The Oxygen Cascade According to HFpEF Likelihood: A Focus on Sex Differences.

Background: Women are at greater risk for heart failure with preserved ejection fraction (HFpEF). Objectives: The aim of the study was to compare sex differences in the pathophysiology of exertional breathlessness in patients with high vs low HFpEF likelihood. Methods: This cohort study evaluated consecutive patients (n = 1,936) with unexplained dyspnea using cardiopulmonary exercise testing and simultaneous echocardiography and quantified peak oxygen uptake (peak VO2) and its determinants. HFpEF was considered likely when the H2FPEF or HFA-PEFF score was ≥6 or ≥5, respectively. Sex differences were evaluated with the Student's t-test or Mann-Whitney U test and determinants of exercise capacity with a multivariable linear regression. Results: The cohort included 1,963 patients (49% women and 28% [n = 555] with a high HFpEF likelihood). HFpEF likelihood did not impact the magnitude of sex differences in peak VO2 and its determinants. Overall, women had lower peak VO2 (mean difference -4.4 mL/kg/min [95% CI: -3.7 to -5.1 mL/kg/min]) secondary to a reduced O2 delivery (-0.5 L/min [95% CI: -0.4 to -0.6 L/min]) and less oxygen extraction (-2.9 mL/dL [95% CI: -2.5 to -3.2 mL/dL]). Reduced O2 delivery was due to lower hemoglobin (-1.2 g/dL [95% CI: -0.9 to -1.5 g/dL]) and smaller stroke volume (-15 mL [95% CI: -14 to -17 mL]). Women demonstrated increased mean pulmonary artery pressure/cardiac output slope (+0.5 mm Hg/L/min [95% CI: 0.3-0.7 mm Hg/L/min]) and left ventricular ejection fraction (+1% [95% CI: 1%-2%]), while they had smaller left ventricular end-diastolic volumes (-9 mL/m2 [95% CI: -8 to -11 mL/m2]) and mass (-12 g/m2 [95% CI: -9 to -14 g/m2]) and more often iron deficiency (55% vs 33%; P < 0.001). Conclusions: Women with unexplained dyspnea had significantly lower peak VO2, regardless of HFpEF likelihood, attributed to both lower peak exercise O2 delivery and extraction. This suggests that physiologic sex differences, and not HFpEF likelihood, are an important factor contributing to functional limitations in females with exertional breathlessness.

Too Little of a Good Thing: Strong Associations Between Cardiac Size and Fitness Among Women.

BACKGROUND: Cardiorespiratory fitness (CRF) is associated with functional impairment and cardiac events, particularly heart failure (HF). However, the factors predisposing women to low CRF and HF remain unclear. OBJECTIVES: This study sought to evaluate the association between CRF and measures of ventricular size and function and to examine the potential mechanism linking these factors. METHODS: A total of 185 healthy women aged >30 years (51 ± 9 years) underwent assessment of CRF (peak volume of oxygen uptake [Vo2peak]) and biventricular volumes at rest and during exercise by using cardiac magnetic resonance (CMR). The relationships among Vo2peak, cardiac volumes, and echocardiographic measures of systolic and diastolic function were assessed using linear regression. The effect of cardiac size on cardiac reserve (change in cardiac function during exercise) was assessed by comparing quartiles of resting left ventricular end-diastolic volume (LVEDV). RESULTS: Vo2peak was strongly associated with resting measures of LVEDV and right ventricular end-diastolic volume (R2 = 0.58-0.63; P < 0.0001), but weakly associated with measures of resting left ventricular (LV) systolic and diastolic function (R2 = 0.01-0.06; P < 0.05). Increasing LVEDV quartiles were positively associated with cardiac reserve, with the smallest quartile showing the smallest reduction in LV end-systolic volume (quartile [Q]1: -4 mL vs Q4: -12 mL), smallest augmentation in LV stroke volume (Q1: +11 mL vs Q4: +20 mL) and cardiac output (Q1: +6.6 L/min vs Q4: +10.3 L/min) during exercise (interaction P < 0.001 for all). CONCLUSIONS: A small ventricle is strongly associated with low CRF because of the combined effect of a smaller resting stroke volume and an attenuated capacity to increase with exercise. The prognostic implications of low CRF in midlife highlight the need for further longitudinal studies to determine whether women with small ventricles are predisposed to functional impairment, exertional intolerance, and HF later in life.

Three-dimensional echocardiography of the athlete's heart: a comparison with cardiac magnetic resonance imaging.

Three-dimensional echocardiography (3DE) is the most accurate cardiac ultrasound technique to assess cardiac structure. 3DE has shown close correlation with cardiac magnetic resonance imaging (CMR) in various populations. There is limited data on the accuracy of 3DE in athletes and its value in detecting alterations during follow-up. Indexed left and right ventricular end-diastolic volume (LVEDVi, RVEDVi), end-systolic volume, ejection fraction (LVEF, RVEF) and left ventricular mass (LVMi) were assessed by 3DE and CMR in two-hundred and one competitive endurance athletes (79% male) from the Pro@Heart trial. Sixty-four athletes were assessed at 2 year follow-up. Linear regression and Bland-Altman analyses compared 3DE and CMR at baseline and follow-up. Interquartile analysis evaluated the agreement as cardiac volumes and mass increase. 3DE showed strong correlation with CMR (LVEDVi r = 0.91, LVEF r = 0.85, LVMi r = 0.84, RVEDVi r = 0.84, RVEF r = 0.86 p < 0.001). At follow up, the percentage change by 3DE and CMR were similar (∆LVEDVi r = 0.96 bias - 0.3%, ∆LVEF r = 0.94, bias 0.7%, ∆LVMi r = 0.94 bias 0.8%, ∆RVESVi r = 0.93, bias 1.2%, ∆RVEF r = 0.87 bias 0.4%). 3DE underestimated volumes (LVEDVi bias - 18.5 mL/m2, RVEDVi bias - 25.5 mL/m2) and the degree of underestimation increased with larger dimensions (Q1vsQ4 LVEDVi relative bias - 14.5 versus - 17.4%, p = 0.016; Q1vsQ4 RVEDVi relative bias - 17 versus - 21.9%, p = 0.005). Measurements of cardiac volumes, mass and function by 3DE correlate well with CMR and 3DE accurately detects changes over time. 3DE underestimates volumes and the relative bias increases with larger cardiac size.

Chronic thromboembolic pulmonary hypertension: diagnosis, operability assessment and patient selection for pulmonary endarterectomy.

Healthcare providers outside pulmonary hypertension (PH) centers having misinformation or insufficient education, and a general lack of treatment awareness contribute to a massive underdiagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), diagnostic delay and refusal of surgery by patients. Together with the subjective operability assessment, this leads to too few patients undergoing pulmonary endarterectomy (PEA); even though this surgery results in improved survival and exercise capacity. Acute pulmonary embolism (PE) survivors should undergo a CTEPH screening strategy. Patients screened positive and those with CTEPH symptoms (with or without history of PE), should undergo transthoracic echocardiography (TTE) to determine the probability of PH. High PH probability patients should undergo a ventilation/perfusion (V/Q) scan. A negative scan rules out CTEPH. Patients with a positive V/Q scan, but also patients with findings suggestive for CTEPH on computed tomography pulmonary angiography (CTPA) to diagnose acute PE, should be referred to a CTEPH center. Further diagnostic work-up currently consists of catheter based pulmonary angiography, CTPA and right heart catheterization. However, new imaging technologies might replace them in the near future, with one single imaging tool to screen, diagnose and assess operability as the ultimate goal. Operability assessment should be performed by a multidisciplinary CTEPH team. PEA surgery should be organized in a single center per country or for each forty to fifty million inhabitants in order to offer the highest level of expertise. Informing patients about PEA should preferably be done by the treating surgeon. Based on the estimated incidence of CTEPH and with a better education of patients and healthcare providers, despite the advent of new interventional and medical therapies for CTEPH, the number of PEA surgeries performed should still have the potential to grow significantly.

Iron Deficiency Is Associated With Impaired Biventricular Reserve and Reduced Exercise Capacity in Patients With Unexplained Dyspnea.

BACKGROUND: Iron deficiency (ID) is frequent and associated with diminished exercise capacity in heart failure (HF), but its contribution to unexplained dyspnea without a HF diagnosis at rest remains unclear. METHODS AND RESULTS: Consecutive patients with unexplained dyspnea and normal echocardiography and pulmonary function tests at rest underwent prospective standardized cardiopulmonary exercise testing with echocardiography in a tertiary care dyspnea clinic. ID was defined as ferritin of <300 µg/L and a transferrin saturation of <20% and its impact on peak oxygen uptake (peakVO2), biventricular response to exercise, and peripheral oxygen extraction was assessed. Of 272 patients who underwent cardiopulmonary exercise testing with echocardiography, 63 (23%) had ID. For a similar respiratory exchange ratio, patients with ID had lower peakVO2 (14.6 ± 7.6 mL/kg/minvs 17.8 ± 8.8 mL/kg/min; P = .009) and maximal workload (89 ± 50 watt vs 108 ± 56 watt P = .047), even after adjustment for the presence of anemia. At rest, patients with ID had a similar left ventricular and right ventricular (RV) contractile function. During exercise, patients with ID had lower cardiac output reserve (P < .05) and depressed RV function by tricuspid s' (P = .004), tricuspid annular plane systolic excursion (P = .034), and RV end-systolic pressure-area ratio (P = .038), with more RV-pulmonary artery uncoupling measured by tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure ratio (P = .023). RV end-systolic pressure-area ratio change from rest to peak exercise, as a load-insensitive metric of RV contractility, was lower in patients with ID (2.09 ± 0.72 mm Hg/cm2 vs 2.58 ± 1.14 mm Hg/cm2; P < .001). ID was associated with impaired peripheral oxygen extraction (peakVO2/peak cardiac output; P = .036). Cardiopulmonary exercise testing with echocardiography resulted in a diagnosis of HF with preserved ejection fraction in 71 patients (26%) based on an exercise E/e' ratio of >14, with equal distribution in patients with (28.6%) or without ID (25.4%, P = .611). None of these findings were influenced in a sensitivity analysis adjusted for a final diagnosis of HFpEF as etiology for the unexplained dyspnea. CONCLUSIONS: In patients with unexplained dyspnea without clear HF at rest, ID is common and associated with decreased exercise capacity, diminished biventricular contractile reserve, and decreased peripheral oxygen extraction.

The effect of posture on maximal oxygen uptake in active healthy individuals.

PURPOSE: Semi-supine and supine cardiopulmonary exercise testing (CPET) with concurrent cardiac imaging has emerged as a valuable tool for evaluating patients with cardiovascular disease. Yet, it is unclear how posture effects CPET measures. We aimed to discern the effect of posture on maximal oxygen uptake (VO2max) and its determinants using three clinically relevant cycle ergometers. METHODS: In random order, 10 healthy, active males (Age 27 ± 7 years; BMI 23 ± 2 kg m2) underwent a ramp CPET and subsequent constant workload verification test performed at 105% peak ramp power to quantify VO2max on upright, semi-supine and supine cycle ergometers. Doppler echocardiography was conducted at peak exercise to measure stroke volume (SV) which was multiplied by heart rate (HR) to calculate cardiac output (CO). RESULTS: Compared to upright (46.8 ± 11.2 ml/kg/min), VO2max was progressively reduced in semi-supine (43.8 ± 10.6 ml/kg/min) and supine (38.2 ± 9.3 ml/kg/min; upright vs. semi-supine vs. supine; all p ≤ 0.005). Similarly, peak power was highest in upright (325 ± 80 W), followed by semi-supine (298 ± 72 W) and supine (200 ± 51 W; upright vs. semi-supine vs. supine; all p < 0.01). Peak HR decreased progressively from upright to semi-supine to supine (186 ± 11 vs. 176 ± 13 vs. 169 ± 12 bpm; all p < 0.05). Peak SV and CO were lower in supine relative to semi-supine and upright (82 ± 22 vs. 92 ± 26 vs. 91 ± 24 ml and 14 ± 3 vs. 16 ± 4 vs. 17 ± 4 l/min; all p < 0.01), but not different between semi-supine and upright. CONCLUSION: VO2max is progressively reduced in reclined postures. Thus, posture should be considered when comparing VO2max results between different testing modalities.

The Utility of Cardiac Reserve for the Early Detection of Cancer Treatment-Related Cardiac Dysfunction: A Comprehensive Overview.

With progressive advancements in cancer detection and treatment, cancer-specific survival has improved dramatically over the past decades. Consequently, long-term health outcomes are increasingly defined by comorbidities such as cardiovascular disease. Importantly, a number of well-established and emerging cancer treatments have been associated with varying degrees of cardiovascular injury that may not emerge until years following the completion of cancer treatment. Of particular concern is the development of cancer treatment related cardiac dysfunction (CTRCD) which is associated with an increased risk of heart failure and high risk of morbidity and mortality. Early detection of CTRCD appears critical for preventing long-term cardiovascular morbidity in cancer survivors. However, current clinical standards for the identification of CTRCD rely on assessments of cardiac function in the resting state. This provides incomplete information about the heart's reserve capacity and may reduce the sensitivity for detecting sub-clinical myocardial injury. Advances in non-invasive imaging techniques have enabled cardiac function to be quantified during exercise thereby providing a novel means of identifying early cardiac dysfunction that has proved useful in several cardiovascular pathologies. The purpose of this narrative review is (1) to discuss the different non-invasive imaging techniques that can be used for quantifying different aspects of cardiac reserve; (2) discuss the findings from studies of cancer patients that have measured cardiac reserve as a marker of CTRCD; and (3) highlight the future directions important knowledge gaps that need to be addressed for cardiac reserve to be effectively integrated into routine monitoring for cancer patients exposed to cardiotoxic therapies.

The effect of minimally invasive surgical aortic valve replacement on postoperative pulmonary and skeletal muscle function.

NEW FINDINGS: What is the central question of this study? How does surgical aortic valve replacement affect cardiopulmonary and muscle function during exercise? What is the main finding and its importance? Early after the surgical replacement of the aortic valve a significant decline in pulmonary function was observed, which was followed by a decline in skeletal muscle function in the subsequent weeks of recovery. These date reiterate, despite restoration of aortic valve function, the need for a tailored rehabilitation programme for the respiratory and peripheral muscular system. ABSTRACT: Suboptimal post-operative improvements in functional capacity are often observed after minimally invasive aortic valve replacement (mini-AVR). It remains to be studied how AVR affects the cardiopulmonary and skeletal muscle function during exercise to explain these clinical observations and to provide a basis for improved/tailored post-operative rehabilitation. Twenty-two patients with severe aortic stenosis (AS) (aortic valve area (AVA) <1.0 cm²) were pre-operatively compared to 22 healthy controls during submaximal constant-workload endurance-type exercise for oxygen uptake ( V̇O2 ), carbon dioxide output ( V̇CO2 ), respiratory gas exchange ratio, expiratory volume ( V̇E ), ventilatory equivalents for O2 ( V̇E / V̇O2 ) and CO2 ( V̇E / V̇CO2 ), respiratory rate (RR), tidal volume (Vt ), heart rate (HR), oxygen pulse ( V̇O2 /HR), blood lactate, Borg ratings of perceived exertion (RPE) and exercise-onset V̇O2 kinetics. These exercise tests were repeated at 5 and 21 days after AVR surgery (n = 14), along with echocardiographic examinations. Respiratory exchange ratio and ventilatory equivalents ( V̇E / V̇O2 and V̇E / V̇CO2 ) were significantly elevated, V̇O2 and V̇O2 /HR were significantly lowered, and exercise-onset V̇O2 kinetics were significantly slower in AS patients vs. healthy controls (P < 0.05). Although the AVA was restored by mini-AVR in AS patients, V̇E / V̇O2 and V̇E / V̇CO2 further worsened significantly within 5 days after surgery, accompanied by elevations in Borg RPE, V̇E and RR, and lowered Vt . At 21 days after mini-AVR, exercise-onset V̇O2 kinetics further slowed significantly (P < 0.05). A decline in pulmonary function was observed early after mini-AVR surgery, which was followed by a decline in skeletal muscle function in the subsequent weeks of recovery. Therefore, a tailored rehabilitation programme should include training modalities for the respiratory and peripheral muscular system.

Exercise and the right ventricle: a potential Achilles' heel.

Exercise is associated with unequivocal health benefits and results in many structural and functional changes of the myocardium that enhance performance and prevent heart failure. However, intense exercise also presents a significant hemodynamic challenge in which the right-sided heart chambers are exposed to a disproportionate increase in afterload and wall stress that can manifest as myocardial fatigue or even damage if intense exercise is sustained for prolonged periods. This review focuses on the physiological factors that result in a disproportionate load on the right ventricle during exercise and the long-term consequences. The changes in cardiac structure and function that define 'athlete's heart' disproportionately affect the right-sided heart chambers and this can raise important diagnostic overlap with some cardiac pathologies, particularly some inherited cardiomyopathies. The interaction between exercise and arrhythmogenic right ventricular cardiomyopathy (ARVC) will be highlighted as an important example of how hemodynamic stressors can combine with deficiencies in cardiac structural elements to cause cardiac dysfunction predisposing to arrhythmias. The extent to which extreme exercise can cause adverse remodelling in the absence of a genetic predisposition remains controversial. In the athlete with profound changes in heart structure, it can be extremely challenging to determine whether common symptoms such as palpitations may be a marker of more sinister arrhythmias. This review discusses some of the techniques that have recently been proposed to identify pathology in these circumstances. Finally, we will discuss recent evidence defining the role of exercise restriction as a therapeutic intervention in individuals predisposed to arrhythmogenic cardiomyopathy.

Signs of RV overload on the athlete's ECG.

There is increasing evidence that regular intense endurance exercise can promote structural and electrical remodeling of the right ventricle (RV). These physiological changes can be profound and are frequently accompanied by ECG changes in the right precordial leads, thereby mimicking features observed in arrhythmogenic right ventricular cardiomyopathy (ARVC). Because the 12-lead ECG is used as both a screening and diagnostic tool for the detection of conditions associated with sudden death in athletes, it is of fundamental importance to have a good understanding of the ECG features that distinguish physiological adaptations to endurance exercise from those related to RV pathology as well as their potential overlap. This article describes ECG findings observed in healthy endurance athletes versus athletes with underlying RV pathology and illustrates their differentiation using 4 case presentations.