Reddy, Yogesh N.V.

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.

Abstract Funding Acknowledgements Type of funding sources: None. Background Aortic valve stenosis (AS) and heart failure with preserved ejection fraction (HFpEF) present with similar cardiac alterations, but their overlap is poorly understood.(1–3). Purpose To study left ventricular (LV) hypertrophy, diastolic dysfunction, left atrial (LA) dysfunction, hemodynamics, and exercise capacity according to HFpEF status versus AS severity. Methods Patients (n=206) with at least moderate AS (aortic valve area ≤0.85 cm2/m2) and discordant symptoms underwent cardiopulmonary exercise testing with simultaneous echocardiography. The population was stratified according to the probability of underlying HFpEF by the H2FPEF score [0–5 (AS/HFpEF-) vs. 6–9 points (AS/HFpEF+)] and AS severity (Moderate vs. Severe). Results Mean age was 73±10 years with 40% women. Stratification yielded 41 AS/HFpEF+ (20%) versus 165 AS/HFpEF- (80%) and 139 Severe (67%) versus 67 Moderate (33%) AS patients. AS/HFpEF+ patients had a lower LV global longitudinal strain, impaired diastolic function, reduced LV compliance, and more pronounced LA dysfunction compared to AS/HFpEF- patients. The mean pulmonary arterial pressure-cardiac output (mPAP/CO) slope was significantly higher in AS/HFpEF+ versus AS/HFpEF- (5.4±3.1 vs. 3.9±2.2 mmHg/L/min, respectively; p = 0.003), mainly driven by impaired cardiac output (CO) reserve and chronotropic incompetence, with signs of right ventricular-pulmonary arterial (RV-PA) uncoupling. AS/HFpEF+ versus AS/HFpEF- was associated with a lower peak aerobic capacity (11.5±3.7 vs. 15.9±5.9 mL/min/kg, respectively; p&lt;0.0001), but did not differ between Moderate and Severe AS (14.7±5.5 vs. 15.2±5.9mL/min/kg, respectively; p = 0.6). Conclusions A high H2FPEF score is associated with a reduced exercise capacity and adverse hemodynamics in patients with moderate to severe AS. Both exercise performance and hemodynamics correspond better with intrinsic cardiac dysfunction than AS severity itself.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is an increasingly common clinical syndrome with diagnostic challenges and no effective treatment. The high heterogeneity of HFpEF clinical syndrome demands novel technologies to distinguish from heart failure with reduced ejection Fraction (HFrEF). Currently, invasive hemodynamic exercise testing is performed to evaluate for HFpEF with right heart catheterization. Hypothesis: We hypothesize that a deep learning model can noninvasively detect patients with HFpEF using phonocardiogram (PCG). Methods: Eligible patients undergoing right heart catheterization were recruited after IRB approval. Eko duo stethoscope was used to record simultaneous ECG & PCG at the mitral area on the patients prior to right heart catheterization at baseline. Each recording was 30 seconds in length with a frequency range between 250 - 5000 Hz. R-wave peak detection was performed & beat to beat PCG annotations were performed. The annotated PCG signals were converted into Mel-frequency cepstral coefficients (MFCC) and padded to account for the difference in lengths. Deep Learning model was developed using a Sequential Neural Network with 80% data to train and validate the model and 20% hold out data was used for testing accuracy of the model. Receiver operating curve (ROC) was obtained to estimate area under the curve (AUC) for performance analysis. Results: 42 patients were enrolled with 25 patients diagnosed as HFpEF by right heart catheterization and 17 were reported as controls. 2544 & 1771 individual PCG annotations for HFpEF and controls were used for model training/validation and testing. The model performed reasonably well with accuracy of 0.89, F1 score of 0.88, precision of 0.80 and recall of 0.97 on the test data. ROC was obtained with AUC of 0.94. Conclusions: The results demonstrate the ability of the deep learning model to noninvasively detect HFpEF using PCG. Larger study is needed to validate these findings.

Abstract Aims It is widely held that heart failure (HF) does not cause exertional hypoxaemia, based upon studies in HF with reduced ejection fraction, but this may not apply to patients with HF and preserved ejection fraction (HFpEF). Here, we characterize the prevalence, pathophysiology, and clinical implications of exertional arterial hypoxaemia in HFpEF. Methods and results Patients with HFpEF (n = 539) and no coexisting lung disease underwent invasive cardiopulmonary exercise testing with simultaneous blood and expired gas analysis. Exertional hypoxaemia (oxyhaemoglobin saturation &lt;94%) was observed in 136 patients (25%). As compared to those without hypoxaemia (n = 403), patients with hypoxaemia were older and more obese. Patients with HFpEF and hypoxaemia had higher cardiac filling pressures, higher pulmonary vascular pressures, greater alveolar–arterial oxygen difference, increased dead space fraction, and greater physiologic shunt compared to those without hypoxaemia. These differences were replicated in a sensitivity analysis where patients with spirometric abnormalities were excluded. Regression analyses revealed that increases in pulmonary arterial and pulmonary capillary pressures were related to lower arterial oxygen tension (PaO2), especially during exercise. Body mass index (BMI) was not correlated with the arterial PaO2, and hypoxaemia was associated with increased risk for death over 2.8 (interquartile range 0.7–5.5) years of follow-up, even after adjusting for age, sex, and BMI (hazard ratio 2.00, 95% confidence interval 1.01–3.96; p = 0.046). Conclusion Between 10% and 25% of patients with HFpEF display arterial desaturation during exercise that is not ascribable to lung disease. Exertional hypoxaemia is associated with more severe haemodynamic abnormalities and increased mortality. Further study is required to better understand the mechanisms and treatment of gas exchange abnormalities in HFpEF.

Abstract Pericardial effusions can result in acute haemodynamic compromise and require rapid intervention. Understanding pericardial restraint is essential to determine the approach to newly identified pericardial effusions in the intensive care unit. As pericardial effusions stretch the pericardium, the pericardial compliance reserve is eventually exhausted, with an exponential rise in compressive pericardial pressure. The severity of pericardial pressure increase depends on both the rapidity and volume of pericardial fluid accumulation. This increase in pericardial pressure is reflected in an increase in measured left- and right-sided ‘filling’ pressures, but paradoxically left ventricular end-diastolic volume (the true left ventricular preload) is decreased. This uncoupling of filling pressures and preload is the hallmark of pericardial restraint. When this occurs acutely from a pericardial effusion, rapid recognition and pericardiocentesis can be lifesaving. In this review, we will discuss the haemodynamics and pathophysiology of acute pericardial effusions, provide a physiological guide to determine the need for pericardiocentesis in acute care, and discuss important caveats to management.

ABSTRACT Aims Cardiac and extracardiac abnormalities play important roles in heart failure with preserved ejection fraction (HFpEF). Biventricular cardiac power output (BCPO) quantifies the total rate of hydraulic work performed by both ventricles, suggesting that it may help to identify patients with HFpEF and more severe cardiac impairments to better individualize treatment. Methods and results Patients with HFpEF (n = 398) underwent comprehensive echocardiography and invasive cardiopulmonary exercise testing. Patients were categorized as low BCPO reserve (n = 199, &lt; median of 1.57 W) or preserved BCPO reserve (n = 199). As compared to those with preserved BCPO reserve, those with low reserve were older and leaner, with more atrial fibrillation, higher N-terminal pro-B-type natriuretic peptide levels, worse renal function, more impaired left ventricular (LV) global longitudinal strain, worse LV diastolic function and right ventricular longitudinal function. Cardiac filling pressures and pulmonary artery pressures at rest were higher in low BCPO reserve, but central pressures were similar during exercise to those with preserved BCPO reserve. Exertional systemic and pulmonary vascular resistances were higher and exercise capacity was more impaired in those with low BCPO reserve. Reduced BCPO reserve was associated with increased risk for the composite endpoint of heart failure hospitalization or death over 2.9 (interquartile range 0.9–4.5) years of follow-up (hazard ratio 2.77, 95% confidence interval 1.73–4.42, p &lt; 0.0001). Conclusions Inability to enhance BCPO during exercise is associated with more advanced HFpEF, increased systemic and pulmonary vascular resistance, reduced exercise capacity and increased adverse events in patients with HFpEF. Novel therapies that enhance biventricular reserve merit further investigation for patients with this phenotype.