Comprehensive Physiological Modeling Provides Novel Insights Into Heart Failure With Preserved Ejection Fraction Physiology

Background Although a rapid rise in left atrial pressure during exertion is considered pathognomonic of heart failure with preserved ejection fraction (HFpEF), the fundamental circulatory determinants of this response are not clear, impacting upon the development of more effective therapies. We aimed to comprehensively describe the circulatory mechanics of patients with HFpEF at rest and during exercise in comparison with controls. Methods and Results We performed simultaneous right‐heart catheterization and echocardiography at rest and during exercise in 22 healthy control volunteers and 60 patients with confirmed HFpEF. Using detailed individual patient‐level hemodynamic and left ventricular ejection fraction data we performed computer simulations to evaluate the circulatory parameters including the estimated stressed blood volumethat contribute to the resting and exercise pulmonary capillary pressure. At rest and during exercise, left ventricular stiffness (V 30 , the end‐diastolic pressure–volume relationship at a filling pressure of 30 mm Hg), left ventricular elastance, and arterial elastance were all significantly greater in HFpEF than in controls. Stressed blood volume was significantly greater in HFpEF (26.9±5.4 versus 20.2±4.7 mL/kg, P <0.001), becoming even more pronounced during exercise (40.9±3.7 versus 27.5±7.0 mL per 70 kg, P <0.001). During exercise, the magnitude of the change in stressed blood volume ( r =0.67, P <0.001) and left ventricular stiffness ( r =−0.44, P <0.001) were key determinants of the rise in pulmonary capillary wedge pressure. Further detailed modeling studies showed that the hemodynamic response to exercise results from a complex non‐linear interaction between circulatory parameters. Conclusions The circulatory determinants of HFpEF physiology are complex. We identified stressed blood volume at rest and during exercise is a novel, key factor, therebyrepresenting an important potential therapeutic target.

Exercise alters Cardiac Function Independent of Acute Systemic Inflammation in Healthy Men

Acute elevations in inflammatory cytokines have been demonstrated to increase aortic and left ventricular stiffness and reduce endothelial function in healthy subjects. As vascular and cardiac function are often transiently reduced following prolonged exercise, it is possible that cytokines released during exercise may contribute to these alterations. The a priori aims of this study were to determine if vaccine-induced increases in inflammatory-cytokines would reduce vascular and left ventricular function, whether vascular alterations would drive cardiac impairments, and whether this would be potentiated by moderate exercise. In a randomized cross-over fashion, sixteen male participants were tested under control (CON) and inflammatory (INF) conditions, wherein INF testing occurred 8h following administration of an influenza vaccine. On both days, participants underwent measures of echocardiography performed during light cycling (stress-echocardiography), carotid-femoral pulse wave velocity (cf-PWV), and superficial femoral flow-mediated dilation (FMD) before and after cycling for 90min at ~85% of their first ventilatory threshold. IL-6 increased significantly (∆1.9±1.3pg/mL, P<0.001), while TNFα was non-significantly augmented (∆0.05±0.11pg/mL, P=0.09), 8h following vaccination. Vascular function was unaltered following cycling or inflammation (all P>0.05). The use of echocardiography during light cycling revealed cardiac alterations traditionally expected to occur only with greater exercise loads, with reduced systolic (e.g. longitudinal strain CON:∆3.3±4.4%, INF:∆1.7±2.7%, P=0.002) and diastolic function (e.g. E/A ratio CON:∆-0.32±0.34a.u., INF:∆-0.25±0.27a.u., P=0.002) following cycling, independent of inflammation. The vaccine reduced stroke volume (SV) (main effect of condition P=0.009) before-and-after cycling. These findings indicate that reduced cardiac function following exercise occurs largely independent of additional inflammatory load.

Rind from Purple Mangosteen (Garcinia mangostana) Attenuates Diet-Induced Physiological and Metabolic Changes in Obese Rats

The pulp of the purple mangosteen, Garcinia mangostana, is a popular tropical fruit but the rind containing xanthones such as α-mangostin together with procyanidins and anthocyanidins is usually discarded as waste. However, this rind has been used in South-East Asia for diarrhoea, dysentery, skin infections and wounds. As xanthones have reported anti-inflammatory and antioxidant responses, this study has determined the bioactive compounds and evaluated the effects of G. mangostana rind on physiological, metabolic, liver and cardiovascular parameters in rats with diet-induced metabolic syndrome. Rats fed a diet with increased simple sugars and saturated fats developed obesity, hypertension, increased left ventricular stiffness, dyslipidaemia and fatty liver. Administration of G. mangostana rind as 5% of the food to rats with diet-induced metabolic syndrome gave a dose of 168 mg/kg/day α-mangostin, 355 mg/kg/day procyanidins, 3.9 mg/kg/day anthocyanins and 11.8 mg/kg/day hydroxycitric acid for 8 weeks which reduced body weight and attenuated physiological and metabolic changes in rats including decreased abdominal fat deposition, decreased abdominal circumference and whole-body fat mass, improved liver structure and function and improved cardiovascular parameters such as systolic blood pressure, left ventricular stiffness and endothelial function. These responses were associated with decreased infiltration of inflammatory cells, decreased deposition of collagen in both heart and liver and decreased mean adipocyte size in retroperitoneal adipose tissues. We conclude that, in rats with diet-induced metabolic syndrome, chronic intake of G. mangostana rind decreased infiltration of inflammatory cells which decreased physiological, metabolic, liver and cardiovascular symptoms.

Increased left ventricular stiffness assessed by diastolic wall strain causes symptoms in patients with premature ventricular contraction

Background Premature ventricular contraction (PVC) is one of common arrhythmias and only some patients complain of PVC-related symptoms, however the mechanisms which cause the symptoms remain unclear in patients with PVCs. Purpose We investigated whether the left ventricular (LV) stiffness assessed by diastolic wall strain (DWS) relate symptoms or not in patients with PVC. Methods We studied 109 patients (48 males, age 60±19) with frequent monomorphic PVCs who underwent 12-leads electrocardiogram (ECG), signal-averaged electrocardiogram (SAECG), 24h-Holter ECG recording, and transthoracic echocardiography (TTE). Patients with structural heart disease or other arrhythmias such as atrial fibrillation were excluded. Clinical factors, blood samples for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), and filtered QRS duration (f-QRS) and root mean square voltage of the terminal 40ms of the QRS complex (RMS40) obtained by SAECG were evaluated. We assessed PVC-SV (stroke volume during PVC), PVC-CI (CI between the previous sinus beat and VPC), and left ventricular (LV) stiffness assessed by diastolic wall strain (DWS). DWS was calculated from the M-mode echocardiographic measurement of the LV posterior wall thickness at end-systole (PWs) and end-diastole (PWd) during sinus rhythm, and DWS was defined as (PWs − PWd)/PWs. Results 31patients (28%) had PVC-related symptoms (18 palpitation and 13 pulse deficit). Patients with PVC-related symptoms showed shorter PVC coupling interval index (52±10 vs. 58±11%, p=0.0140), reduced PVC-SV (21±12 vs. 29±17ml, p=0.0103) and decreased DWS (0.38±0.06 vs. 0.42±0.06, p=0.0011). Meanwhile, the level of BNP and ANP, f-QRS, RMS40, QRS morphology of PVC and the total number of PVC per day were not associated with PVC-related symptoms. On multivariate analysis, decreased DWS was only independently associated with PVC-related symptoms (p=0.0357, OR 2.3629 for each 0.1 decrease in DWS 95% CI 1.0583–5.5815). Conclusion The reduced diastolic wall strain relates with PVC-related symptoms. The increased left ventricular stiffness might cause symptoms in patients with PVC. Funding Acknowledgement Type of funding source: None