Heart rate variability metrics and myocardial recovery in heart failure with reduced ejection fraction.

PURPOSE: Autonomic dysregulation is observed in heart failure (HF) with reduced ejection fraction (HFrEF). Abnormal heart rate variability (HRV), a measure of such dysregulation, is associated with poor prognosis in HFrEF. It is unknown if novel HRV metrics normalize in the patients with recovered ejection fraction (HFrecEF) compared to persistent HFrEF. The aim of this study was to investigate novel HRV indexes in persistent HFrEF in comparison to HFrecEF METHODS: A standard 10-min electrocardiography measurement was performed in patients categorized in four groups: persistent HFrEF (n = 40), HFrecEF (n = 41), stage A HF (n = 73) and healthy controls (n = 40). RESULTS: All HRV indexes were significantly different between the four groups. Specifically, novel metrics, such as higher parasympathetic nervous system (PNS) index and lower sympathetic nervous system (SNS) index, were observed in the HFrecEF group compared to the persistent HFrEF group. In multiple logistic regression analysis, higher PNS index (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.17-3.49; p = 0.01) and lower SNS index (OR 0.68, 95% CI 0.52-0.87; p = 0.002) were associated with HFrecEF. Receiver operating characteristic analysis showed that the SNS index had the highest area under the curve (AUC), followed by the PNS index and mean heart rate for the HF phenotype regarding EF recovery (AUC = 0.71, 0.69 and 0.69, respectively). CONCLUSION: Myocardial functional recovery in HFrEF is associated with improved parasympathetic activity and reduced sympathetic activity, as reflected in the PNS and SNS indexes. These novel metrics can be potentially used to aid in identifying recovered versus non-recovered phenotypes in patients with HFrEF.

Senescence and associated blood-brain barrier alterations in vitro.

Progressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood-brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within.

The insular cortex as a vestibular area in relation to autonomic function.

The forebrain cerebral network including the insular cortex plays a crucial role in the regulation of the central autonomic nervous system in relation to emotional stress. Numerous studies have recently shown that the insular cortex also has roles as a vestibular area in addition to auditory function. In this review, we summarize the recent literature regarding the relationship between the insular cortex and vestibular function, and we describe our hypothesis that the insular cortex has a pivotal role in vestibular-cardiovascular integration.

The Insular Cortex, Alzheimer Disease Pathology, and Their Effects on Blood Pressure Variability.

Recent findings indicate that the human cardiovascular system is regulated by a cortical network comprised of the insular cortex (Ic), anterior cingulate gyrus, and amygdala which is necessary for the regulation of the central autonomic network system. Alzheimer disease (AD) affects the Ic at a preclinical stage. The pathology of AD at the Ic is suggested to predispose the cardiovascular system to detrimental changes such as increased blood pressure variability (BPV). In this review article, we focus on the physiology of the Ic in the relationship between the central autonomic network and BPV. We provide a summary of the published evidence regarding the relationship between Ic damage and exaggerated BPV in the context of AD pathology.

Early drop in systolic blood pressure, heart rate at admission, and their effects on worsening renal function in elderly patients with acute heart failure.

BACKGROUND: Regardless of patients' baseline renal function, worsening renal function (WRF) during hospitalization is associated with poor outcomes. In individuals with acute heart failure (AHF), one predictor of WRF is an early drop in systolic blood pressure (SBP). Few studies have investigated WRF in elderly AHF patients or the influence of these patients' heart rate (HR) at admission on the relationship between an early SBP drop SBP and the AHF. METHODS: We measured the SBP and HR of 245 elderly AHF inpatients (83 ± 6.0 years old, females 51%) at admission and another six times over the next 48 h. We defined 'WRF' as a serum creatinine increase ≥0.3 mg/dL by Day 5 post-admission. We calculated the 'early SBP drop' as the difference between the admission SBP value and the lowest value during the first 48 h of hospitalization. RESULTS: There were significant differences between the 36 patients with WRF and the 209 patients without WRF: early SBP drop (51 vs. 33 mmHg, p < 0.01) and HR at admission (79 vs. 90 bpm, p < 0.05), respectively. In the multiple logistic regression analysis adjusted for the confounders, higher early SBP drop (p < 0.04) and lower HR at admission (p < 0.01) were significantly associated with WRF. No significant association was shown for the interaction term of early SBP drop × HR at admission with WRF. CONCLUSIONS: In these elderly AHF patients, exaggerated early SBP drop and lower HR at admission were significant independent predictors of WRF, and these factors were additively associated with WRF.

The Prospective Studies of Atherosclerosis (Proof-ATHERO) Consortium: Design and Rationale.

Atherosclerosis - the pathophysiological mechanism shared by most cardiovascular diseases - can be directly or indirectly assessed by a variety of clinical tests including measurement of carotid intima-media thickness, carotid plaque, -ankle-brachial index, pulse wave velocity, and coronary -artery calcium. The Prospective Studies of Atherosclerosis -(Proof-ATHERO) consortium (https://clinicalepi.i-med.ac.at/research/proof-athero/) collates de-identified individual-participant data of studies with information on atherosclerosis measures, risk factors for cardiovascular disease, and incidence of cardiovascular diseases. It currently comprises 74 studies that involve 106,846 participants from 25 countries and over 40 cities. In summary, 21 studies recruited participants from the general population (n = 67,784), 16 from high-risk populations (n = 22,677), and 37 as part of clinical trials (n = 16,385). Baseline years of contributing studies range from April 1980 to July 2014; the latest follow-up was until June 2019. Mean age at baseline was 59 years (standard deviation: 10) and 50% were female. Over a total of 830,619 person-years of follow-up, 17,270 incident cardiovascular events (including coronary heart disease and stroke) and 13,270 deaths were recorded, corresponding to cumulative incidences of 2.1% and 1.6% per annum, respectively. The consortium is coordinated by the Clinical Epidemiology Team at the Medical University of Innsbruck, Austria. Contributing studies undergo a detailed data cleaning and harmonisation procedure before being incorporated in the Proof-ATHERO central database. Statistical analyses are being conducted according to pre-defined analysis plans and use established methods for individual-participant data meta-analysis. Capitalising on its large sample size, the multi-institutional collaborative Proof-ATHERO consortium aims to better characterise, understand, and predict the development of atherosclerosis and its clinical consequences.

Insular cortex lesion and autonomic instability in a herpes simplex virus encephalitis patient.

The cardiovascular system is regulated by a central autonomic network (CAN) consisting of the insular cortex, anterior cingulate gyrus, and amygdala. Because the insular cortex often tends to be damaged in patients with herpes simplex virus (HSV) encephalitis, the autonomic instability observed in these patients was suggested to be moderated by an insular cortex lesion. Here, we report the case of a 51-year-old Japanese male who was hospitalized following a collapse 5 days earlier; he was diagnosed as herpes encephalitis. Diffusion-weighted MRI revealed asymmetric right greater hyperintensity throughout his insular cortex and anterior cingulate gyrus. At 1 week after admission, transthoracic echo showed diffuse hypokinesis in the left ventricle (LV). Cardiac 123I-meta-iodobenzylguanidine uptake (123I-MIBG) scintigraphy revealed reduced uptake in the inferior and posterior wall. Electrocardiograhy at rest showed that the coefficient variation of RR intervals (CVR-R) was reduced, and the corrected QT (QTc) interval length was prolonged. In this HSV encephalitis patient, signs of a right insular cortex lesion and autonomic instability were observed: LV hypokinesis, regional reduced 123I-MIBG uptake, decreased CVR-R, and QTc interval prolongation. Our patient's autonomic instability may thus be derived from disrupted autonomic balance due to the right insular cortex lesion.

Blood Pressure Variability in Acute Ischemic Stroke: Influence of Infarct Location in the Insular Cortex.

BACKGROUND: The aim of this study was to elucidate the influence of insular infarction on blood pressure (BP) variability and outcomes according to the region of the insular cortex affected. METHODS: A total of 90 patients diagnosed with acute unilateral ischemic stroke were registered. The BP variability was calculated over 24 h after admission (hyperacute) and for 2-3 days after admission (acute). Patients were classified into groups of right and left, and then right anterior, right posterior, left anterior, and left posterior insular infarction. RESULTS: Patients with insular infarction showed a significantly larger infarct volume, higher modified Rankin scale scores, and lower SD and coefficient of variation (CV) of -systolic BP in the hyperacute phase than shown by patients without insular infarction (p < 0.01, p < 0.01, p = 0.02, and p = 0.03, respectively). The SD and CV of systolic BP in the hyperacute phase showed significant differences among the 3 groups with right insular infarction, with left insular infarction, and without insular infarction (p < 0.05 and p < 0.05, respectively). There was a tendency for the systolic BP variability to be lower in patients with right anterior insular infarction than in patients with infarcts in other areas. CONCLUSION: The right insular cortex, especially the anterior part, might be a hub for autonomic nervous regulation.

A Case of Left Atrial Myxoma Whose Initial Symptom Was Finger Ischemic Symptom.

We experienced a 45-year-old Japanese man who was transferred to our hospital complaining of acute onset of pain and pallor in the right lower limb. Two years earlier, he had complained of repetitive pain at rest and pallor in the left third and fourth fingers. The physical exam and angiography demonstrated occlusion of finger arteries, however we could not reach final diagnosis. Acute arterial occlusive disease in the right lower limb was suspected. Transthoracic echocardiography demonstrated a gross tumor in the left atrium, which suggested left atrial myxoma. An emergency tumorectomy was successfully conducted. Pathologically, the fragile tumor and resultant thrombosis could have caused the patient's peripheral circulatory failure at least two years prior to this episode. A rigorous systemic survey is important even when the ischemic symptom is localized in peripheral circulation.

[Ischemic heart disease, heart failure, and their effects on cognitive function].

Recent studies have shown that ischemic heart disease and heart failure are closely associated with cognitive impairment via injury of the small cerebral arteries. On the other hand, these factors are suggested to be associated with Alzheimer's disease as well as vascular dementia. This review paper focuses on the role of ischemic heart disease and heart failure as risk factors for cognitive impairment, and summarizes current knowledge on the relationships between vascular risk factors and Alzheimer's disease pathology.

Cardio-respiratory coupling and myocardial recovery in heart failure with reduced ejection fraction.

INTRODUCTION: The interaction between the cardiovascular and respiratory systems in healthy subjects is determined by the autonomic nervous system and reflected in respiratory sinus arrhythmia. Recently, another pattern of cardio-respiratory coupling (CRC) has been proposed linking synchronization of heart and respiratory system. However, CRC has not been studied precisely in heart failure (HF) with reduced ejection fraction (EF) (HFrEF) according to the myocardial recovery. METHODS: 10-min resting electrocardiography measurements were performed in persistent HFrEF patients (n=40) who had a subsequent left ventricular EF (LVEF) of ≤ 40 %, HF with recovered EF patients (HFrecEF) (n=41) who had a subsequent LVEF of > 40 % and healthy controls (n=40). Respiratory frequency, respiratory rate, CRC index, time-domain, frequency-domain and nonlinear heart rate variability indices were obtained using standardized software-Kubios™. CRC index was defined as respiratory high-frequency peak minus heart rate variability high-frequency peak. RESULTS: Respiratory rate was positively correlated with high-frequency (HF) peak (Hz) in both persistent HFrEF group (p<0.001) and HFrecEF group (p<0.001), while respiratory rate was negatively correlated with HF power (ms2) in the healthy controls (p<0.05). CRC index was lowest in the persistent HFrEF group followed by HFrecEF and was high in healthy controls (0.008 vs 0.012 vs 0.056 Hz, p=0.03). CONCLUSION: CRC index was lowest in patients with impaired myocardial recovery, which indicates that cardio-respiratory synchrony is stronger in persistent HFrEF. This may represent a higher HF peak (Hz)/lower HF power (ms2) and abnormal sympathovagal balance in persistent HFrEF group compared to healthy controls. Further work is underway to tests this hypothesis and determine the utility of CRC index in HF phenotypes and its utility as a potential biomarker of response with neuromodulation.

Autonomic neuromodulation for cardiomyopathy associated with metabolic syndrome - Prevention of precursors for heart failure with preserved ejection fraction.

Metabolic syndrome (MetS) induces a systemic inflammatory state which can lead to cardiomyopathy, manifesting clinically as heart failure (HF) with preserved ejection fraction (HFpEF). MetS components are intricately linked to the pathophysiologic processes of myocardial remodeling. Increased sympathetic nervous system activity, which is noted as an upstream factor of MetS, has been linked to adverse myocardial structural changes. Since renal denervation and vagus nerve stimulation have a sympathoinhibitory effect, attention has been paid to the cardioprotective effects of autonomic neuromodulation. In this review, the pathophysiology underlying the relationship between MetS and HF is elucidated, and the evidence regarding autonomic neuromodulation in HFpEF is summarized.

Neuromodulation of Cardiovascular Risks Associated With Cardiotoxic Chemotherapy: A First-in-Human Randomized Pilot Study. Neuromodulation in Cancer Study (NCAN).

OBJECTIVES: Cardiotoxic chemotherapy is used to treat malignancies such as breast cancer and lymphoma. These treatments predispose patients to cardiotoxicity that can lead to cancer treatment-related cardiac dysfunction (CTRCD). The use of high doses of anthracyclines or in combination with human epidermal growth factor receptor 2 antagonists is associated with a progressively higher risk of CTRCD. CTRCD is preceded by increased activation of the sympathetic nervous system and abnormal left ventricular mechanical deformation as measured by abnormal global longitudinal strain (GLS). Low-level tragus stimulation (LLTS) is a new, safe, noninvasive technique that offers great potential to reduce increased sympathetic activation and improve GLS. Here, we describe a study method to examine the effects of LLTS on autonomic balance and cardiac function in breast cancer or lymphoma patients treated with anthracyclines. METHODS: A first-in-human pilot, randomized, double-blind feasibility study will evaluate 104 patients (age >50 y) with breast cancer or lymphoma who receive anthracyclines with one additional CTRCD risk factor. Patients undergo 2 weeks of LLTS daily (1 h/d). Autonomic balance will be measured using heart rate variability metrics. Strain imaging using GLS will be performed pre and post-LLTS. Endothelial inflammation and oxidative stress measures will be performed using in vitro assays at baseline and after 2 weeks. CONCLUSION: We hypothesize that LLTS stabilizes sympathovagal imbalance and improves cardiac performance in anthracycline-treated patients with breast cancer or lymphoma.

Blood Pressure Variability After Non-invasive Low-level Tragus Stimulation in Acute Heart Failure.

Higher blood pressure (BP) variability (BPV) was shown to be strong predictors of poor cardiovascular outcomes in heart failure (HF). It is currently unknown if low-level tragus stimulation (LLTS) would lead to improvement in BPV in acute HF (AHF). The 22 patients with AHF (median 80 yrs, males 60%) were randomly assigned to active or sham group using an ear clip attached to the tragus (active group) or the earlobe (sham group) for 1 h daily over 5 days. In the active group, standard deviation (SD), coefficient of variation (CV) and δ in SBP were significantly decreased after LLTS (all p < 0.05). All the changes in SD, CV and δ in SBP before and after stimulation were also significantly different between active and sham groups (all p < 0.05). This proof-of-concept study demonstrates the beneficial effects of LLTS on BPV in AHF.