Popović, Dejana

Multimodal imaging plays a central role in optimizing the evaluation and management of myocardial ischemia by leveraging the complementary strengths of echocardiography, cardiac magnetic resonance imaging (CMR), single photon emission computed tomography (SPECT), positron emission tomography (PET), and invasive coronary angiography (ICA). Noninvasive functional imaging is typically recommended for patients with intermediate to high pre-test probability of coronary artery disease, while coronary computed tomography angiography (CCTA) is preferred for low to intermediate risk. Stress echocardiography is valuable for detecting wall motion abnormalities and is particularly effective in multivessel or left main disease, where perfusion techniques may miss balanced ischemia. CMR offers high spatial resolution and quantitative assessment of myocardial blood flow (MBF), while SPECT and PET quantify ischemic burden, with PET providing superior accuracy for MBF and microvascular disease. ICA remains the gold standard for defining the presence, location, and severity of epicardial coronary stenosis. It is indicated when noninvasive imaging reveals high-risk features, when symptoms are refractory to medical therapy, or when noninvasive results are inconclusive. While ICA offers high spatial resolution, it alone cannot assess the hemodynamic significance of intermediate lesions, nor the coronary microvasculature. Adjunctive invasive hemodynamic and provocative coronary testing (e.g., Fractional Flow Reserve—FFR, invasive Coronary Flow Reserve—CFR, Index of Microcirculatory Resistance—IMR, acetylcholine test) provide essential insights, especially in ischemia with nonobstructive coronary arteries. Given its procedural risks, ICA should be reserved for cases where it will impact management. Intravascular imaging may be used to further characterize lesions. In summary, modality selection should be individualized based on patient characteristics, comorbidities, contraindications, and the need for anatomical versus physiological data. Integrating noninvasive and invasive modalities provides a comprehensive, patient-centered approach to ischemia evaluation.

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is a common heart disorder characterized by the thickening of the heart muscle, particularly in the left ventricle, which increases the risk of cardiac complications. This study aims to analyze the expression of apoptosis-regulating genes (CASP8, CASP9, CASP3, BAX, and BCL2) in blood samples from HCM patients, to better understand their potential as biomarkers for disease progression. Methods: Quantitative real-time PCR (qPCR) was used to evaluate gene expression in blood samples from 93 HCM patients. The correlation between apoptosis-regulating genes was conducted and clinical parameters were integrated for feature importance and clustering analysis. Results: Most patients exhibited significant downregulation of CASP8, CASP9, and CASP3. In contrast, BAX expression was elevated in 71 out of 93 patients, while BCL2 was increased in 55 out of 93 patients. Correlation analysis revealed weak negative correlations between the BAX/BCL2 ratio and CASP gene expression. Conclusions: These findings suggest that reduced expression of apoptotic genes may indicate a protective cellular mechanism, which could serve as a biomarker for disease progression. Further studies are needed to investigate the potential for therapeutic modulation of these pathways to improve patient outcomes.

Background: The aim of this study was to examine the effect of applying synchronized music and appropriate music selection on motivation for exercise and achieving better results in individuals of different fitness levels. Methods: The study included a total of 20 female participants, who for certain analyses were divided into two groups with slightly different levels of aerobic fitness: students from the Faculty of Sport and Physical Education (n = 10, age 23.0 ± 2.8), and middle-aged adult women exercising recreationally (n = 10, age 38.3 ± 11.6). Cardiopulmonary exercise testing (CPET) was conducted using a treadmill and gas analysis equipment, and motivational music qualities were assessed using the BMRI-2 questionnaire. The procedure included an initial maximal CPET test, echocardiography, and spirometric tests, followed by an interview to select preferred music tracks. A second CPET test was then performed with the chosen motivational music. The Borg Rating of Perceived Exertion (RPE) scale was used in both tests. Results: The internal consistency of the questionnaire was confirmed with a Cronbach’s Alpha of 0.982. The synchronized motivational music significantly improved cardiopulmonary parameters such as peak oxygen consumption (peak VO2), oxygen consumption (VO2) at the second ventilatory threshold (VT2), peak heart rate (peak HR), test duration, and reduced perceived exertion (RPE) at the beginning of the test and at the intensity level corresponding to the VT2. Negligible differences were noted between students and recreational athletes, so it can be assumed that music had an equal impact on these two groups of subjects. Conclusions: The study concluded that synchronous motivational music significantly enhances cardiopulmonary performance and reduces perceived fatigue during physical exertion by serving as a key motivational element and facilitating more economical movement.

ImportanceIncreases in pulmonary capillary wedge pressure (PCWP) during exercise reduce pulmonary artery (PA) compliance, increase pulsatile right ventricular (RV) afterload, and impair RV-PA coupling in patients with heart failure with preserved ejection fraction (HFpEF). The effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on pulmonary vascular properties and RV-PA coupling are unknown.ObjectiveTo test the effect of dapagliflozin on right ventricular performance and pulmonary vascular load during exertion in HFpEF.Design, Setting, and ParticipantsEvaluation of the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction (CAMEO-DAPA) randomized clinical trial demonstrated improvement in PCWP at rest and exercise over 24 weeks with dapagliflozin compared with placebo with participants recruited between February 2021 and May 2022. This secondary analysis evaluates the effects of dapagliflozin on pulsatile pulmonary vascular load and RV-PA coupling using simultaneous echocardiography and high-fidelity invasive hemodynamic testing with exercise. This was a single-center study including patients with hemodynamically confirmed HFpEF with exercise PCWP of 25 mm Hg or greater.InterventionsDapagliflozin or placebo for 24 weeks.Main Outcomes and MeasuresPulsatile pulmonary vascular load (PA compliance and elastance) and right ventricular performance (PA pulsatility index, RV systolic velocity [s′]/PA mean) during rest and exercise.ResultsAmong 37 randomized participants (mean [SD] age, 67.4 [8.5] years; 25 female [65%]; mean [SD] body mass index, 34.9 [6.7]; calculated as weight in kilograms divided by height in meters squared), there was no effect of dapagliflozin on PA loading or RV-PA interaction at rest. However, with exercise, dapagliflozin improved PA compliance (placebo-corrected mean difference, 0.57 mL/mm Hg; 95% CI, 0.11-1.03 mL/mm Hg; P = .02) and decreased PA elastance (stiffness; −0.17 mm Hg/mL; 95% CI, −0.28 to −0.07 mm Hg/mL; P = .001). RV function during exercise improved, with increase in PA pulsatility index (0.33; 95% CI, 0.08-0.59; P = .01) and increase in exercise RV s′ indexed to PA pressure (0.09 cm·s−1/mm Hg; 95% CI, 0.02-0.16 cm·s−1/mm Hg; P = .01). Improvements in pulsatile RV load and RV-PA coupling were correlated with reduction in right atrial (RA) pressure (PA elastance Pearson r = 0.55; P =.008; RV s′/PA elastance Pearson r = −0.60; P =.002) and PCWP (PA elastance Pearson r = 0.58; P <.001; RV s′/PA elastance Pearson r = −0.47; P = .02). Dapagliflozin increased resistance-compliance time (dapagliflozin, median [IQR] change, 0.06 [0.03-0.15] seconds; placebo, median [IQR] change, 0.01 [−0.02 to 0.05] seconds; P =.046), resulting in higher PA compliance for any exercise pulmonary vascular resistance.Conclusions and RelevanceResults of this randomized clinical trial reveal that treatment with dapagliflozin for 24 weeks reduced pulsatile pulmonary vascular load and enhanced dynamic RV-PA interaction during exercise in patients with HFpEF, findings that are related to the magnitude of PCWP reduction. Benefits on dynamic right ventricular–pulmonary vascular coupling may partially explain the benefits of SGLT2 inhibitors in HFpEF.Trial RegistrationClinicalTrials.gov Identifier: NCT04730947

Abstract Aims We aimed to clarify the extent to which cardiac and peripheral impairments to oxygen delivery and utilization contribute to exercise intolerance and risk for adverse events, and how this relates to diversity and multiplicity in pathophysiologic traits. Methods and results Individuals with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnoea (controls) underwent invasive cardiopulmonary exercise testing and clinical follow-up. Haemodynamics and oxygen transport responses were compared. HFpEF patients were then categorized a priori into previously-proposed, non-exclusive descriptive clinical trait phenogroups, including cardiometabolic, pulmonary vascular disease, left atrial myopathy, and vascular stiffening phenogroups based on clinical and haemodynamic profiles to contrast pathophysiology and clinical risk. Overall, patients with HFpEF (n = 643) had impaired cardiac output reserve with exercise (2.3 vs. 2.8 L/min, p = 0.025) and greater reliance on peripheral oxygen extraction augmentation (4.5 vs. 3.8 ml/dl, p < 0.001) compared to dyspnoeic controls (n = 219). Most (94%) patients with HFpEF met criteria for at least one clinical phenogroup, and 67% fulfilled criteria for multiple overlapping phenogroups. There was greater impairment in peripheral limitations in the cardiometabolic group and greater cardiac output limitations and higher pulmonary vascular resistance during exertion in the other phenogroups. Increasing trait multiplicity within a given patient was associated with worse exercise haemodynamics, poorer exercise capacity, lower cardiac output reserve, and greater risk for heart failure hospitalization or death (hazard ratio 1.74, 95% confidence interval 1.08–2.79 for 0–1 vs. ≥2 phenogroup traits present). Conclusions Though cardiac output response to exercise is limited in patients with HFpEF compared to those with non-cardiac dyspnoea, the relative contributions of cardiac and peripheral limitations vary with differing numbers and types of clinical phenotypic traits present. Patients fulfilling criteria for greater multiplicity and diversity of HFpEF phenogroup traits have poorer exercise capacity, worsening haemodynamic perturbations, and greater risk for adverse outcome.

ABSTRACT Aim Left atrial (LA) myopathy is increasingly recognized as an important phenotypic trait in heart failure (HF) with preserved ejection fraction (HFpEF). Right atrial (RA) remodelling and dysfunction also develop in HFpEF, but little data are available regarding the clinical characteristics and pathophysiology among patients with isolated LA, RA, or biatrial myopathy. Methods and results Patients with HFpEF underwent invasive haemodynamic exercise testing, comprehensive imaging including speckle tracking strain echocardiography, and clinical follow-up at Mayo Clinic between 2006 and 2018. LA myopathy was defined as LA volume index >34 ml/m2 and/or LA reservoir strain ≤24% and RA myopathy by RA volume index >39 ml/m2 in men and >33 ml/m2 in women and/or RA reservoir strain ≤19.8%. Of 476 consecutively evaluated patients with HFpEF defined by invasive exercise testing with evaluable atrial structure/function, 125 (26%) had no atrial myopathy, 147 (31%) had isolated LA myopathy, 184 (39%) had biatrial myopathy, and 20 (4%) had isolated RA myopathy. Patients with HFpEF and biatrial myopathy had more atrial fibrillation, poorer left ventricular systolic and diastolic function, more severe pulmonary vascular disease, tricuspid regurgitation, ventricular interdependence and right ventricular dysfunction, and poorer cardiac output reserve with exercise. There were 94 patients with events over a median follow-up of 2.9 (interquartile range 1.4–4.6) years. Individuals with biatrial myopathy had an 84% higher risk of HF hospitalization or death as compared to those with isolated LA myopathy (hazard ratio 1.84; 95% confidence interval 1.16–2.92, p = 0.01). Conclusions Biatrial myopathy identifies patients with more advanced HFpEF characterized by more severe pulmonary vascular disease, right HF, poorer cardiac reserve, and a greater risk for adverse outcomes. Further study is required to define optimal strategies to treat and prevent biatrial myopathy in HFpEF.

Abstract Background Pulmonary abnormalities are common in patients with prevalent heart failure (HF). Arterial hypoxemia is considered rare in HF, but this has not been rigorously evaluated in patients with HF and preserved EF (HFpEF). Methods Results Patients with HFpEF (n=539) and no clinically-relevant lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxemia was defined by oxyhaeemoglobin saturation <94%. As compared to those without hypoxemia (n=403), patients with hypoxemia (n=136, 25%) were slightly older, heavier, and had higher NT-proBNP levels. They had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar-arterial O2 difference compared to those without hypoxemia. These differences were replicated in a sensitivity analysis where patients with any spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and capillary pressures were related to lower PaO2. The presence of exertional hypoxemia was associated with two-fold increased risk for death over 2.8 (IQR 0.7-5.5) years of follow up, (Adjusted:HR 2.00 (95%CI: 1.01−3.96), p=0.046). Conclusion One quarter of HFpEF patients displayed arterial desaturation during exercise. Patients with hypoxemia display more severely abnormal hemodynamics and increased mortality. Further study is required to better understand the mechanisms in patients with HFpEF.Hemodynamic changes at rest/exerciseRisk of death in HFpEF with hypoxemia

Abstract Background Right ventricular (RV) dysfunction is common in heart failure with preserved ejection fraction (HFpEF), portends worse prognosis, and is believed to be caused by contractile impairment and remodeling due to afterload mismatch from pulmonary hypertension (PH). The goal of this study was to examine the right heart in patients with HFpEF and resting mean pulmonary arterial (PA) pressure (MPAP)≤20 mmHg. Methods and results Among 621 patients with HFpEF undergoing comprehensive echocardiography and invasive cardiopulmonary exercise testing, 159 (26%) had resting MPAP≤20 mmHg (HFpEFMPAP≤20mmHg). In comparison to 73 controls, they were more obese, had more coronary disease and atrial fibrillation. After adjusting for BMI, there were no differences in plasma volume but NTproBNP was higher and peak oxygen consumption lower in HFpEFMPAP≤20mmHg than in controls (p = 0.002, <0.001, respectively). While RV dimension was similar, tricuspid annular plane systolic excursion and RVs’ were lower in HFpEFMPAP≤20mmHg (18±5 vs. 22±4 mm, p = 0.005; 10±2 vs. 12±2 cm/s, p = 0.047, respectively). HFpEFMPAP≤20mmHg and controls displayed similar pulmonary vascular resistance, MPAP and right atrial pressure at rest, but during exercise, MPAP and right atrial pressure were higher in patients with HFpEFMPAP≤20mmHg (41±10 vs. 33±10 mmHg; 18±7 vs. 12±4 mmHg, p<0.001, respectively). PA compliance was lower at both rest and exercise (rest 4.1±2.1 vs. 5.0±1.8; exercise 2.9±1.4 vs. 3.2±1.4 ml/mmHg, p<0.001, for both). Conclusion Right heart dysfunction is present in patients with HFpEF even in the absence of frank PH. These patients display greater pulsatile RV loading by PA compliance even as resistance is not markedly elevated. These data support further study into novel therapies targeting pulsatile RV afterload in HFpEF.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors reduce risk of hospitalization for heart failure in patients who have heart failure with preserved ejection fraction (HFpEF), but the hemodynamic mechanisms underlying these benefits remain unclear. This study sought to determine whether treatment with dapagliflozin affects pulmonary capillary wedge pressure (PCWP) at rest and during exercise in patients with HFpEF. METHODS: This was a single-center, double-blinded, randomized, placebo-controlled trial testing the effects of 10 mg of dapagliflozin once daily in patients with HFpEF. Patients with New York Heart Association class II or III heart failure, ejection fraction ≥50%, and elevated PCWP during exercise were recruited. Cardiac hemodynamics were measured at rest and during exercise using high-fidelity micromanometers at baseline and after 24 weeks of treatment. The primary end point was a change from baseline in rest and peak exercise PCWPs that incorporated both measurements, and was compared using a mixed-model likelihood ratio test. Key secondary end points included body weight and directly measured blood and plasma volumes. Expired gas analysis was performed evaluate oxygen transport in tandem with arterial lactate sampling. RESULTS: Among 38 patients completing baseline assessments (median age 68 years; 66% women; 71% obese), 37 completed the trial. Treatment with dapagliflozin resulted in reduction in the primary end point of change in PCWP at rest and during exercise at 24 weeks relative to treatment with placebo (likelihood ratio test for overall changes in PCWP; P <0.001), with lower PCWP at rest (estimated treatment difference [ETD], −3.5 mm Hg [95% CI, −6.6 to −0.4]; P =0.029) and maximal exercise (ETD, −5.7 mm Hg [95% CI, −10.8 to −0.7]; P =0.027). Body weight was reduced with dapagliflozin (ETD, −3.5 kg [95% CI, −5.9 to −1.1]; P =0.006), as was plasma volume (ETD, −285 mL [95% CI, −510 to −60]; P =0.014), but there was no significant effect on red blood cell volume. There were no differences in oxygen consumption at 20-W or peak exercise, but dapagliflozin decreased arterial lactate at 20 W (−0.70 ± 0.77 versus 0.37 ± 1.29 mM; P =0.006). CONCLUSIONS: In patients with HFpEF, treatment with dapagliflozin reduces resting and exercise PCWP, along with the favorable effects on plasma volume and body weight. These findings provide new insight into the hemodynamic mechanisms of benefit with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04730947.

This review emphasizes the importance of cardiopulmonary exercise testing (CPET) in patients diagnosed with hypertrophic cardiomyopathy (HCM). In contrast to standard exercise testing and stress echoes, which are limited due to the ECG changes and wall motion abnormalities that characterize this condition, CPET allows for the assessment of the complex pathophysiology and severity of the disease, its mechanisms of functional limitation, and its risk stratification. It is useful tool to evaluate the risk for sudden cardiac death and select patients for cardiac resynchronization therapy (CRT), cardiac transplantation, or mechanical circulatory support, especially when symptomatology and functional status are uncertain. It may help in differentiating HCM from other forms of cardiac hypertrophy, such as athletes’ heart. Finally, it is used to guide and monitor therapy as well as for exercise prescription. It may be considered every 2 years in clinically stable patients or every year in patients with worsening symptoms. Although performed only in specialized centers, CPET combined with echocardiography (i.e., CPET imaging) and invasive CPET are more informative and provide a better assessment of cardiac functional status, left ventricular outflow tract obstruction, and diastolic dysfunction during exercise in patients with HCM.