Lower Heart Research Articles

Duration of diabetes, glycemic control, and low heart rate variability: The atherosclerosis risk in communities (ARIC) study

Persons with long-standing, poorly controlled diabetes or recent hyperglycemia had the highest burden of cardiac autonomic neuropathy. Cardiac autonomic neuropathy contributed to elevated long-term incidence of cardiovascular disease and mortality even in persons with well-controlled diabetes.

Investigating heart rate responses of children to active travel: a mixed effects modeling analysis.

The active travel concept has gained recognition as an effective method to enhance physical activity in children's everyday mobility. Yet, there is a notable gap of quantitative evidence on its direct impacts, especially regarding physiological outcomes that can concretely demonstrate its influences on physical intensity and overall health of children. This study investigates the effects of active travel on children, focusing on trip-level physiological responses, specifically heart rate. Through a mixed survey design, we obtained a repeated-measures dataset from a cohort of 73 children (average age 13) across three Austrian secondary schools, each observed for 7 days. By applying mixed effects modelling approach, both fixed and random effects to children's heart rates were explored. According to results from developed mixed linear models (maximum R2 = 0.22), it revealed a significant positive association between active travel mode(s) engagement and heightened physiological responses (Low, Medium and High active level of trip compare to None: β = 1.81, 5.01 and 8.34, t-value = 4.70, 10.29 and 21.34), indicating that increased usage of active travel modes led to elevated heart rate values. Additionally, subjective perceptions also played an important role in influencing children's physiological responses. Feelings of exhausted, anxiety, and stress contributing to a higher heart rate (β = 14.79, 16.69 and 1.99, t-value = 20.42, 5.67 and 3.0), while unhappiness was associated with a lower heart rate (β = -5.96, t-value = -14.62). Effects of social interactions were also found during the trip. The presence of adults was associated with a calming effect (β = -1.92, t-value = -5.72), whereas solo travel resulted in lower heart rate compared to travel with peers (β = -1.95, t-value = -6.59). Our article innovatively employs mixed survey methods and heart rate data to quantitatively demonstrate the positive association between engagement in active travel modes and heightened physiological responses in children, elucidating the intricate interplay of subjective perceptions and social interactions during trips, thus offering valuable insights into the health implications of active travel at a trip level. Future research will keep on leveraging survey and experimental methods.

Timolol Maleate Microspheres: An Ingenious Carrier for Sustained Release Antihypertensive Formulation

Background: Timolol maleate is classified as a BCS Class I drug and functions as a non-selective β-adrenergic receptor blocker. Its ability to lower heart rate and cardiac output has led to its widespread use in the treatment of hypertension. Objective: Timolol maleate has a short half-life and is rapidly cleared from the body, which limits its therapeutic effectiveness, requiring frequent dosing and potentially affecting patient adherence. To overcome these challenges, sustained-release microspheres of Timolol maleate were developed using the ion gelation method. Method: The ion gelation technique was employed to create the microspheres due to its various advantages, including ease of use, scalability and gentle processing conditions. Results: All batches exhibited a comparatively lower swelling index in 0.1M HCl (pH 1.2) than in SIF (pH 6.8). It was observed that increasing the concentration of sodium alginate resulted in higher drug content. The microspheres were sized between 400 and 900 μm and demonstrated excellent flow characteristics. An optimized batch achieved an entrapment efficiency of 88.83% and released 92.15% of the drug over 7 hrs. Furthermore, stability studies conducted according to ICH Q1A(R2) for 3 months at 5±3°C and 25±2°C/60±5% RH indicated no significant changes in evaluation parameters. Conclusion: The optimized Timolol maleate-loaded microspheres effectively provided sustained drug release through the membrane over 7 hrs. This study contributes to the development of improved drug delivery systems for better hypertension management, addressing the unmet needs in patient compliance. Keywords: Timolol Maleate, Microspheres, Ion gelation method, Sodium alginate, Calcium chloride, Sustained release, Hypertension

Safety and Efficacy of opioid-sparing Anesthesia Compared with Traditional opioid-anesthesia

Objectives: The rationale of adoption opioid sparing anesthesia (OSA) is to achieve perioperative analgesia with a minimal amount of opioid combined to non-opioid adjuvants during and after surgery, namely multimodal anesthesia. The OSA approach was originally developed to overcome the known complications of opioid-based anesthesia (OA) and the present scoping review (ScR) aims at providing the clinical evidence of safety and efficacy of OSA with respect to OA. Methods: This ScR is mainly focused on studies presenting evidence on the safety and efficacy of OSA versus OA. PubMed, EMBASE databases were utilized to find relevant studies. Search strategy included the following keywords: “opioid sparing anesthesia complications, opioid sparing anesthesia efficacy, opioid sparing anesthesia safety”. The findings from the 25 included studies were categorized into the following subsections: article characteristics, goals of the studies, OSA protocols, and surgical settings analyzed. Results: In the 25 reviewed studies, evidence related to the impact of OSA versus OA was considered. Intraoperative safety and efficacy endpoints include hemodynamic stability and anesthetic/analgesic requirements. Postoperative endpoints include early cognitive dysfunction, opioid-induced bowel disorder, the physical status of mothers and newborns after labor and emergency cesarean, systemic immune and inflammation modifications, postoperative recovery, in-hospital and long-term opioid requirement, early postoperative pain, chronic postsurgical pain. The studies reported a lower intraoperative mean arterial pressure and heart rate fluctuations when α2 agonists are adopted, while no differences were recorded for other complication rates. Analysis of OSA approaches for the postoperative conditions includes α2 agonists, NMDA receptor blocking agents, gabapentinoids, nefopam hydrocloride and locoregional anesthesia techniques with a positive impact on most of the endpoints considered. Discussion: The clinical implementation of OSA encompasses the perioperative use of non-opioid drugs and locoregional anesthesia techniques. The reviewed studies reported OSA as a feasible approach to reduce opioid-related complications with no impact on patient’s safety.

Abstract 4135211: Children with the D801N Variant of the ATP1A3- Encoded Sodium-Potassium ATPase Alpha-3 Subunit Demonstrate Paradoxical QT Response to Bradycardia and Increased Ventricular Arrhythmia Risk

Introduction: Alternating hemiplegia of childhood (AHC) is a rare condition most frequently caused by mutations in ATP1A3, encoding for the alpha-3 subunit of Na + /K + -ATPase, and D801N is the most common variant. Individuals with ATP1A3-D801N have shorter corrected QT (QTc) than those with other variants and can experience ventricular arrhythmias following bradycardia; however, the mechanism of why this occurs is unknown. Goals: To analyze how QT and QTc change with heart rate in ATP1A3-D801N compared to healthy individuals. Hypothesis: Individuals with ATP1A3-D801N have increased shortening of QT and QTc at lower heart rate. Methods: In this retrospective observational study, patients seen for evaluation of AHC at Duke University Medical Center were categorized by genotype: ATP1A3-D801N, ATP1A3 non-D801N single nucleotide variant, ATP1A3 loss-of-function variant, and genotype negative. A cohort of matched healthy children was also compiled. We collected average heart rate, QT, and QTc measurements over 5-minute intervals from Holter recordings using HScribe TM software and conducted manual blinded validation to ensure accuracy. We then used linear regression to investigate the relationship between heart rate, QT, and QTc. Results: The cohort consisted of 44 patients with ATP1A3 -related phenotypes with 81 total Holter recordings (52.27% female; mean age at first Holter 8.04 years), compared to 36 healthy individuals with 57 total Holter recordings (52.78% female; mean age at first Holter 9.84 years). Patients with ATP1A3-D801N showed diminished prolongation of QT with decreasing heart rate, manifested as a reduced mean slope for heart rate vs QT compared to healthy (-0.85 ± 0.46 vs -1.52 ± 0.42, p<0.0001). This blunted QT response resulted in paradoxical shortening of QTc at lower heart rate, demonstrated by an increased mean slope for heart rate vs QTc compared to healthy (0.80 ± 0.51 vs 0.22 ± 0.43, p<0.0001). Further, patients with ATP1A3- related phenotypes and very short baseline QTc showed increased shortening of QT and QTc at lower heart rate compared to those with normal QTc (p=0.0025 and p=0.0013, respectively). Conclusions: Children with AHC and ATP1A3-D801N demonstrate a paradoxical shortening of QT and QTc with slowing of heart rate. The impaired prolongation of QT and resultant further shortening of QTc increase the risk of arrhythmia. We put this forward as a novel mechanism of sudden cardiac arrest in patients with ATP1A3 mutations.

Abstract 4137186: No Room for Chronotropic Incompetence in Living Fontan Patients: Enhanced Heart Rate Increase in Response to Exercise to Compensate Low Stroke Volume Reserve

Background: Fontan patients reveal decreased peak exercise performance in combination with low peak heart rate (HR), which is frequently interpreted as chronological incompetence. This is counterproductive as HR increase has to be enhanced to compensate limited stroke volume increase in Fontan physiology. Methods: Cardiopulmonary exercise testing (CPET) data in asymptomatic Fontan patients and age-matched control subjects were retrospectively studied. Peak and submaximal CPET parameters were obtained by cycle ergometer. Chronotropic capacity was assessed by peak HR/peak [WR/kg] and submaximal slope of HR/[work rate (WR)/kg] (ΔHR/Δ[WR/kg]) for males and females, separately. Results: Table 1 presents CPET data of Fontan patients (51) and controls (65). Fontan patients showed significantly lower peak HR, peak WR, peak oxygen consumption (VO2)/kg, %predicted maximum VO2, and peak oxygen pulse (pOP)/kg than controls in both sexes whereas peak HR/peak [WR/kg] was significantly higher in Fontan patients, indicating higher HR at the maximum effort in Fontan patients than in controls. Fontan patients showed higher ΔHR/Δ[WR/kg], a marker for HR-dependency, and lower Δ[VO2/kg]/ΔHR, a surrogate of stroke volume, suggesting higher HR was compensating lower stroke volume during submaximal phase of exercise in Fontan patients. Figure 1 demonstrates a linear relationship between ΔHR/ΔWR and peak HR/peak WR in both sexes. Male Fontan patients revealed a comparable trend with controls, whereas female Fontan patients showed higher HR increase at the peak exercise effort than controls with the same ΔHR/ΔWR, suggesting more limited stroke volume reserve than male Fontan patients. Conclusions: Fontan patients showed higher HR-response to exercise than controls in both sexes due to limitation in stroke volume increase. Our data indicate that lower peak HR in Fontan patients results from early exhaustion due to limited stroke volume reserve rather than primary chronotropic incompetence.

Pupil size correlates with heart rate, skin conductance, pulse wave amplitude, and respiration responses during emotional conflict and valence processing.

Pupil size is a non-invasive index for autonomic arousal mediated by the locus coeruleus-norepinephrine (LC-NE) system. While pupil size and its derivative (velocity) are increasingly used as indicators of arousal, limited research has investigated the relationships between pupil size and other well-known autonomic responses. Here, we simultaneously recorded pupillometry, heart rate, skin conductance, pulse wave amplitude, and respiration signals during an emotional face-word Stroop task, in which task-evoked (phasic) pupil dilation correlates with LC-NE responsivity. We hypothesized that emotional conflict and valence would affect pupil and other autonomic responses, and trial-by-trial correlations between pupil and other autonomic responses would be observed during both tonic and phasic epochs. Larger pupil dilations, higher pupil size derivative, and lower heart rates were observed in the incongruent condition compared to the congruent condition. Additionally, following incongruent trials, the congruency effect was reduced, and arousal levels indexed by previous-trial pupil dilation were correlated with subsequent reaction times. Furthermore, linear mixed models revealed that larger pupil dilations correlated with higher heart rates, higher skin conductance responses, higher respiration amplitudes, and lower pulse wave amplitudes on a trial-by-trial basis. Similar effects were seen between positive and negative valence conditions. Moreover, tonic pupil size before stimulus presentation significantly correlated with all other tonic autonomic responses, whereas tonic pupil size derivative correlated with heart rates and skin conductance responses. These results demonstrate a trial-by-trial relationship between pupil dynamics and other autonomic responses, highlighting pupil size as an effective real-time index for autonomic arousal during emotional conflict and valence processing.

Effect of age on clinical impact and mid-term denervation in patients undergoing cardioneuroablation.

Cardioneuroablation (CNA) represents a promising therapy for recurrent vasovagal syncope (VVS), extrinsically driven atrioventricular block (AVB) and sinus node dysfunction (SND). However, effectiveness in patients aged 50 and above is not well-established. In this prospective study of patients referred for CNA, we compared syncope and pacemaker implantation free survival, heart rate (HR) variability (HRV) and quality of life between two age groups: group A (< 50 years) and B (≥ 50 years). A total of 50 patients were included (17 Group A and 33 Group B). The etiologies comprised VVS (56%), AVB (22%), and SND (22%). After a median follow-up of 17.0 (12.5-26.0) months, there were no differences of the combined endpoint of syncope or pacemaker implantation free-survival between groups (29.4.% vs. 21.2%; p-log-rank = 0.736). 84% of the entire cohort remained free from syncope, with a better but not significant syncope free survival in the older group (23.5% vs. 12.1%; p-log rank = 0.486). There were no differences in pacemaker implantation rate (A 5.9% vs. B 17.6%; p log-rank = 0.658). Notably, older patients had lower HR values post-procedure compared to younger patients (68.9 ± 13.3 vs. 80.4 ± 16.3bpm; p = 0.012). Both groups exhibited a decrease in HRV parameters and an improvement in quality of life. In conclusion, CNA has comparable clinical benefits for patients aged 50 and above in terms of syncope or pacemaker implantation free survival and HRV reduction when compared to younger patients.

Effects of concentric and eccentric exercise regimens on bioenergetic efficiency of lymphocytes in sedentary males.

Eccentric exercise training (EET) increases physical performance while having lower metabolic demand than concentric exercise training (CET). Whether EET influences bioenergetic efficiency in peripheral blood mononuclear cells (PBMCs) remains unclear. This study investigates the effects of EET and CET on PBMC phenotypes and mitochondrial functions in blood. Thirty three sedentary healthy males were randomly assigned to either EET (n=11) or CET (n=11) that performed at progressively increased from 60% to 80% of maximal absolute workload for 30min/day, 5days/week for 6weeks, or a control group (n=11) that did not receive any exercise intervention. A graded exercise stress test (GXT) was performed before and after the intervention. PBMC phenotypes and mitochondrial respiratory capacity were analyzed using flowcytometry and high-resolution respirometry, respectively. In the same absolute workload, EET elicited lower heart rate and rating of perceived exertion than CET. However, EET as CET increased the VO2 level at the ventilatory threshold. Notably, both EET and CET increased central memory (CD45RO+/CD62+/CD3+) T cells and decreased effector memory T cells reexpressing CD45RA (CD45RA+/CD62-/CD3+). Moreover, the two exercise regimens diminished the loss of mitochondrial membrane potential (ΔΨm) caused by GXT, increased maximal/reserve O2 consumption rates (OCR), and bioenergetic health index in intact PBMCs and enhanced complex I-/II-related OCR in PBMCs with a substrate-rich environment. EET improves aerobic fitness with a lower cardiovascular response to exercise than CET. Moreover, EET as CET reduces senescent T-cell distribution in blood and improves PBMC bioenergetic efficiency by stabilizing ΔΨm and increasing capacity of oxidative phosphorylation.

Mechanisms of the Native American pain inequity: predicting chronic pain onset prospectively at 5 years in the Oklahoma Study of Native American Pain Risk.

A pain inequity exists for Native Americans (NAs), but the mechanisms are poorly understood. The Oklahoma Study of Native American Pain Risk (OK-SNAP) addressed this issue and recruited healthy, pain-free NAs and non-Hispanic Whites (NHWs) to attend 2 laboratory visits and assessed mechanisms consistent with the biopsychosocial model of pain: demographics, physical variables, psychosocial factors, and nociceptive/pain phenotypes. Then participants were surveyed every 6 months to assess for chronic pain onset. Results at the 2-year follow-up found that NAs were ∼3x more likely than NHWs to develop chronic pain. Moreover, psychosocial factors (discrimination, stress, pain-related anxiety), cardiometabolic load (higher body mass index and blood pressure, lower heart rate variability), and impaired inhibition of spinal nociception partly mediated the pain inequity. The present study examined mechanisms of chronic pain at the 5-year follow-up for OK-SNAP. Results found that the NA pain inequity worsened-NAs were 4x more likely to develop chronic pain (OR = 4.025; CI = 1.966, 8.239), even after controlling for baseline age, sex assigned at birth, income, and education. Moreover, serial mediation models replicated paths from the 2-year follow-up that linked psychosocial variables, cardiometabolic load, and impaired inhibition of spinal nociception to chronic pain onset. Further, 2 new significant paths were observed. One linked discrimination, stress, sleep problems, and facilitated pain perception to increased pain risk. The other linked discrimination with higher spinal nociceptive threshold and pain risk. These results provide further evidence for a NA pain inequity and identify multiple psychosocial, cardiometabolic, and pronociceptive targets for primary interventions.

Introducing a Novel Pacemaker‐Mediated Arrhythmia: The Pseudo‐RNRVAS Arising From Atrial Capture Challenges

ABSTRACTBackgroundThis study aimed to define and explain a novel form of pacemaker‐mediated arrhythmia which is initiated and sustained by atrial capture loss coinciding with ventriculoatrial (VA) conduction within the postventricular atrial refractory period (PVARP). Unlike repetitive nonreentrant VA synchrony (RNRVAS), in the pseudo‐RNRVAS, the atrium is not stimulated due to pacing below the threshold level, rather than because of refractory atrial myocardium.ObjectiveThe objective was to elucidate the mechanisms of this pseudo‐RNRVAS, identify predisposing factors, and propose preventive strategies.MethodsTwenty‐one patients with dual‐chamber cardiac implantable electronic devices (CIEDs) exhibiting stable VA conduction within the PVARP were included. Pseudo‐RNRVAS were induced by altering atrial amplitude and lower rate interval while keeping other CIED parameters constant.ResultsPseudo‐RNRVAS developed after atrial capture loss in 20 out of 21 patients. Notably, 11 patients experienced pseudo‐RNRVAS at heart rates ≤ 70 bpm, and 7 patients at AV delay ≤ 150 ms. The condition initiated immediately following the first ventricular pace beat after atrial capture loss in 18 patients. In six cases, pseudo‐RNRVAS terminated intermittently and then restarted; in 14 cases, it did not resolve.ConclusionPseudo‐RNRVAS can occur even at low heart rates and without specific predisposing factors seen in RNRVAS. Conditions that increase atrial pacing probability and threshold raise the likelihood of pseudo‐RNRVAS. Early postimplantation may pose a heightened risk, correlating with pacemaker syndrome and susceptibility to heart failure.

Children and Adolescent Patients with Variants in the ATP1A3 -encoded Sodium-Potassium ATPase Alpha-3 Subunit Demonstrate an Impaired QT Response to Bradycardia and Predisposition to Sinus Node Dysfunction.

Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arrhythmia predisposition. We performed a retrospective observational study of individuals who underwent clinical evaluation, Holter monitoring, and genetic testing for AHC at Duke University Hospitals. We also compiled a group of healthy individuals as a control cohort. A larger, worldwide cohort of individuals with ATP1A3 -related phenotypes was compiled to investigate sinus node dysfunction. Linear regression analysis was then performed. The cohort consisted of 44 individuals with ATP1A3 -related phenotypes with 81 Holter recordings (52.27% female; mean age at first Holter 8.04 years, range 0.58 - 33 years), compared to 36 healthy individuals with 57 Holter recordings (52.78% female; mean age at first Holter 9.84 years, range 0.08 - 38 years). Individuals with ATP1A3-D801N had reduced prolongation of QT at lower HR, manifest as a significantly lower slope for HR vs QT compared to healthy (P<0.0001). This resulted in a significantly higher slope of the relationship for HR vs QTc compared to healthy (P<0.0001). Individuals with ATP1A3 -related phenotypes and baseline QTc <350 milliseconds (ms) had increased shortening of QT and QTc at lower HR compared to those with normal QTc (P=0.003; P=0.001). Among worldwide cases, 3 out of 131 individuals with ATP1A3 -related phenotypes required device implantation and/or had sinus pauses >4 seconds. Individuals with the ATP1A3-D801N variant exhibit paradoxical shortening of QT and QTc at lower HR, which contributes to an increased risk of arrhythmias during bradycardia. This is exacerbated by an underlying risk of sinus node dysfunction. What is Known:Individuals with ATP1A3-D801N have a short baseline QTc.Two individuals with AHC experienced ventricular fibrillation following bradycardia.What the Study Adds:The QT and QTc shorten to a greater extent at lower heart rate in individuals with ATP1A3-D801N than in healthy individuals. Individuals with ATP1A3 -related phenotypes and QTc <350ms show greater impairment of QT and QTc dynamics than those with normal QTc. There is low prevalence of device implantation and significant sinus pauses in individuals with ATP1A3 -related phenotypes, with a relatively greater prevalence in those with ATP1A3-D801N.

SAFETY OF DIRECT ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION 80 YEARS AND OLDER: CLINICAL RISK FACTORS

BACKGROUND: Direct oral anticoagulants (DOACs) use is complicated by bleeding, especially in the geriatric population. Most studies focus on predicting major bleeding, while clinically relevant non-major bleeding (CRNMB) is no less important for practice. АIM: of the study was to evaluate the ability of clinical factors to predict the risk of CRNMB while taking DOACs in patients with atrial fibrillation (AF) aged 80 years and older. MATERIALS AND METHODS: 367 patients were examined with non-valvular AF aged 80 years and older (median age 84 [82; 88] years) taking DOACs. The main population parameters (gender and age composition of groups, body mass index), risk of ischemic stroke according to the CHA2DS2-VASc scale, risk of bleeding according to the HAS-BLED scale, comorbidity, Charlson comorbidity index, risk factors for chronic non-communicable diseases, number of medications taken, objective examination data, vascular wall stiffness, and laboratory test results were assessed. RESULTS: In univariate analysis, significant risk factors for developing CRNMB with all DOACs were: higher frequency of walking (p=0.022), lower heart rate (p=0.08), and history of gastric and duodenal ulcer (GDU) (odds ratio (OR) 5.34 [95% confidence interval (CI): 2.31; 12], p0.001). As a result of multivariate analysis, a model for predicting CRNMB was developed, with age, type of DOAC, liver disease, acute cerebrovascular accident, history of GDU selected as predictors. The resulting model was characterized by 62.6% [95% CI: 57.4; 67.6] predictive accuracy, 66.5% [95% CI: 59.4; 73.1] sensitivity and 58.2% [95% CI: 50.4; 65.7] specificity. CONCLUSION: The study identified specific modifiable, potentially modifiable, and non-modifiable risk factors for the development of CRNMB in patients with AF over 80 years of age taking DOACs. The results of the study can be used to create an electronic system to support medical decision-making, manage risk factors, and improve the quality of life of the population.

Heart Rate Variability and Cerebral Autoregulation in Patients with Traumatic Brain Injury with Paroxysmal Sympathetic Hyperactivity Syndrome.

Severe traumatic brain injury (TBI) can lead to transient changes in autonomic nervous system (ANS) functioning and development of paroxysmal sympathetic hyperactivity (PSH) syndrome. Clinical manifestation of ANS disorders may be obscured by therapeutic interventions in TBI. This study aims to analyze ANS metrics and cerebral autoregulation in patients with PSH syndrome to determine their significance in early prognostication. This single-center retrospective study investigated the relationship between changes in ANS metrics, cerebral autoregulation, and PSH syndrome. Arterial blood pressure and intracranial pressure signals were monitored for 5 days post TBI. ANS metrics included time and frequency domain heart rate variability (HRV) metrics. Cerebral autoregulation was assessed using the pressure reactivity index. Sixty-six patients with severe TBI (median age 33 [interquartile range 26-50] years) were analyzed, and PSH was confirmed in nine cases. Impairment of cerebral autoregulation was observed in 67% of patients with PSH and 72% without the syndrome. Patients with PSH had higher HRV in the low-frequency range (LF; 253 ± 178 vs. 176 ± 227 ms2; p = 0.035) and lower heart rates (HRs; 70 ± 7 vs. 78 ± 19 bpm; p = 0.027) compared to those without PSH. A receiver operating characteristic curve analysis indicated that HR (area under the curve(AUC) = 0.73, p = 0.006) and HRV in the LF (AUC = 0.70, p = 0.009) are moderate predictors of PSH. In the multiple logistic regression model for PSH, diffuse axonal trauma (odds ratio(OR) = 10.82, 95% confidence interval(CI) = 1.70-68.98, p = 0.012) and HR (OR =0.91, 95% CI 0.84-0.98, p = 0.021) were significant factors. Elevated HRV in the LF and decreased HR may serve as early predictors of PSH syndrome development, particularly in patients with diffuse axonal trauma. Further research is needed to investigate the utility of the cerebral autoregulation-ANS relationship in PSH prognostication.

Prognostic value of peak heart rate on cardiopulmonary exercise testing in patients with chronic heart failure

Abstract Backgrounds Many factors are known to be related to impaired exercise capacity or worse clinical outcomes in patients with chronic heart failure (CHF). Peak heart rate achievement by cardiopulmonary exercise testing (CPET) can be easily obtained on CPET. However, less data is available regarding the impact of peak heart rate on exercise capacity or long-term clinical outcomes in patients with CHF. Purpose We sought to investigate whether lower heart rate during peak exercise displayed poorer exercise capacity and worse clinical outcomes in patients with CHF. Methods We examined consecutive 435 patients with CHF referred for CPET in our university hospital between 2013 and 2018. The primary outcome was a composite of all-cause death or hospitalization due to worsening heart failure. Patients were divided into two groups according to the optimal cut-off value of peak heart rate based on receiver operating characteristic curve analysis. Results Patients with lower peak heart rate (≤112/min, n=164) were older and, higher brain natriuretic peptide level compared to those with higher peak heart rate (&amp;gt;112/min, n=271). Heart rate during peak exercise was significantly correlated with peak oxygen consumption (peak V̇O2) (Figure 1A), peak workload achievement (Figure 1B), and ventilatory efficiency (V̇E/V̇CO2 slope) (Figure 1C). There were 80 patients with events over a median follow-up period of 3.4 (Interquartile range 0.7–5.6) years. Patients with lower peak heart rate had about 3.0-fold higher risk of events compared to those with high peak heart rate (hazard ratio [HR] 3.17; 95% confidence interval [CI], 2.01–4.98) (Figure 2). In a multivariable Cox regression, 10 bpm-decreased in peak heart rate was associated with 12% increased adverse events (HR 0.88; 95%CI, 0.78–0.98). Conclusions Peak heart rate achievement on CPET was associated with reduced exercise capacity and worse clinical outcomes, suggesting that peak heart rate is useful for risk stratification in patients with CHF. Further study is required to identify therapies targeting peak heart rate to improve the exercise capacity or clinical outcomes in patients with CHF.Figure1Figure2

Divergent hemometabolic dynamics: understanding the differences between acute myocardial infarction and heart failure related cardiogenic shock

Abstract Background Understanding the hemodynamic trajectories between acute myocardial infarction(AMI) &amp; non-AMI cardiogenic shock(CS) is crucial for tailored management. Purpose Describe different hemometabolic patterns in AMI vs AMI-CS, AMI vs AMI-CS survivors &amp; AMI vs AMI-CS non-survivors. Methods 354 AMI &amp; 81 Non-AMI CS patients with PAC-hemodynamics were included. ANOVA of repeated measures was used to compare trajectories. Cox regression analysis for hazard ratios of conventional cut-off values hemometabolic goals &amp; ideal with Youden index for LVSWi at baseline &amp; 24h(Fig2B/C). Results AMI-CS were older(62 vs 52,P&amp;lt;0.001), exhibit a higher prevalence of smoking, dyslipidemia, HTN, &amp; DM2(P&amp;lt;0.05). HF history &amp; AF were more prevalent in Non-AMI-CS(P&amp;lt;0.001). AMI-CS had lower heart rate, respiratory rate, BUN, pH; higher LVEF, hemoglobin, leucocytes, platelets, glucose, Cl-, Na+, AST, ALT, LDH(P&amp;lt;0.05). Treatment modalities, AMI-CS had higher mechanical circulatory support (P&amp;lt;0.001). AKI was more common in non-AMI(P=0.004). There were no differences in number of vasoactives(P=0.46), but non-AMI had more dobutamine use(P&amp;lt;0.001). MODS score, organ failures, VT/VF, Phenotype, SCAI, and mortality(46.9 vs 47.7% Non-AMI vs AMI-CS) had no differences(P&amp;gt;0.05). Dynamics congestion associated with phenotypes &amp; SCAI are shown in Fig 2A. SBP(F=12.39,P&amp;lt;0.001), DBP(4.72,0.03) &amp; MAP(9.98,0.002) (Fig1A) had differences in AMI vs non-AMI-CS, but none were seen in survivors(P&amp;gt;0.05), only in non-survivors (SBP 17.52, &amp;lt;0.001; DBP 6.59, 0.011 &amp; MAP 13.98, &amp;lt;0.001). RAP(7.4,0.007) &amp; PCWP(53.51,&amp;lt;0.001) (Fig1B/C) also differ among AMI vs non-AMI &amp; non-survivors(5.69,0.018 &amp; 28.77,&amp;lt;0.001); but only PCWP differs across survivors(27.49,&amp;lt;0.001). Cardiac output &amp; index(Fig1D)(13.65,&amp;lt;0.001 &amp; 18.88,&amp;lt;0.001) had both differences among survivors(4.17,0.042 &amp; 6.67,0.01) &amp; non-survivors(10.98,&amp;lt;0.001 &amp; 13.57,&amp;lt;0.001). Cardiac power, index, &amp; CPIRAP(Fig1E) also had this behavior being higher in AMI. Coronary perfusion pressure (Fig1F) differs among all 3 classes (P&amp;lt;0.001), AMI vs non-AMI(F=31.17), survivors(11.63) &amp; non-survivors(25.81). Perfusion pressure only had in AMI vs non-AMI(15.91,&amp;lt;0.001) &amp; non-survivors(20.39,&amp;lt;0.001). PAPI(Fig1G) had differences in AMI vs non-AMI(F=9.3,P=0.002) &amp; non-survivors(8.69,&amp;lt;0.001). API(Fig1H) differs across all spectrums(14.87 groups, 5.89 survivors &amp; 11.61 non-survivors). Finally, LVSWi &amp; RVSWi(Fig1I/J) had differences among AMI vs non-AMI in all categories: groups(22.5 &amp; 14.27 both &amp;lt;0.001), survivors(7.88,0.005 &amp; 9.29,0.003) &amp; non-survivors(21.27,&amp;lt;0.001 &amp; 5.17, 0.024). In the metabolic, only lactate(Fig1K) shows differences in AMI vs non-AMI(5.46,0.02) &amp; non-survivors(8.02,0.005); no differences were noted in survivors. Hazard ratios were assessed with the whole cohort, AMI, &amp; non-AMI; full data is shown in Fig 2B/C. Conclusion Our investigation elucidates nuanced hemodynamic disparities between AMI vs non AMI-CS, even in survivors and non-survivors of CS.Figure 1.Hemodynamic trajectoriesFigure 2.Alluvial. B/C Baseline &amp; 24h goals

Left atrial parameters predict incident atrial fibrillation and flutter in patients with heart failure with reduced ejection fraction

Abstract Background Left atrial (LA) function parameters have shown prognostic value in relation to incidence of atrial fibrillation in the general population, but this remains to be investigated in patients with heart failure with reduced ejection fraction (HFrEF). Purpose This study aimed to investigate the relationship between LA function parameters and the risk of incident atrial fibrillation/atrial flutter (AF/AFL) in patients with HFrEF. Methods Subjects free of AF/AFL were retrospectively included from a HF clinic and followed using the Danish National Patient Registry. Cox proportional hazards regression was used to assess the prognostic value of LA function parameters. These included LA ejection fraction (LAEF), peak atrial longitudinal strain (PALS), peak atrial contractile strain (PACS) and LA conduit strain (LACS). In addition, multivariable Cox regression was performed to adjust for demographic and echocardiographic parameters, including LA volume index (LAVi). The LA function parameters that remained significant in adjusted analysis were examined using cubic splines, and cutoff values corresponding to a hazard ratio (HR) equal to 1 were derived from these. Results The total study population consisted of 435 subjects with a left ventricular ejection fraction (LVEF) ≤45% (mean age 65.6±11.7 years, male sex 70.1%) free from AF/AFL at baseline. During a median follow-up of 11.4 years [IQR: 10.8, 14.2], 111 (25.5%) developed AF/AFL. Subjects who met the outcome were generally older (69.0±8.8 years vs. 64.4±12.4, p&amp;lt;0.001), had lower baseline heart rate, and a higher prevalence of moderate or severe valve disease (12.6% vs. 3.1%, p&amp;lt;0.001). They also had higher LV mass index and LV internal diastolic diameter index, but similar LVEF. These subjects had larger LAVi (30 ml/m2 [IQR: 24, 38] vs. 26 ml/m2 [IQR: 20, 32], p&amp;lt;0.001), while LAEF (33±14.8% vs. 39±14.9%, p&amp;lt;0.001), PALS (20.3% [IQR: 16.2, 26.5] vs. 23.2% [IQR: 18.6, 29.6], p=0.001), and PACS (9.7% [IQR: 6.9, 13.5] vs. 12.0% [IQR: 7.8, 16.4], p=0.004) were all significantly lower. LACS was similar between groups. In univariable Cox regression, all LA parameters were significant predictors of the AF/AFL (LAEF: HR 0.98 per 1% increase, 95% CI 0.96-0.99, p=0.0002, PALS: HR 0.96 per 1% increase, 95% CI 0.94–0.98, p=0.0008, PACS: HR 0.95 per 1%, 95% CI 0.93–0.98, p=0.0024, LACS: HR 0.96, 95% per 1% increase CI 0.92–0.998, p=0.039. In adjusted analysis, however, only LAEF (HR 0.98, 95% CI 0.976-0.995, p=0.0087) and PACS (HR 0.96, 95% CI 0.993–0.999, p=0.044) remained significant. Splines were constructed for LAEF and PACS (Figure 1), and a cutoff for increased risk of AF/AFL at 38% for LAEF and 12% for PACS, respectively, were derived (Figure 2). Conclusion LAEF and PACS are associated with risk of incident AF/AFL in patients with HFrEF, independent of clinical and echocardiographic risk factors. Our results suggest an increased risk of AF/AFL at LAEF below 38% and PACS below 12%.Figure 1 SplinesFigure 2 Cumulative incident curves

Circadian heart rate fluctuations predict 21-year cardiovascular and all-cause mortality in type 2 and type 1 diabetes

Abstract Background Alterations in circadian heart rate (HR) fluctuations have been associated with cardiovascular events in the general population. This study aimed at defining their long-term prognostic value for cardiovascular and all-cause mortality in patients with diabetes. Methods We examined a cohort of 349 patients with type 2 or type 1 diabetes (52% women, age 57.1±11.9 years, BMI 29.4±5.9 kg/m2, HbA1c 8.6±2.1%, 81% type 2 diabetes) who underwent 24h ambulatory blood pressure and HR monitoring (ABPM) and assessment of diabetic microvascular complications. The median standard deviation (SD) value of ABPM-derived HR measurements was used to define patients with low daily HR fluctuations (low 24h-HR SD), while a &amp;lt;10% decline in average night-time vs day-time HR identified patients with blunted nocturnal HR dip (n=107, 31%). The clinical features and time-dependent prognostic impact of these conditions were evaluated over a 21-year observational follow-up. Results Low 24h-HR SD and blunted nocturnal HR dip were associated with an adverse cardiometabolic risk profile and high prevalence of cardiac autonomic neuropathy and nephropathy. After 6,251 person-years of follow-up (21.0 [14.0-21.0] years), a total of 136 (39%) deaths occurred, of which 100 (68%) of cardiovascular cause. After adjustment for potential confounders, the low 24h-HR SD group had a higher risk for both cardiovascular (hazard ratio 1.99, 95% CI 1.29–3.06, p=0.002) and all-cause mortality (hazard ratio 1.50, 95% CI 1.03–2.18, p=0.033), compared with high 24h-HR SD. Consistently, patients with blunted nocturnal HR dip had a higher adjusted risk for cardiovascular (1.61, 95% CI 1.07–2.43, p=0.023) and all-cause mortality (1.61, 95% CI 1.11–2.34, p=0.012), compared with those with preserved nocturnal HR dip. Conclusions Impaired circadian HR fluctuations are frequent in patients with long-standing diabetes and are associated with microvascular disease and increased long-term cardiovascular and all-cause mortality. Identifying these conditions via 24h-ABPM may provide a cost-effective risk stratification tool in this high-risk population.Kaplan-Meier curves

Improving exercise cardiac reserve assessment using a novel cardiopulmonary and echocardiography testing protocol (CPET-ESE) based on individualised exercise intensity domains

Abstract Background Functional exercise stress echocardiography (ESE) is used to quantify changes in cardiac reserve and can improve early cardiac dysfunction diagnosis and follow-up.[1.2] Current ESE protocols do not account for individual variations in fitness and heart rate response, leading to difficulties in defining normal reference values.[2,3] Physiologically defined exercise intensity domains could be implemented as part of combined cardiopulmonary and ESE testing (CPET-ESE) to address this problem. Purpose We propose that using exercise intensity domains as part of CPET-ESE will result in cardiac reserve values not influenced by individual cardiorespiratory fitness or physical activity (PA) levels. We also hypothesise by matching work-rates and heart rates (HR), respectively, cardiac reserve will be higher in those exercising at the higher exercise intensity domain. Methods A total of 45 healthy adults (mean age 43.8 ± 14.2, range 18-65 y) underwent a CPET followed by a CPET-ESE consisting of two 6-minute stages: 1. Moderate intensity (MOD) at 90% of the work-rate at the gas exchange threshold (GET) and 2. High intensity (HIGH) at 40% of the difference between GET and peak. Global left ventricular and right ventricular free wall (LV and RV) longitudinal strain (Sl), RV fractional area change (RV-FAC), peak LV and RV TDI derived systolic (S’) and diastolic velocities (E’) were measured at each step, including rest. HIGH steps were matched 1-to-n with MOD steps from other participants based on work-rate and HR, respectively. Questionnaire derived PA was classified as low, moderate, and high active. Cardiorespiratory fitness was measured as peak oxygen uptake relative to body mass (mL·kg-1·min-1). Results After adjusting for age and sex, neither higher PA nor peak VO2 were associated with higher cardiac function parameters at either intensity (Table 1). Higher peak VO2 was associated with higher work-rate for HIGH only, while higher PA was associated with lower HR for MOD only (interaction term p&amp;lt;0.05). When paired by matching HR and work-rate, respectively, HIGH was associated with higher cardiac function parameters compared to MOD (all except for LV-S’ and RV-FAC when HR matched, Table 2), despite those matched from HIGH being older, less physically active and having lower peak VO2 (p&amp;lt;0.05 for all). Conclusions Current ESE protocols, which define submaximal exercise intensity using arbitrary work-rate or HR targets,[3] do not account for the complex differences in exercise response between healthy individuals. Cardiac function augmentation during exercise is likely a response to VO2 kinetics and this is not accurately described by either HR or work-rate alone. We derived normal reference values for cardiac reserve from implementing physiologically defined exercise intensity domains within the combined CPET-ESE testing frameworks. These values could be more appropriately used when comparing diverse clinical populations using CPET-ESE.

Hemodynamics and thermal characteristics of a deformable stenosed carotid artery with heat generation: Effect of heart rate, stenotic severity, and wall elasticity

The formation of the stenosis in the carotid artery may lead to ischemic stroke, cerebral infarction, and other severe health-related complications. The present study aims to investigate the effects of heart rates on the blood flow dynamics and the heat transfer characteristics of a deformable stenosed carotid artery. This investigation employs an Arbitrary Lagrangian-Eulerian fluid-structure interaction based on the finite element-based solver COMSOL Multiphysics® to model the incompressible continuity, momentum, and energy equations. The model incorporates the elasticity of the carotid artery and the realistic non-Newtonian behavior of pulsatile blood flow. The effect of heart rates (75, 100, 120 bpm), degree of stenosis (25 %, 50 %, 75 %), arterial wall stiffness values (2–3 MPa), and macrophage heat generation (Q̇m = 0.05–0.2 W/mm3) have given insights into pulsatile blood flow dynamics and resultant alterations in thermal characteristics. As heart rates and degree of stenosis increase, the blood supply is severely affected in the internal carotid artery (ICA) connected to cerebral tissues, potentially increasing the risk of ischemic stroke due to inadequate oxygenation. Notably, recirculation zones or vortices form at 100 and 120 bpm heart rates, particularly at 75 % stenotic severity. Higher heart rates correspond to increased wall shear stress in the stenosed ICA region, potentially leading to endothelial damage and vessel rupture, posing significant health risks. At a heart rate of 75 bpm, the temperature increase in macrophages and plaques is 2.07 °C and 0.17 °C, respectively. It highlights the notable impact of heart rate and changes in stenotic severity on temperature distribution, particularly within macrophages in the presence of arterial plaque. These effects are more pronounced with lower heart rates, higher stenosis, and higher heat generation rates associated with arterial plaque. These findings suggest clinical relevance in understanding the complex interplay between heart rates, blood flow dynamics, and thermal characteristics in arterial stenosis scenarios.