Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure

Background Recent studies indicated that sodium glucose cotransporter (SGLT)2 inhibition increases levels of ketone bodies in the blood in patients with type 1 and 2 diabetes. Other studies suggested that in patients with chronic heart failure (CHF), increased myocardial oxygen demand can be provided by ketone bodies as a fuel substrate. Experimental studies reported that ketone bodies, specifically beta-hydroxybutyrate (β-OHB) may increase blood pressure (BP) by impairing endothelium-dependant relaxation, thereby leading to increased vascular stiffness. In our study we assessed whether the SGLT 2 inhibition with empagliflozin increases ketone bodies in patients with stable CHF and whether such an increase impairs BP and vascular function. Methods In a prospective, double blind, placebo controlled, parallel-group single centre study 75 patients with CHF (left ventricular ejection fraction 39.0 ± 8.2%) were randomised (2:1) to the SGLT-2 inhibitor empagliflozin 10 mg orally once daily or to placebo, 72 patients completed the study. After a run-in phase we evaluated at baseline BP by 24 h ambulatory blood pressure (ABP) monitoring, vascular stiffness parameters by the SphygmoCor system (AtCor Medical, Sydney, NSW, Australia) and fasting metabolic parameters, including β-OHB by an enzymatic assay (Beckman Coulter DxC 700 AU). The same measurements were repeated 12 weeks after treatment. In 19 of the 72 patients serum levels of β-OHB were beneath the lower border of our assay (< 0.05 mmol/l) therefore being excluded from the subsequent analysis. Results In patients with stable CHF, treatment with empagliflozin (n = 36) was followed by an increase of β-OHB by 33.39% (p = 0.017), reduction in 24 h systolic (p = 0.038) and diastolic (p = 0.085) ABP, weight loss (p = 0.003) and decrease of central systolic BP (p = 0.008) and central pulse pressure (p = 0.008). The increase in β-OHB was related to an attenuated decrease of empagliflozin-induced 24 h systolic (r = 0.321, p = 0.069) and diastolic (r = 0.516, p = 0.002) ABP and less reduction of central systolic BP (r = 0.470, p = 0.009) and central pulse pressure (r = 0.391, p = 0.033). No significant changes were seen in any of these parameters after 12 weeks of treatment in the placebo group (n = 17). Conclusion In patients with stable CHF ketone bodies as assessed by β-OHB increased after treatment with empagliflozin. This increase led to an attenuation of the beneficial effects of empagliflozin on BP and vascular parameters. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT03128528).

Aortic Root Diameter and Arterial Stiffness: Conjoint Relations to the Incidence of Cardiovascular Disease in the Framingham Heart Study

Higher central pulse pressure is associated with higher carotid-femoral pulse wave velocity (CFPWV) and an increased risk of cardiovascular disease (CVD). A smaller aortic root diameter (AoR) is associated with higher central pulse pressure. We hypothesized that the combination of a smaller AoR and higher CFPWV is associated with increased CVD risk (relative to a larger AoR and lower CFPWV). We tested this hypothesis in the community-based Framingham Study (N=1970, mean age 60 years, 57% women). We created sex-specific longitudinal echocardiographic AoR trajectories over 2 decades, categorizing participants into smaller versus larger AoR groups. We cross-classified participants based on their AoR trajectory and CFPWV (dichotomized at the sex-specific median). We used Cox regression to relate the cross-classified groups to CVD incidence on follow-up (median 17 years): lower CFPWV, larger AoR (referent group; 6.4/1000 person-years); lower CFPWV, smaller AoR (6.9/1000 person-years); higher CFPWV, larger AoR (23.1/1000 person-years); and higher CFPWV, smaller AoR (21.9/1000 person-years). In sex-pooled analyses, groups with higher CFPWV were associated with a multivariable-adjusted 1.8-fold risk of CVD ( P <0.01) regardless of AoR size. We observed effect modification by sex ( P for sex×AoR-CFPWV group interaction 0.04). In men, the group with smaller AoR and higher CFPWV was associated with a 2.5- to 2.8-fold risk of CVD ( P <0.001). In women, the group with larger AoR and higher CFPWV experienced a statistically nonsignificant 70% to 80% higher CVD risk. Our observations indicate that the prognostic significance of a smaller versus larger AoR varies in men versus women. Additional studies are warranted to confirm our findings.

Augmentation Index Predicts the Sweat Volume in Young Runners

Sweating during exercise is regulated by objective parameters, body weight, and endothelial function, among other factors. However, the relationship between vascular arterial stiffness and sweat volume in young adults remains unclear. This study aimed to identify hemodynamic parameters before exercise that can predict sweat volume during exercise, and post-exercise parameters that can be predicted by the sweat volume. Eighty-nine young healthy subjects (aged 21.9 ± 1.7 years, 51 males) were recruited to each perform a 3-km run on a treadmill. Demographic and anthropometric data were collected and hemodynamic data were obtained, including heart rate, blood pressure and pulse wave analysis using non-invasive tonometry. Sweat volume was defined as pre-exercise body weight minus post-exercise body weight. Post-exercise hemodynamic parameters were also collected. Sweat volume was significantly associated with gender, body surface area (BSA) (b = 0.288, p = 0.010), peripheral systolic blood pressure (SBP), peripheral and central pulse pressure (PP), and was inversely associated with augmentation index at an HR of 75 beats/min (AIx@HR75) (b = -0.005, p = 0.019) and ejection duration. While BSA appeared to predict central PP (B = 19.271, p ≤ 0.001), central PP plus AIx@HR75 further predicted sweat volume (B = 0.008, p = 0.025; B = -0.009, p = 0.003 respectively). Sweat volume was associated with peripheral SBP change (B = -17.560, p = 0.031). Sweat volume during a 3-km run appears to be influenced by hemodynamic parameters, including vascular arterial stiffness and central pulse pressure. Results of the present study suggest that vascular arterial stiffness likely regulates sweat volume during exercise.

Albuminuria intensifies the link between urinary sodium excretion and central pulse pressure in the general population: the Wakuya study

Background Central pulse pressure is responsible for the hemodynamics of vital organs, and monitoring this parameter is important for cardiovascular disease prevention. Excess sodium intake and (micro)albuminuria (a manifestation of renal microvascular damage) are known to be strong predictors of cardiovascular disease. We sought to investigate the cross-sectional relationships among dietary sodium intake, albuminuria, and central pulse pressure in a general population cohort. Methods The subjects were 933 apparently healthy adults (mean age, 56 ± 10 years). Radial pressure waveforms were recorded with applanation tonometry to estimate mean arterial pressure, central pulse pressure, forward and backward pressure amplitudes, and augmentation index. The urinary sodium/creatinine and albumin/creatinine ratios were measured in spot urine samples. Results Both the urinary sodium/creatinine and albumin/creatinine ratios were positively correlated with central pulse pressure, even after adjusting for mean arterial pressure (P &lt; 0.001). Moreover, both ratios had a synergistic influence on increasing the central pulse pressure independent of age, sex, estimated glomerular filtration rate, hyperlipidemia, and diabetes (interaction P = 0.04). A similar synergistic influence was found on the forward pressure amplitude, but not on the backward pressure amplitude or augmentation index. The overall results were not altered when the urinary albumin/creatinine ratio was replaced with the existence of chronic kidney disease. Conclusion (Micro)albuminuria strengthens the positive association between urinary sodium excretion and central pulse pressure and systolic forward pressure. Excess sodium intake may magnify the cardiovascular risk by widening the aortic pulsatile pressure, particularly in the presence of concomitant chronic kidney disease.

Personalized physiologic flow waveforms improve wave reflection estimates compared to triangular flow waveforms in adults

Central aortic pressure waveforms contain valuable prognostic information in addition to central systolic pressure. Using pressure-flow relations, wave separation analysis can be used to decompose aortic pressure waveforms into forward- (Pf) and backward-travelling (Pb) components. Reflection magnitude, the ratio of pressure amplitudes (RM=Pb/Pf), is a predictor of heart failure and all-cause mortality. Aortic flow can be measured via Doppler echocardiography or estimated using a triangular flow waveform; however, the latter may underestimate the flow waveform convexity and overestimate Pb and RM. We sought to determine the accuracy of a personalized synthetic physiologic flow waveform, compared to triangular and measured flow waveforms, for estimating wave reflection indices in 49 healthy young (27±6 yrs) and 29 older adults (66±6 yrs; 20 healthy, 9 CKD). Aortic pressure and measured flow waveforms were acquired via radial tonometry and echocardiography, respectively. Triangular and physiologic flow waveforms were constructed from aortic pressure waveforms. Compared to the measured flow waveform, the triangular waveform underestimated Pf in older, but not young, adults and overestimated Pb and RM in both groups. The physiologic waveform was equivalent to measured flow in deriving all wave reflection indices and yielded smaller mean absolute biases than the triangular waveform in all instances (p<0.05). Lastly, central pulse pressure was associated with triangular, but not physiologic, mean biases for Pb and RM independent of age or central arterial stiffness (p<0.05). These findings support the use of personalized physiologic flow waveforms as a more robust alternative to triangular flow waveforms when true flow cannot be measured.

Association of central arterial blood pressure and left ventricular hypertrophy in patients with chronic kidney disease

Aims: In the general population, central arterial blood pressure has proved to be more closely related to left ventricular hypertrophy than brachial arterial blood pressure. We aimed to investigate whether this relationship was true in patients with chronic kidney disease. Methods: In this retrospective study, we reviewed the medical records of 289 adult patients with chronic kidney disease from the Zhejiang Provincial People’s Hospital in Zhejiang, China. Demographic, echocardiographic, and brachial and central blood pressure parameters were retrieved from medical records. Central blood pressure was measured using the SphygmoCor® CvMS (AtCor, Australia) device and its corresponding software. Multivariate logistic regression analyses were performed to identify independent predictors of left ventricular hypertrophy. Receiver operating characteristic curves were used to determine the ability of central and brachial blood pressure to predict left ventricular hypertrophy.Results: The left ventricular mass index was positively associated with both central and brachial blood pressures. However, multiple logistic regression analysis demonstrated that a central pulse pressure ≥ 58 mm Hg was an independent risk factor for left ventricular hypertrophy (OR=5.597, 95%CI 2.363-13.259, P <0.001). Brachial pulse pressure is not superior to central pulse pressure in predicting left ventricular hypertrophy (AUC = 0.695, 95%CI 0.634-0.756, P < 0.001 vs. AUC = 0.687, 95%CI: 0.626 to 0.748, P < 0.001, respectively; P = 0.4824).Conclusions: Our results suggested that, similarly to the general population, central pulse pressure is a better parameter for predicting the occurrence of left ventricular hypertrophy in patients with chronic kidney disease.

Cardiovascular Effects of Aerobic Exercise With Self-Selected or Predetermined Intensity in Adolescents With Obesity

This study compared the effects of self-selected exercise intensity (SEI) versus predetermined exercise intensity (PEI) on blood pressure (BP) and arterial stiffness in adolescents with obesity. A total of 37 adolescents, 14.7 (1.6) years old, body mass index ≥95th percentile were randomly allocated into SEI (n = 18; 12 boys) or PEI (n = 19; 13 boys). Both groups exercised for 35 minutes on a treadmill, 3 times per week, for 12 weeks. The SEI could set the speed at the beginning of the sessions and make changes every 5 minutes. The PEI adolescents were trained at an intensity set at 60% to 70% of heart rate reserve. Brachial and central BP, pulse pressure, augmentation index, and carotid–femoral pulse wave were determined at baseline and after 12 weeks. Both groups reduced brachial systolic BP (SEI, Δ = −9 mm Hg; PEI, Δ = −4 mm Hg; P < .01), central systolic BP (SEI, Δ = −4 mm Hg; PEI, Δ = −4 mm Hg; P = .01), and central pulse pressure (SEI, Δ = −4 mm Hg; PEI, Δ = −3 mm Hg; P = .02) without differences between groups. No changes in the augmentation index and carotid–femoral pulse wave were observed in either group. The SEI induced similar changes in various cardiovascular outcomes compared with PEI in adolescents with obesity.