Mitigating Initial Orthostatic Hypotension: Mechanistic Roles of Muscle Contraction Versus Sympathetic Activation

Background: Initial orthostatic hypotension (IOH) is defined by a large drop in blood pressure (BP) within 15 s of standing. IOH often presents during an active stand, but not with a passive tilt, suggesting that a muscle activation reflex involving lower body muscles plays an important role. To our knowledge, there is no literature exploring how sympathetic activation affects IOH. We hypothesized involuntary muscle contractions before standing would significantly reduce the drop in BP seen in IOH while increasing sympathetic activity would not. Methods: Study participants performed 4 sit-to-stand maneuvers including a mental stress test (serial 7 mental arithmetic stress test), cold pressor test, electrical stimulation, and no intervention. Continuous heart rate and beat-to-beat BP were measured. Cardiac output and systemic vascular resistance were estimated from these waveforms. Data are presented as mean±SD. Results: A total of 23 female IOH participants (31±8 years) completed the study. The drops in systolic BP following the serial 7 mental arithmetic stress test (−26±12 mm Hg; P =0.004), cold pressor test (−20±15 mm Hg; P <0.001), and electrical stimulation (−28±12 mm Hg; P =0.01) were significantly reduced compared with no intervention (−34±11 mm Hg). The drops in systemic vascular resistance following the serial 7 mental arithmetic stress test (−391±206 dyne×s/cm 5 ; P =0.006) and cold pressor test (−386±179 dyne×s/cm 5 ; P =0.011) were significantly reduced compared with no intervention (−488±173 dyne×s/cm 5 ). Cardiac output was significantly increased upon standing (7±2 L/min) compared with during the sit (6±1 L/min; P <0.001) for electrical stimulation. Conclusion: Sympathetic activation mitigates the BP response in IOH, while involuntary muscle contraction mitigates the BP response and reduces symptoms. Active muscle contractions may induce both of these mechanisms of action in their pretreatment of IOH. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03970551.

Remote Hind-Limb Ischemia Mechanism of Preserved Ejection Fraction During Heart Failure

During acute heart failure (HF), remote ischemic conditioning (RIC) has proven to be beneficial; however, it is currently unclear whether it also extends benefits from chronic congestive, cardiopulmonary heart failure (CHF). Previous studies from our laboratory have shown three phases describing CHF viz. (1) HF with preserved ejection fraction (HFpEF), (2) HF with reduced EF (HFrEF), and (3) HF with reversed EF. Although reciprocal organ interaction, ablation of sympathetic, and calcium signaling genes are associated with HFpEF to HFrEF, the mechanism is unclear. The HFrEF ensues, in part, due to reduced angiogenesis, coronary reserve, and leakage of endocardial endothelial (EE) and finally breakdown of the blood-heart barrier (BHB) integrity. In fact, our hypothesis states that a change in phenotype from compensatory HFpEF to decompensatory HFrEF is determined by a potential decrease in regenerative, proangiogenic factors along with a concomitant increase in epigenetic memory, inflammation that combinedly causes oxidative, and proteolytic stress response. To test this hypothesis, we created CHF by aorta-vena-cava (AV) fistula in a group of mice that were subsequently treated with that of hind-limb RIC. HFpEF vs. HFrEF transition was determined by serial/longitudinal echo measurements. Results revealed an increase in skeletal muscle musclin contents, bone-marrow (CD71), and sympathetic activation (β2-AR) by RIC. We also observed a decrease in vascular density and attenuation of EE-BHB function due to a corresponding increase in the activity of MMP-2, vascular endothelial growth factor (VEGF), caspase, and calpain. This decrease was successfully mitigated by RIC-released skeletal muscle exosomes that contain musclin, the myokine along with bone marrow, and sympathetic activation. In short, based on proteome (omics) analysis, ∼20 proteins that appear to be involved in signaling pathways responsible for the synthesis, contraction, and relaxation of cardiac muscle were found to be the dominant features. Thus, our results support that the CHF phenotype causes dysfunction of cardiac metabolism, its contraction, and relaxation. Interestingly, RIC was able to mitigate many of the deleterious changes, as revealed by our multi-omics findings.

The Assessment of Autonomic Nervous System Activity Based on Photoplethysmography in Healthy Young Men

Noninvasive assessment of autonomic nervous system (ANS) activity is of great importance, but the accuracy of the method used, which is primarily based on electrocardiogram-derived heart rate variability (HRV), has long been suspected. We investigated the feasibility of photoplethysmography (PPG) in ANS evaluation. Data of 32 healthy young men under four different ANS activation patterns were recorded: baseline, slow deep breathing (parasympathetic activation), cold pressor test (peripheral sympathetic activation), and mental arithmetic test (cardiac sympathetic activation). We extracted 110 PPG-based features to construct classification models for the four ANS activation patterns. Using interpretable models based on random forest, the main PPG features related to ANS activation were obtained. Results showed that pulse rate variability (PRV) exhibited similar changes to HRV across the different experiments. The four ANS patterns could be better classified using more PPG-based features compared with using HRV or PRV features, for which the classification accuracies were 0.80, 0.56, and 0.57, respectively. Sensitive features of parasympathetic activation included features of nonlinear (sample entropy), frequency, and time domains of PRV. Sensitive features of sympathetic activation were features of the amplitude and frequency domain of PRV of the PPG derivatives. Subsequently, these sensitive PPG-based features were used to fit the improved HRV parameters. The fitting results were acceptable (p &lt; 0.01), which might provide a better method of evaluating ANS activity using PPG.

Cold Pressor Test Influences the Cardio-Ankle Vascular Index in Healthy Overweight Young Adults

<b><i>Objective:</i></b> The cold pressor test (CPT) has been shown a potential sympathoexcitatory stimulus which increases aortic pulse wave velocity and the aortic augmentation index, suggesting that noninvasively, arterial stiffness parameters are altered by the CPT. The cardio-ankle vascular index (CAVI) is widely used for reflecting arterial stiffness, and the ankle-brachial index (ABI) for evaluating peripheral artery disease in obesity. We aimed to assess CAVI and ABI in overweight young adults in the context of sympathetic activation by using the CPT. <b><i>Methods:</i></b> 160 participants were divided into 2 groups: 86 normal-weight (body mass index [BMI] 18.50–22.99 kg/m²) and 74 overweight (BMI ≥23 kg/m²). The CPT was performed by immersing a participant’s left hand into cold water (3–5°C) for 3 min, and CAVI and ABI assessment. <b><i>Results:</i></b> At baseline, the CAVI in the overweight group was significantly less than that in the normal-weight group (5.79 ± 0.85 vs. 6.10 ± 0.85; <i>p</i> &#x3c; 0.05). The mean arterial pressure (MAP) for overweight was significantly greater than that for normal-weight subjects (93.89 ± 7.31 vs. 91.10 ± 6.72; <i>p</i> &#x3c; 0.05). During the CPT, the CAVI increased in both normal-weight and overweight subjects, the CAVI value was greater during the CPT in overweight subjects by 14.36% (6.62 ± 0.95 vs. 5.79 ± 0.85, <i>p</i> &#x3c; 0.05) and in normal-weight subjects by 8.03% (6.59 ± 1.20 vs. 6.10 ± 0.85, <i>p</i> &#x3c; 0.05) than those baseline values. The CPT evoked an increase in systolic blood pressure (SBP), diastolic BP (DBP), heart rate (HR,) and pulse pressure (PP) in both groups. After a 4-min CPT period, the CAVI returned values similar to the baseline values in both groups, and the SBP, DBP, MAP, and PP in overweight participants were significantly higher than those in normal-weight participants. However, there was no significant difference in the ABI at baseline, during CPT, and post-CPT in either group. <b><i>Conclusions:</i></b> Our results indicated that the CAVI was influenced by sympathetic activation response to the CPT in both normal-weight and overweight young adults. Specifically, during the CPT, the percentage change of the CAVI in overweight response was greater in normal-weight participants than baseline values in each group. The ABI was not found significantly associated with CPT. These findings suggesting that sympathoexcitatory stimulus by CPT influence CAVI results.

Modulation of Sirt1 and FoxO1 on Hypothalamic Leptin‐Mediated Sympathetic Activation and Inflammation in Diet‐Induced Obese Rats

Background Hypothalamic leptin‐mediated signaling contributes to the exaggerated sympatho‐excitation and increased blood pressure in obesity‐associated hypertension. The aim of the study was to investigate the roles of energy‐sensing enzyme sirtuin1 (Sirt1) and forkhead box protein O1 (FoxO1) on the hypothalamic leptin‐mediated high sympathetic nerve activity and inflammation in obesity. Methods and Results Sprague Dawley rats were fed with high‐fat diet (HFD) for 12 weeks. In vivo, the potential of Srit1 and FoxO1 in the sympathetic effects of leptin was investigated via siRNA injection to knockdown Sirt1 or FoxO1 gene in the arcuate nucleus (ARCN) of hypothalamus in rats. In vitro, the effects of Sirt1 or FoxO1 on leptin‐mediated inflammation were observed in proopiomelanocortin (POMC) and microglial cells. Knockdown Sirt1 by siRNA significantly reduced the renal sympathetic nerve activity (RSNA) and blood pressure responses to leptin injection in the ARCN in the HFD rats. Conversely, knockdown FoxO1 significantly enhanced the RSNA and blood pressure responses to leptin injection in the HFD rats. Knockdown Sirt1 reduced the levels of pro‐inflammatory cytokines interleukin 6 (IL‐6), tumor necrosis factor α (TNF‐α), interleukin 1β (IL‐1β), C1q/TNF‐related protein‐1 (CTRP1), and immune cell infiltration in the ARCN in the HFD rats. Knockdown FoxO1 significantly increased the level of IL‐6 in the ARCN of HFD rats. In cultured hypothalamic POMC and microglial cells, knockdown Sirt1 significantly reduced leptin‐induced IL‐6 expression, affected the levels of AMP‐activated protein kinase (AMPK) and serine/threonine‐specific protein kinase (Akt). Knockdown FoxO1 significantly increased leptin‐induced IL‐6 in both POMC cells and microglial cells. Conclusions These data suggest that both Sirt1 and FoxO1 are the key modulators of leptin signaling in the hypothalamus contributed to the over sympathetic activation and inflammation in obesity.