50–86 years), cardiac examinations were performed a median of three days [Interquartile range (IQR (1–5))] before CRT and one day [IQR (0–6)] after CRT. At rest, GLS and LVEF decreased, 17.6 vs. 16.4% and 56.4 vs. 55.1%, respectively (p = 0.004; p = 0.030). Furthermore, an absolute decrease of at least 5% in LVEF and 2.5% in GLS was noted in 21% of the patients. Signs of LV diastolic dysfunction increased from 13 to 21% (p = ns). VO2max significantly decreased; 21.2 ml/kg/min vs. 18.8 ml/kg/min (p < 0.001). Conclusion LV function and physical performance decreased in EC patients after CRT, and the LV systolic reserve capacity declined. This study highlighted that EC treatment was associated with early cardiac side effects, which may have clinical and prognostic implications.

Impaired Right Atrial Reserve Function in Heart Failure with Preserved Ejection Fraction

Patients with heart failure with preserved ejection fraction (HFpEF) have multiple cardiac reserve limitations during exercise. However, no data are available regarding right atrial (RA) reserve capacity in HFpEF. The aim of this study was to determine the association of RA reserve impairments with right ventricular function and exercise capacity in HFpEF and to explore its diagnostic value. Patients with HFpEF (n=89) and control subjects without heart failure (n=108) underwent bicycle exercise echocardiography. RA reservoir, conduit, and booster pump strain at rest and during exercise were measured using speckle-tracking echocardiography. In a subset, simultaneous expired gas analysis was performed to measure peak oxygen consumption. At rest, RA reservoir strain was lower in patients with HFpEF than control subjects (27.0±17.1% vs 38.6±17.1%, P<.0001), while RA conduit and booster pump strain were similar between groups. During peak exercise, patients with HFpEF displayed marked reserve limitations in RA reservoir and booster pump function compared with control subjects, and the differences remained significant even after adjusting for confounding factors. During peak exercise, RA reservoir and booster pump strain were correlated with right ventricular systolic function. Lower RA booster pump strain during exercise was also weakly associated with lower cardiac output (r=0.34, P<.0001) and reduced peak oxygen consumption (r=0.47, P<.0001). RA reservoir strain during exercise had incremental diagnostic value to differentiate patients with HFpEF from control subjects over the established HFpEF diagnostic algorithms and left-sided strain parameters. Limitations in RA reservoir and booster pump function during exercise are present in patients with HFpEF, and the severity is associated with right ventricular systolic reserve, poor cardiac output, and depressed exercise capacity. Exercise RA strain assessment may help in the diagnosis of HFpEF.

Impaired biventricular contractile reserve in patients with diastolic dysfunction: insights from exercise stress echocardiography.

Cardiac output limitation is a fundamental feature of heart failure with preserved ejection fraction (HFpEF) but the relative contribution of its determinants in symptomatic vs. asymptomatic stages are not well characterized. We aimed to gain insight into disease mechanisms by performing comprehensive comparative non-invasive exercise imaging in patients across the disease spectrum. We performed bicycle stress echocardiography in 10 healthy controls, 13 patients with hypertensive left ventricular (LV) concentric remodelling and asymptomatic diastolic dysfunction (HTDD), 15 HFpEF patients, and 15 subjects with isolated right ventricular (RV) dysfunction secondary to chronic thromboembolic pulmonary hypertension (CTEPH). During exercise, ventricular performance differed across the groups (all P ≤ 0.01 for interaction). Notably in controls, LV and RV function significantly increased (all P < 0.05) while both LV systolic and diastolic reserve were significantly reduced in HFpEF patients. Likewise, RV systolic reserve was also impaired in HFpEF but not to the extent of CTEPH patients (P < 0.001 between groups). HTDD patients behaved as an intermediary group with borderline LV systolic and diastolic reserve and reduced RV systolic reserve. The increased pulmonary vascular (PV) load in HFpEF and CTEPH patients in combination with impaired RV reserve resulted in RV-pulmonary artery uncoupling during exercise. The multifaceted decline of cardiac and PV function accompanying disease progression in HFpEF is unmasked by exercise and already emerges in preclinical disease. The revelation of these subtle abnormalities during exercise illustrates the benefit of exercise imaging and creates new prospects for early diagnosis and management.

Exercise Systolic Reserve and Exercise Pulmonary Hypertension Improve Diagnosis of Heart Failure With Preserved Ejection Fraction.

AimsDiastolic stress testing (DST) is recommended to confirm heart failure with preserved ejection fraction (HFpEF) in patients with exertional dyspnea, but current algorithms do not detect all patients. We aimed to identify additional echocardiographic markers of elevated pulmonary arterial wedge pressure during exercise (exPAWP) in patients referred for DST.Methods and ResultsWe identified candidate parameters in 22 patients referred for exercise right heart catheterization with simultaneous echocardiography. Elevated exPAWP (≥25 mmHg) was present in 14 patients, and was best identified by peak septal systolic annular velocity <9.5 cm/s [exS', area under the receiver operating characteristic curve (AUC) 0.97, 95% confidence interval 0.92–1.0] and mean pulmonary artery pressure/cardiac output slope ≥3.2 mmHg/L [mPAP/CO, AUC 0.88 (0.72–1.0)]. We propose a decision tree to identify patients with elevated exPAWP. Applying this decision tree to 326 patients in an independent non-invasive DST cohort showed that patients labeled as “high probability of HFpEF” (n = 85) had reduced peak oxygen uptake [13.0 (10.7–15.1) mL/kg/min, p < 0.001 vs. intermediate/low probability], high H2FPEF score [53 (40–72) %, p < 0.001 vs. intermediate/low probability], and typical clinical characteristics. The diagnostic yield of DST increased from 11% using exercise E/e', to 62% using the decision tree.ConclusionIn DST for suspected HFpEF, exS' was the most accurate echocardiographic parameter to identify elevated PAWP. We propose a decision tree including exS' and mPAP/CO for interpretation of DST. Application of this decision tree revealed typical HFpEF characteristics in patients labeled as high probability of HFpEF, and substantially reduced the number of inconclusive results.

Abstract 11241: Longitudinal Myocardial Mechanics in Covid-19 Survivors with Normal Left Ventricular Ejection Fraction, a Single Center Study

Introduction: Subclinical cardiovascular involvement in COVID-19 patients has not been well described. 2D-Speckle Tracking Echocardiography derived global longitudinal strain (GLS) and systolic and early diastolic strain rate (SRs, SRe) measurements are more sensitive than standard echocardiographic parameters to diagnose subclinical mechanical dysfunction in patients with normal Left Ventricle Ejection Fraction (LVEF). Hypothesis: Evaluate subclinical myocardial mechanical function and reserve in active COVID-19 systemic disease patients with normal LVEF vs controls and between survivors and non survivors of COVID-19 in the longitudinal domain of contractility. Methods &amp; Results: 166 adult patients with active COVID 19 having normal LVEF were included and compared to 89 healthy volunteers. Baseline parameters were recorded. Peak GLS, SRs and SRe, were measured offline. Mean age was 62.53 ± 18.96 years and 87 (52%) were males and Mean LVEF was 62±5%. COVID-19 patients had higher GLS compared to controls (-20.93%±0.30 vs. -18.48%±0.40; p value &lt;0.0001), SRs was similar (-0.97 s -1 ±0.10 vs. -0.98 s -1 ±0.02, p value 0.2528) and SRe was lower (0.85 s -1 ±0.0 vs. 1.05 s -1 ±0.02; p value &lt;0.0001) respectively. After adjusting for age and sex, GLS, SRs and SRe was significant (p&lt;0.001). GLS, SRs and SRe were similar in survivors vs. non survivors (p NS), both groups had elevated biomarkers (cardiac troponin, NT-pro BNP, CRP), but non survivors had higher levels (3.22±0.18 vs 3.62±0.28, p = 0.2371, 5.86±0.19 vs 7.15±0.27, p = 0.0004, 3.75±0.14 vs 4.31±0.21, p = 0.0422, 7.64±0.17 vs 8.26±0.25, p=0.0487 respectively) (Table 1). Conclusions: In our cohort, COVID-19 patients had better systolic reserve and abnormal relaxation compared to controls. There was no significant difference in strain (GLS) and strain rate (SRs &amp; SRe) amongst survivors and non survivors in the longitudinal domain of contractility despite of higher inflammatory biomarkers in non-survivors.

Troponin I phosphorylation is essential for cardiac reserve

With an increase in the body's metabolic demand (e.g., exercise), the heart must increase its pumping performance. To achieve this increased performance, the heart relies on its cardiac reserve, which is the ability to increase its systolic and diastolic function. The mechanism responsible for cardiac reserve is poorly understood. The myofilaments are essential for contraction/relaxation, with troponin I (the inhibitory subunit of troponin, TnI) being a key regulatory protein. Studies have shown that TnI serine 23/24 (S23/S24) phosphorylation is a key mechanism for accelerating relaxation by decreasing Ca2+ sensitivity. However, the role of TnI in cardiac reserve is unknown. For this study, we characterized the systolic and diastolic reserve in TnI S23/S24 phosphorylation-null transgenic mice (S23/S24 mutated to alanine [AA] mice). Even with increased Ca2+ sensitivity, the AA mice exhibited normal function at resting heart rate with no difference in cardiac structure compared with wild type. To examine the role TnI S23/S24 phosphorylation in systolic and diastolic reserve, we assessed hemodynamics via left ventricular catheterization on the Bowditch effect (i.e., an increase in contractile function with increasing heart rate) by increasing heart rate (from 240 to 420 beats per minute) and sympathetic stimulation (dobutamine). Our data exhibited a clear loss of diastolic and systolic reserve in the AA mice with increasing heart rate and dobutamine. Since we observed a clear inability to increase systolic and diastolic function in AA mice, we performed speckle tracking echocardiography to quantitatively characterize function at resting heart rate. We observed that AA mice demonstrated normal systolic function (radial strain rate) and impaired directional diastolic function (reverse radial strain rate) at resting heart rate. We conclude that TnI S23/S24 phosphorylation is essential for cardiac reserve by enhancing systolic and diastolic function. A blunted cardiac reserve leads to heart disease making TnI S23/S24 phosphorylation a potential therapeutic strategy.

Abstract MP209: Troponin I Phosphorylation Is Essential For Cardiac Reserve

In response to increase in metabolic demand (e.g., exercise), the heart must increase its pumping performance to meet this demand. To achieve this increase, the heart relies on its cardiac reserve, which is the ability to increase in its contractile and diastolic function. The mechanism responsible for cardiac reserve is poorly understood. The myofilament is the mechanism responsible for contraction and relaxation. Troponin I (the inhibitory subunit of troponin, TnI) is a key regulatory protein. Studies have shown TnI serine 23/24 (S23/S24) phosphorylation, the most abundant and important TnI phosphorylation, is a key mechanism for accelerating relaxation by decreasing Ca 2+ senstivity. The role of TnI in cardiac reserve is unknown. For this study, we thoroughly characterized the systolic and diastolic reserve in TnI S23/S24 phosphorylation-null transgenic mice (S23/S24 mutated to alanine, AA mice). Even with increased Ca 2+ sensitivity, the AA mice exhibited normal function at resting heart rate and no difference in cardiac structure compared to wildtype. To increase in vivo heart performance, the most important system is the Bowditch effect (i.e., an increase in contractile function with increasing heart rate). To examine the role TnI S23/S24 phosphorylation in systolic and diastolic reserve, we assessed hemodynamics via left ventricular catheterization on the Bowditch effect by increasing heart rate from 240 to 420 beats per minute. Our data exhibited a clear loss of diastolic and systolic reserve in the AA mice. Since we observed a clear inability to increase systolic and diastolic function in AA mice, we performed speckle tracking echocardiography to more quantitatively investigate AA mice function. We observed that AA mice demonstrated normal systolic function (radial strain rate) and impaired directional diastolic function (reverse radial strain rate) at resting heart rate. We conclude that TnI S23/S24 phosphorylation is essential for cardiac reserve by enhancing systolic and diastolic function. A blunted cardiac reserve leads to heart disease making TnI S23/S24 phosphorylation a potential therapeutic strategy.