Cardiac Sympathetic Activity Research Articles

Sympathetic and parasympathetic cardiac responses to phobia-relevant and disgust-specific emotion provocation in blood-injection-injury phobia with and without fainting history.

The autonomic regulation in blood-injection-injury (BII) phobia has received particular attention due to the unique link between fear and fainting in this anxiety disorder. However, systematic exploration of sympathetic and parasympathetic cardiac activity during exposure to phobia-relevant emotional stimuli has remained rare and inconclusive, including with regard to disgust, a frequent response to BII stimuli. Existing studies using respiratory sinus arrhythmia (RSA) as a noninvasive index of parasympathetic cardiac activity also have not accounted sufficiently for effects of respiration. We compared 60 participants with BII phobia (27 with and 33 without history of loss of consciousness) and 20 healthy controls during emotion induction with films, including a disgust and a BII-relevant surgery film. Cardiorespiratory activity was measured continuously, with RSA (controlled for respiration) and T-wave amplitude (TWA; as a noninvasive index of sympathetic cardiac activity) extracted. Significant increases in RSA during the surgery film were observed for participants with a history of loss of consciousness compared to others, but controlling for respiration eliminated these differences. Sympathetic effects with heart rate accelerations, which were most pronounced for the disgust film, did not differentiate groups. However, substantial increases in RSA and TWA, suggesting parasympathetic excitation and sympathetic withdrawal, were observed in five participants that became presyncopal during the surgery film. Thus, parasympathetic excitation and sympathetic withdrawal appear to be cardinal autonomic features in BII phobia, but larger studies of participants reaching presyncopal states in BII-relevant stimulus exposure are needed to consolidate these findings.

Comparative effects of long and short-acting loop diuretics on mortality in patients with chronic heart failure

BackgroundWe previously reported that the long-acting loop diuretic azosemide improves cardiac sympathetic nerve activity (CSNA) in patients with chronic heart failure (CHF), compared with short-acting furosemide. However, its influence on mortality has not been determined. MethodsThe present study was a further analysis of our previously published study in which azosemide showed improved 123I-metaiodobenzylguanidine scintigraphic findings compared with furosemide in CHF patients with reduced left ventricular ejection fraction (LVEF). Patients with CHF were identified according to their histories of acute decompensated heart failure requiring hospitalization. A total of 108 patients were selected and propensity score matching was used to compare patients treated with azosemide (n=54) or furosemide (n=54). ResultsDuring the median follow-up period of 5.22years, 24 out of 108 patients experienced cardiac death events. In multivariate Cox regression analysis (adjusted for age, non-beta-blocker treatments, and impaired CSNA), furosemide treatment was an independent predictor of cardiac death events (p=0.034, hazard ratio 2.624, 95% confidence interval 1.074 to 6.047). On Kaplan-Meier analysis, the cardiac death-free rate in the azosemide group was significantly higher than that in the furosemide group (p<0.05). ConclusionsThese findings indicate the superior effectiveness of azosemide in reducing mortality compared with furosemide.

Regular physical exercise improves cardiac autonomic and muscle vasodilatory responses to isometric exercise in healthy elderly

The objective of this study was to evaluate cardiac autonomic control and muscle vasodilation response during isometric exercise in sedentary and physically active older adults. Twenty healthy participants, 10 sedentary and 10 physically active older adults, were evaluated and paired by gender, age, and body mass index. Sympathetic and parasympathetic cardiac activity (spectral and symbolic heart rate analysis) and muscle blood flow (venous occlusion plethysmography) were measured for 10 minutes at rest (baseline) and during 3 minutes of isometric handgrip exercise at 30% of the maximum voluntary contraction (sympathetic excitatory maneuver). Variables were analyzed at baseline and during 3 minutes of isometric exercise. Cardiac autonomic parameters were analyzed by Wilcoxon and Mann–Whitney tests. Muscle vasodilatory response was analyzed by repeated-measures analysis of variance followed by Tukey’s post hoc test. Sedentary older adults had higher cardiac sympathetic activity compared to physically active older adult subjects at baseline (63.13±3.31 vs 50.45±3.55 nu, P=0.02). The variance (heart rate variability index) was increased in active older adults (1,438.64±448.90 vs 1,402.92±385.14 ms, P=0.02), and cardiac sympathetic activity (symbolic analysis) was increased in sedentary older adults (5,660.91±1,626.72 vs 4,381.35±1,852.87, P=0.03) during isometric handgrip exercise. Sedentary older adults showed higher cardiac sympathetic activity (spectral analysis) (71.29±4.40 vs 58.30±3.50 nu, P=0.03) and lower parasympathetic modulation (28.79±4.37 vs 41.77±3.47 nu, P=0.03) compared to physically active older adult subjects during isometric handgrip exercise. Regarding muscle vasodilation response, there was an increase in the skeletal muscle blood flow in the second (4.1±0.5 vs 3.7±0.4 mL/min per 100 mL, P=0.01) and third minute (4.4±0.4 vs 3.9±0.3 mL/min per 100 mL, P=0.03) of handgrip exercise in active older adults. The results indicate that regular physical activity improves neurovascular control of muscle blood flow and cardiac autonomic response during isometric handgrip exercise in healthy older adult subjects.

Higher exercise intensity delays postexercise recovery of impedance-derived cardiac sympathetic activity.

Systolic time intervals (STIs) provide noninvasive insights into cardiac sympathetic neural activity (cSNA). As the effect of exercise intensity on postexercise STI recovery is unclear, this study investigated the STI recovery profile after different exercise intensities. Eleven healthy males cycled for 8 min at 3 separate intensities: LOW (40%-45%), MOD (75%-80%), and HIGH (90%-95%) of heart-rate (HR) reserve. Bio-impedance cardiography was used to assess STIs - primarily pre-ejection period (PEP; inversely correlated with cSNA), as well as left ventricular ejection time (LVET) and PEP:LVET - during 10 min seated recovery immediately postexercise. Heart-rate variability (HRV), i.e., natural-logarithm of root mean square of successive differences (Ln-RMSSD), was calculated as an index of cardiac parasympathetic neural activity (cPNA). Higher preceding exercise intensity elicited a slower recovery of HR and Ln-RMSSD (p < 0.001), and these measures did not return to baseline by 10 min following any intensity (p ≤ 0.009). Recovery of STIs was also slower following higher intensity exercise (p ≤ 0.002). By 30 s postexercise, higher preceding intensity resulted in a lower PEP (98 ± 14 ms, 75 ± 6 ms, 66 ± 5 ms for LOW, MOD, and HIGH, respectively, p < 0.001). PEP recovered to baseline (143 ± 11 ms) by 5 min following LOW (139 ± 13 ms, p = 0.590) and by 10 min following MOD (145 ± 17 ms, p = 0.602), but was still suppressed at 10 min following HIGH (123 ± 21 ms, p = 0.012). Higher preceding exercise intensity attenuated the recovery of indices for cSNA (from STIs) and cPNA (from HRV) in a graded dose-response fashion. While exercise intensity must be considered, acute recovery may be a valuable period during which to concurrently monitor these noninvasive indices, to identify potentially abnormal cardiac autonomic responses.

Cardiac Autonomic Responses during Exercise and Post-exercise Recovery Using Heart Rate Variability and Systolic Time Intervals-A Review.

Cardiac parasympathetic activity may be non-invasively investigated using heart rate variability (HRV), although HRV is not widely accepted to reflect sympathetic activity. Instead, cardiac sympathetic activity may be investigated using systolic time intervals (STI), such as the pre-ejection period. Although these autonomic indices are typically measured during rest, the “reactivity hypothesis” suggests that investigating responses to a stressor (e.g., exercise) may be a valuable monitoring approach in clinical and high-performance settings. However, when interpreting these indices it is important to consider how the exercise dose itself (i.e., intensity, duration, and modality) may influence the response. Therefore, the purpose of this investigation was to review the literature regarding how the exercise dosage influences these autonomic indices during exercise and acute post-exercise recovery. There are substantial methodological variations throughout the literature regarding HRV responses to exercise, in terms of exercise protocols and HRV analysis techniques. Exercise intensity is the primary factor influencing HRV, with a greater intensity eliciting a lower HRV during exercise up to moderate-high intensity, with minimal change observed as intensity is increased further. Post-exercise, a greater preceding intensity is associated with a slower HRV recovery, although the dose-response remains unclear. A longer exercise duration has been reported to elicit a lower HRV only during low-moderate intensity and when accompanied by cardiovascular drift, while a small number of studies have reported conflicting results regarding whether a longer duration delays HRV recovery. “Modality” has been defined multiple ways, with limited evidence suggesting exercise of a greater muscle mass and/or energy expenditure may delay HRV recovery. STI responses during exercise and recovery have seldom been reported, although limited data suggests that intensity is a key determining factor. Concurrent monitoring of HRV and STI may be a valuable non-invasive approach to investigate autonomic stress reactivity; however, this integrative approach has not yet been applied with regards to exercise stressors.

Azelnidipine is a useful medication for the treatment of heart failure preserved ejection fraction

ABSTRACTBackground: The optimal therapy in patients with heart failure preserved ejection fraction (HFpEF) and hypertension (HT) has not been revealed. The beta blocker (BB) and the renin angiotensin aldosterone system inhibitor (RAAS-I) are recommend as class IIa in patients with HFpEF. The calcium channel blocker (CCB), a major anti-hypertensive drugs in Japan, is also recommend as class IIa in patients with HFpEF. However, the difference between azelnidipine, an L type CCB, and cilnidipine, an N type CCB, is unclear. We investigated the difference between azelnidipine and cilnidipine in patients with HFpEF and HT. Methods: Twenty-five consecutive HFpEF patients treated with BB and RAAS-I from April 2013 to March 2015 were enrolled. Initially, cilnidipine was used, and then switched to azelnidipine. Age, gender, blood pressure (BP), heart rate (HR), blood tests, echocardiography, and cardiac-scintigraphy (123I-metaiodobenzylguanidine: MIBG) were measured before and after six months from azelnidipine administration. Results: There was no statistically significant difference in BP. B type natriuretic peptides were significantly reduced (pre-state: 195.4 ± 209.7 pg/ml and post-state: 140.7 ± 136.4 pg/ml, p = 0.050). In echocardiography, the TEI index tended to be decreased (pre-state: 0.47 ± 0.15 and post-state: 0.42 ± 0.08, p = 0.057). As for MIBG, there was no significant change in the heart/mediastinum ratio. However, the washout rate was significantly reduced (pre-state: 44.7 ± 12.2 and post-state: 40.7 ± 12.1, p = 0.011). In addition, there was no statistically significant change, although HR tended to decrease by switching to azelnidipine (pre-state: 62.7 ± 11.6 and post-state: 61.8 ± 16.5, p = 0.373). Conclusions: In patients with HT and HFpEF, azelnidipine improved the severity of HF and cardiac sympathetic nerve activity compared with cilnidipine.

Blood pressure reactivity to mental stress is attenuated following resistance exercise in older hypertensive women.

PurposeThis study aimed to investigate the effects of resistance exercise (RE) on autonomic control and blood pressure (BP) reactivity during mental stress (MS) in treated older hypertensive women.MethodsTen older hypertensive women (age =71.1±5.5 years; body mass index =24.2±3.9; mean BP [MBP] =85.4±3.5) underwent a protocol consisting of BP and heart rate variability (HRV) output assessments at baseline and during MS, and these measurements were taken before and 60 minutes after two bouts of RE (traditional and circuit). MS was induced through a computerized 3-minute Stroop color–word test before and 1 hour after each exercise session; BP was measured every minute during MS, and HRV was monitored as a measure of cardiac autonomic control.ResultsA significant effect of time on systolic BP (Δpre =17.4±12.8 versus Δpost =12.5±9.6; P=0.01), diastolic BP (Δpre =13.7±7.1 versus Δpost =8.8±4.5; P=0.01), and MBP (Δpre =14.0±7.7 versus Δpost =9.3±5.4; P<0.01) after RE was observed, with no differences between the two sessions. In addition, a significant effect of time on log-normalized low-frequency component of HRV (ms2; 5.3±0.8 pre-exercise MS versus 4.8±1.0 baseline value; P=0.023) was also observed, showing a significant change from baseline to MS before RE, but not after RE sessions. These results may be related to a lessened RE-mediated cardiac sympathetic activity during MS.ConclusionRE is an effective tool to reduce BP reactivity to MS, which could therefore be associated with an acute reduction in cardiovascular risk. This result presents relevant clinical implications, combining previous evidence that recommends this exercise modality as an important component of an exercise program designed for the older and hypertensive subjects.

Beta blocker dose and markers of sympathetic activation in heart failure patients: interrelationships and prognostic significance.

AimsExtent of cardiac sympathetic activation can be estimated from physiological parameters, blood biomarkers, and imaging findings. This study examined the prognostic value of three markers of sympathetic activity and their relationship to beta blocker dose in heart failure patients.Methods and resultsA post hoc analysis of 858 heart failure subjects in the ADMIRE‐HF trial was performed. Variables related to sympathetic activity were plasma norepinephrine, baseline heart rate, the heart to mediastinum (H/M) ratio of 123I‐mIBG uptake, and beta blocker dose. Univariate and multivariate analyses for occurrence of mortality (all‐cause and cardiac) and arrhythmic events were performed. Beta blocker dose was significantly related to age, heart rate, b‐type natriuretic peptide (negatively), body mass index, body weight and plasma norepinephrine. Univariate predictors of all‐cause and cardiac mortality were baseline heart rate (χ 2 = 4.5, P = 0.029 and χ 2 = 5 .2, P = 0.022, respectively), plasma norepinephrine level (χ 2 = 8.9, P = 0.0006 and χ 2 = 8.6, P = 0.003, respectively), and H/M (χ = 22.4, P < 0.0001 and χ 2 = 17.8, P < 0.0001, respectively). In multivariate analyses, carvedilol‐equivalent dose (P = 0.017), plasma norepinephrine (P = 0.002), and H/M (P = 0.0001) were significant predictors of all‐cause mortality. In separate analyses using multiple measurements of heart rate, mean heart rate >67 b.p.m. was associated with significantly higher cardiac mortality.ConclusionsHigher beta blocker dose was associated with lower mortality, but of the variables associated with sympathetic activity examined, cardiac 123I‐mIBG uptake was the most powerful prognostic marker in heart failure patients. Elevated heart rate was associated with greater risk for cardiac death.

Evaluation of Cardiac Autonomic Balance and Sympathetic Vasomotor Activation to Different Targets in a Model of Hypertension Induced by Nitric Oxide Synthase Blockade

High blood pressure is a global public health problem. Several factors are involved in the generation and maintenance of hypertension, such as increased sympathetic nerve activity (SNA), although controversies have been reported. Our aims were to evaluate cardiac autonomic balance and sympathetic activation of the renal (rSNA) and the splanchnic nerve (sSNA), in animals with hypertension induced by nitric oxide synthase blockade (L‐NAME). Wistar rats were treated with L‐NAME (20mg/kg/day, once a day, for 8 days). L‐NAME treated group presented increased blood pressure (152 ± 02 mmHg, n=17), compared with control group (101±01 mmHg, n= 15).Plasma nitric oxide (NO) measurement presented a significantly reduction in L‐NAME (6.8 ±0.4 pg/L n=15), compared to CTL group (9.9 ± 1.2 pg/L n=06), both rSNA (147 ± 10spikes/s, n=16) and sSNA (137 ± 13 spike/s n=14) were higher in L‐NAME treated group, compared with control group (114 ± 5, n=10 and 74 ± 13spikes/s, n=09, respectively). The spectral analysis of the pulse interval (PI) demonstrated that the L‐NAME group presented increased low frequency component (LF) (19.75±1.75, n=07 vs CTL: 6.75±1,10, n=07), reduced high frequency component (HF) (81.29 ± 1.80 n=07 vs CTL: 92.50±1.20, n=07) leading to a sympatho‐vagal imbalance (LF/HF) (0.24 ± 0.02, n=07 vs CTL: 0.08 ± 0.01, n=07).Taken altogether, our data show that the hypertension induced by nitric oxide synthase blockade is characterized by cardiac autonomic imbalance and sympathoexcitation to more than one territory and that can be involved in the generation and/or maintenance of high blood pressure.Support or Funding InformationCAPES, CNPq, UNAH.

Significant correlation between renal 123I-metaiodobenzylguanidine scintigraphy and muscle sympathetic nerve activity in patients with primary hypertension

BackgroundIodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy is used as a noninvasive imaging method for assessing cardiac sympathetic nerve activity. We tested the hypothesis that renal 123I-MIBG imaging is correlated with muscle sympathetic nerve activity (MSNA) in patients with primary hypertension. MethodsThirty-one consecutive patients with primary hypertension were included. Multiunit MSNA was recorded from the peroneal nerve to evaluate direct efferent sympathetic nerve activity. Planar renal and cardiac 123I-MIBG images were acquired. Early and delayed kidney-to-mediastinum ratio (K/M), early and delayed heart-to-mediastinum ratio (H/M), and washout rates (WR) were calculated. ResultsIn 27 of 31 patients, blood pressure was controlled on antihypertensive medication. Mean systolic and diastolic blood pressures were 118 ± 18 and 67 ± 15 mmHg, respectively. Although early and late K/M and H/M were not significantly correlated with MSNA, both cardiac and average renal WR were significantly correlated with MSNA (r = 0.45, P = .0035 and r = 0.68, P < .001, respectively). Right and left renal WR were similarly correlated with MSNA. Renal WR was significantly higher than cardiac WR (43.2% vs 25.8%, P < .001) in these patients with hypertension. ConclusionsRenal 123I-MIBG WR was significantly associated with multiunit MSNA. Renal 123I-MIBG imaging offers a noninvasive clinical methodology for assessing renal sympathetic nerve function.

Altered regulation of cardiac sympathetic nerve activity during hypertension

Hypertension remains one of the strongest predictors of premature death and an increase in sympathetic nerve activity has been implicated in the pathogenesis of hypertension. In this context, increased sympathetic drive to the heart promotes arrhythmias and sudden death in patients, but the level of cardiac sympathetic nerve activity (CSNA) in hypertension has been assessed only by indirect methods. We tested the hypothesis that directly recorded CSNA is increased in renovascular hypertension.Renovascular hypertension was induced by surgical clipping of one renal artery. Following three weeks post‐clip, electrodes were surgically implanted into cardiac sympathetic nerve fascicles of adult sheep. Following recovery from surgery, resting levels of mean arterial pressure, heart rate and cardiac sympathetic nerve activity were recorded. In conscious sheep, the renal clipping procedure induced hypertension relative to sham operated controls (106 ± 4 vs. 86 ± 6 mmHg, p&lt;0.05, n=6 per group). However, no significant change in heart rate was observed between the two groups. Direct cardiac sympathetic nerve activity recording in conscious sheep showed that burst frequency of cardiac sympathetic nerves was higher in renovascular hypertensive sheep compared to sham control ewes (39 ± 2.6 vs. 28 ± 1.8 bursts per minute, p &lt; 0.05). In addition, our data suggest that baroreflex control of CSNA at lower pressures was impaired (upper plateau of 226 ± 23 vs 386 ± 64 % of control).Our data includes the first ever recordings of cardiac sympathetic nerve activity in hypertension and suggest a potential role for CSNA in mediating the chronic elevation in arterial pressure in hypertensive animals.Support or Funding InformationThe University of Auckland Faculty Research Development Fund

Reliability of Heart Rate Variability as an Assessment of Cardiac Sympathetic Activity in Humans

Spectral analysis of heart rate variability (HRV) has been widely used as an indirect, non‐invasive method for assessing cardiac autonomic function in numerous psychophysiological and clinical research studies. However, there is debate whether or not the low‐frequency (LF) component of the analysis provides accurate insight into cardiac sympathetic activity in humans. The purpose of this study was to evaluate the reliability of the LF component of HRV compared to that of peripheral muscle sympathetic nerve activity (MSNA), which remains the only direct method to assess sympathetic neural outflow in humans and has been consistently shown to have high intra‐individual reproducibility. Sixteen adults (9 men and 7 women, 21 ± 1 years, body mass index of 23 ± 1 kg/m2) were examined, and completed three experimental sessions across two laboratory visits. Experimental sessions one and two were conducted during the first laboratory visit and separated by 45 minutes of supine rest, while the third session was completed approximately one month after the first laboratory visit. Each session included a five‐minute supine baseline that included recordings of MSNA via microneurography and R‐R intervals using a three‐lead electrocardiogram. Intraclass correlation analyses (Cronbach's α coefficient) were performed to determine the consistency of HRV and MSNA across the three sessions. The spectral analysis revealed that the high‐frequency (HF) component, which is primarily associated with cardiac parasympathetic activity, was highly reliable (Cronbach's α = 0.90, P &lt; 0.001). In contrast, the LF component, which is often utilized as a noninvasive estimate of cardiac sympathetic activity, was not significantly consistent across the three sessions (Cronbach's α = 0.45, P = 0.078). As previously reported (Fonkoue &amp; Carter, Am J Physiol Regul Integr Comp Physiol, 2015), MSNA was highly consistent across the three sessions (Cronbach's α = 0.84, P &lt; 0.001). In summary, our findings demonstrate that unlike MSNA, which has been consistently shown to be a stable and reliable measurement of peripheral sympathetic activity, the LF component of HRV is not a stable and reliable measurement of cardiac sympathetic activity in humans.

Cervicothoracic Transcutaneous Electrical Nerve Stimulation Attenuates Cardiac Sympathetic Overdrive in Heart Failure: A 123l‐MIBG Myocardial Scintigraphy, Randomized Double‐Blind Crossover Trial

IntroductionCardiac sympathetic drive provides inotropic support to the failing heart and preserves cardiovascular homeostasis. Nonetheless, as myocardial insult evolves, this compensatory response leads to a progressive decline in contractile function, increases the vulnerability to arrhythmias and constitutes an independent mortality predictor. Despite advanced pharmacological therapies, side effects and persistent cardiac sympathetic overdrive highlights the modulation of the adrenergic system as a primary target for non‐pharmacological strategies in the heart failure (HF) treatment. In this scenario, we propose cervicothoracic transcutaneous electrical nerve stimulation (TENS) as a non‐pharmacological therapy to attenuate cardiac sympathetic overdrive in patients with heart failure.MethodsIn this prospective, randomized, sham‐controlled, double‐blind crossover trial, seven HF patients (6 men and 1 women, 54 ± 6 years of age, and body mass of 61 ± 11 kg, NYHA class II–III, ejection fraction 28.1 ± 2.5%,) were randomly assigned to either an in‐home cervicothoracic transcutaneous electrical nerve stimulation therapy (TENS: 30 min twice a day with 80 Hz frequency and pulse duration of 150 μs) or a sham control intervention (SHCI) for two weeks. Following a two‐month washout phase from TENS/SHCI, patients crossed over and started the opposite condition. Washout rate and heart‐to‐mediastinum ratio, indexes of cardiac sympathetic activity and innervation density, were obtained from planar 123l‐metaiodobenzylguanidine myocardial scintigraphy images at the beginning and end of each condition.ResultsBaseline washout rate (TENS 27.1 ± 4.4% vs. SHCI 25.2 ± 6.8%, p = 0.657), early (TENS 1.78 ± 0.1 vs. SHCI 1.78 ± 0.05, p = 0.916) and late (TENS 1.74 ± 0.19 vs. SHCI 1.68 ± 0.16, p = 0.222) heart‐to‐mediastinum ratios were similar between both conditions. While early and late heart‐to‐mediastinum ratio did not change throughout the study (p &gt; 0.05), TENS, but not SHCI, promoted a significant reduction in the washout rate (TENS ‐ 12.8 ± 4.3 vs. STHI + 8.0 ± 8.9%, p = 0.03).ConclusionThese findings indicate that short‐term TENS therapy attenuates cardiac sympathetic overdrive in patients with heart failure with no impact on myocardial innervation density.Support or Funding InformationGrant Funding Source: CAPES, CNPq, FAPERJ, FINEP and IEN

Cardiac and peripheral autonomic control in restrictive cardiomyopathy.

AimsAutonomic dysfunction determines the advance of dilated cardiomyopathy (DCM) and is related to poor outcomes. However, this autonomic imbalance is unknown in patients with restrictive cardiomyopathy (RCM) even though they have similar symptoms and poor quality of life as DCM patients have. The aim of this study was to evaluate if autonomic and neurovascular controls were altered in RCM patients.Methods and resultsFifteen RCM patients, 10 DCM patients, and 10 healthy subjects were evaluated. Heart rate and blood pressure (BP) were recorded. Peripheral sympathetic activity [muscle sympathetic nerve activity (MSNA)] by microneurography and cardiac sympathetic activity by power spectrum analysis of heart rate variability. Spontaneous baroreflex sensitivity (BRS) was evaluated by the sequence method and forearm blood flow by venous occlusion plethysmography. Both cardiomyopathy groups had higher MSNA frequency (P < 0.001) and MSNA incidence (P < 0.001), higher cardiac sympathovagal balance (P < 0.02), reduced BRS for increase (P = 0.002) and for decrease in BP (P = 0.002), and lower forearm blood flow (P < 0.001) compared with healthy subjects. We found an inverse correlation between BRS for increase and decrease in BP and peripheral sympathetic activity (r = −0.609, P = 0.001 and r = −0.648, P < 0.001, respectively) and between BRS for increase and decrease in BP and cardiac sympathetic activity (r = −0.503, P = 0.03 and r = −0.487, P = 0.04, respectively).ConclusionsThe RCM patients had cardiac and peripheral autonomic dysfunctions associated with peripheral vasoconstriction. Nonetheless, the presence of normal ejection fraction underestimates the evolution of the disease and makes clinical treatment difficult. These alterations could lead to a similar cardiovascular risk as that observed in DCM patients.

Effects of Spinal Cord Stimulation on Cardiac Sympathetic Nerve Activity in Patients with Heart Failure.

Spinal cord stimulation (SCS) reduces sympathetic activity in animal models of heart failure with reduced ejection fraction (HF) but limited data exist of SCS in patients with HF. The aim of the present study was to test the primary hypothesis that SCS reduces cardiac sympathetic nerve activity in HF patients. Secondary hypotheses were that SCS improves left ventricular function and dimension, exercise capacity, and clinical variables relevant to HF. HF patients with a SCS device previously participating in the DEFEAT-HF trial were included in this crossover study with 6-week intervention periods (SCS-ON and SCS-OFF). SCS (50 Hz, 210-μs pulse duration, aiming at T2-T4 segments) was delivered for 12 hours daily. Indices of myocardial sympathetic neuronal function (heart-to-mediastinum ratio, HMR) and activity (washout rate, WR) were assessed using 123 I-metaiodobenzylguanidine (MIBG) scintigraphy. Echocardiography, exercise testing, and clinical data collection were also performed. We included 13 patients (65.3 ± 8.0 years, nine males) and MIBG scintigraphy data were available in 10. HMR was not different comparing SCS-ON (1.37 ± 0.16) and SCS-OFF (1.41 ± 0.21, P = 0.46). WR was also unchanged comparing SCS-ON (41.5 ± 5.3) and SCS-OFF (39.1 ± 5.8, P = 0.30). Similarly, average New York Heart Association class (2.4 ± 0.5 vs 2.3 ± 0.6, P = 0.34), quality of life score (24 ± 16 vs 24 ± 16, P = 0.94), and left ventricular dimension and function as well as exercise capacity were all unchanged comparing SCS-ON and SCS-OFF. In patients with HF, SCS (12 hours daily, targeting the T2-T4 segments of the spinal cord) does not appear to influence cardiac sympathetic neuronal activity or function as assessed by MIBG scintigraphy.

Journal Digest

Journal Digest

Autonomic, functional, skeletal muscle, and cardiac abnormalities are associated with increased ergoreflex sensitivity in mitochondrial disease.

Mitochondrial disease (MD) is a genetic disorder affecting skeletal muscles, with possible myocardial disease. The ergoreflex, sensitive to skeletal muscle work, regulates ventilatory and autonomic responses to exercise. We hypothesized the presence of an increased ergoreflex sensitivity in MD patients, its association with abnormal ventilatory and autonomic responses, and possibly with subclinical cardiac involvement. Twenty-five MD patients (aged 46 ± 3 years, 32% male) with skeletal myopathy but without known cardiac disease, underwent a thorough evaluation including BNPs, galectin-3, soluble suppression of tumorigenesis 2 (sST2), high sensitivity troponin T/I, catecholamines, ECG, 24-h ECG recording, cardiopulmonary exercise testing, echocardiography, cardiac/muscle magnetic resonance (C/MMR), and ergoreflex assessment. Thirteen age- and sex-matched healthy controls were chosen. Among these myopathic patients, subclinical cardiac damage was detected in up to 80%, with 44% showing fibrosis at CMR. Ergoreflex sensitivity was markedly higher in patients than in controls (64% vs. 37%, P < 0.001), and correlated with muscle fat to water ratio and extracellular volume at MMR (both P < 0.05). Among patients, ergoreflex sensitivity was higher in those with cardiac involvement (P = 0.034). Patients showed a lower peak oxygen consumption (VO2 /kg) than controls (P < 0.001), as well as ventilatory inefficiency (P = 0.024). Ergoreflex sensitivity correlated with reduced workload and peak VO2 /kg (both P < 0.001), and several indicators of autonomic imbalance (P < 0.05). Plasma norepinephrine was the unique predictor of myocardial fibrosis at univariate analysis (P < 0.05). Skeletal myopathy in MD is characterized by enhanced ergoreflex sensitivity, which is associated with a higher incidence of cardiac involvement, exercise intolerance, and sympathetic activation.

Increased Cardiac Sympathetic Activity and Oxidative Stress in Habitual Electronic Cigarette Users

Electronic cigarettes (e-cigarettes) have gained unprecedented popularity, but virtually nothing is known about their cardiovascular risks. To test the hypothesis that an imbalance of cardiac autonomic tone and increased systemic oxidative stress and inflammation are detectable in otherwise healthy humans who habitually use e-cigarettes. Cross-sectional case-control study of habitual e-cigarette users and nonuser control individuals from 2015 to 2016 at the University of California, Los Angeles. Otherwise healthy habitual e-cigarette users between the ages of 21 and 45 years meeting study criteria, including no current tobacco cigarette smoking and no known health problems or prescription medications, were eligible for enrollment. Healthy volunteers meeting these inclusion criteria who were not e-cigarette users were eligible to be enrolled as control individuals. A total of 42 participants meeting these criteria were enrolled in the study including 23 self-identified habitual e-cigarette users and 19 self-identified non-tobacco cigarette, non-e-cigarette user control participants. Heart rate variability components were analyzed for the high-frequency component (0.15-0.4 Hz), an indicator of vagal activity, the low-frequency component (0.04-0.15 Hz), a mixture of both vagal and sympathetic activity, and the ratio of the low frequency to high frequency, reflecting the cardiac sympathovagal balance. Three parameters of oxidative stress were measured in plasma: (1) low-density lipoprotein oxidizability, (2) high-density lipoprotein antioxidant/anti-inflammatory capacity, and (3) paraoxonase-1 activity. Of the 42 participants, 35% were women, 35% were white, and the mean age was 27.6 years. The high-frequency component was significantly decreased in the e-cigarette users compared with nonuser control participants (mean [SEM], 46.5 [3.7] nu vs 57.8 [3.6] nu; P = .04). The low-frequency component (mean [SEM], 52.7 [4.0] nu vs 39.9 [3.8] nu; P = .03) and the low frequency to high frequency ratio (mean [SEM], 1.37 [0.19] vs 0.85 [0.18]; P = .05) were significantly increased in the e-cigarette users compared with nonuser control participants, consistent with sympathetic predominance. Low-density lipoprotein oxidizability, indicative of the susceptibility of apolipoprotein B-containing lipoproteins to oxidation, was significantly increased in e-cigarette users compared with nonuser control individuals (mean [SEM], 3801.0 [415.7] U vs 2413.3 [325.0] U; P = .01) consistent with increased oxidative stress, but differences in high-density antioxidant/anti-inflammatory capacity and paraoxonase-1 activity were not significant. In this study, habitual e-cigarette use was associated with a shift in cardiac autonomic balance toward sympathetic predominance and increased oxidative stress, both associated with increased cardiovascular risk.

Assessment of late anthracycline-induced cardiotoxicity by 123I-mIBG cardiac scintigraphy in patients treated during childhood and adolescence

PurposeThe goal of this study was to evaluate late cardiotoxic effects of anthracyclines (ATC) by evaluating cardiac sympathetic activity in a cohort of asymptomatic patients previously treated with ATC for childhood cancers. MethodsWe studied 89 asymptomatic patients previously treated with ATC with a normal echocardiogram (49 men and 40 women) and a control group of 40 healthy individuals (26 men and 14 women). Both groups underwent planar myocardial 123I-meta-iodobenzylguanidine scintigraphy (123I-mIBG). From these images, the early and late heart-to-mediastinum (H/M) ratio and washout rate (WR) were assessed. ResultsThe mean survival at the time of the 123I-mIBG scintigraphy was 5.3 ± 3.4 years. Patients treated with ATC had a lower but clinical normal left ventricular ejection fraction (LVEF) compared to controls (60.44 ± 6.5 vs 64.1 ± 6.0%, P < 0.01). Both the late H/M ratio and WR were not able to discriminate ATC treated patients from controls. The cumulative ATC dose was the only independent predictor of the LVEF, explaining approximately 12% of the variation in LVEF (P = 0.01). ConclusionsAlthough the pathophysiology behind ATC cardiotoxicity is most likely multifactorial, myocardial sympathetic activity is not associated with a reduction in LVEF 5-years after completion of chemotherapy.

Synergistic prognostic implications of left ventricular mechanical dyssynchrony and impaired cardiac sympathetic nerve activity in heart failure patients with reduced left ventricular ejection fraction

Impairment of cardiac sympathetic innervation is a potent prognostic marker in heart failure, while left ventricular mechanical dyssynchrony (LVMD) has recently been noted as a novel prognosis determinant in heart failure patients with reduced LV ejection fraction (HFrEF). This study was designed to determine the correlation between cardiac sympathetic innervation quantified by metaiodobenzylguanidine (MIBG) activity and LVMD measured by electrocardiogram-gated myocardial perfusion imaging and to evaluate their incremental prognostic values in HFrEF patients. A total of 570 consecutive HFrEF patients were followed up for 19.6 months with a primary endpoint of lethal cardiac events (CE) such as sudden cardiac death, death due to pump failure and appropriate ICD shock against life-threatening ventricular tachyarrhythmias. Cardiac sympathetic function and innervation were quantified as heart-to-mediastinum ratio (HMR) and washout kinetics of cardiac MIBG activity. LVMD was assessed by a standard deviation (SD) of systolic phase angle in gated myocardial perfusion imaging. Patients with CE (n = 166, 29%) had a significantly lower HMR and a significantly greater phase SD than did non-CE patients: 1.46 ± 0.28 vs. 1.63 ± 0.29, P < 0.0001 and 39.1 ± 11.6 vs. 33.1 ± 10.1, P < 0.0001, respectively. Compared to the single use of optimal cut-offs of late HMR (1.54) and phase SD (38), their combination more precisely discriminated high-risk or low-risk patients from others with log rank values from 7.78 to 65.2 (P = 0.0053 to P ≤ 0.0001). Among significant univariate variables, multivariate Cox proportional hazards model identified NYHA functional class, estimated glomerular filtration rate (eGFR), HMR 1.54 and phase SD 60 as significant determinants of CE with hazard ratios of 3.108 (95% CI, 2.472-3.910; P < 0.0001), 0.988 (95% CI, 0.981-0.996; P = 0.0021), 0.257 (95% CI, 0.128-0.498; P < 0.0001) and 1.019 (95% CI, 1.019-1.037; P = 0.0228), respectively. By combining the four independent determinants, the prognostic powers synergistically (P < 0.0001) increased maximally to 263.8. Left ventricular mechanical dyssynchrony and impairment of cardiac sympathetic innervation are synergistically related to lethal cardiac events, contributing to better stratification of lethal cardiac event-risks and probably to optimization of therapeutic strategy in patients with HFrEF.