Cardiac Sympathetic Innervation Research Articles

Long-Term Caloric Restriction Improves Cardiac Function, Remodeling, Adrenergic Responsiveness, and Sympathetic Innervation in a Model of Postischemic Heart Failure

Caloric restriction (CR) has been described to have cardioprotective effects and improve functional outcomes in animal models and humans. Chronic ischemic heart failure (HF) is associated with reduced cardiac sympathetic innervation, dysfunctional β-adrenergic receptor signaling, and decreased cardiac inotropic reserve. We tested the effects of a long-term CR diet, started late after myocardial infarction on cardiac function, sympathetic innervation, and β-adrenergic receptor responsiveness in a rat model of postischemic HF. Adult male rats were randomly assigned to myocardial infarction or sham operation and 4 weeks later were further randomized to a 1-year CR or normal diet. One year of CR resulted in a significant reduction in body weight, heart weight, and heart weight/tibia length ratio when compared with normal diet in HF groups. At the end of the study period, echocardiography and histology revealed that HF animals under the CR diet had ameliorated left ventricular remodeling compared with HF rats fed with normal diet. Invasive hemodynamic showed a significant improvement of cardiac inotropic reserve in CR HF rats compared with HF-normal diet animals. Importantly, CR dietary regimen was associated with a significant increase of cardiac sympathetic innervation and with normalized cardiac β-adrenergic receptor levels in HF rats when compared with HF rats on the standard diet. We demonstrate, for the first time, that chronic CR, when started after HF established, can ameliorate cardiac dysfunction and improve inotropic reserve. At the molecular level, we find that chronic CR diet significantly improves sympathetic cardiac innervation and β-adrenergic receptor levels in failing myocardium.

Validation of Iodine-131-meta-iodobenzylguanidine cardiac scintigraphy in Parkinsonism: A preliminary study

Introduction123I-MIBG is the most commonly used radiopharmaceutical to depict cardiac sympathetic innervation. The purpose of this study was to validate the feasibility of 131I-MIBG as an alternative myocardial sympathetic imaging probe in differential diagnosis of Parkinsonism. MethodsWe recruited 17 patients with PD, 21 patients with other parkinsonism (17 with MSA and 4 with PSP), and 6 normal controls. All participants underwent 131I-MIBG scintigraphy for both early and delayed imaging. The image quality was independently assessed by two experienced nuclear medicine specialists and graded into three categories: 1, good image quality; 2, suboptimal but sufficient for diagnosis; and 3, poor or nondiagnostic. Cardiac MIBG uptake was quantitatively measured using H/M ratio and washout rate. ResultsThe image quality was good (Grade 1) in 74 and 73 of a total of 88 images by the two reviewers, respectively. No image was poor or nondiagnostic (Grade 3). Patients with PD had a significantly lower H/M ratio for both the early and the delayed images than did those with MSA or PSP and the controls (P < 0.001). For differentiating PD from other parkinsonism, the sensitivity and specificity were 95% and 94% for the early images and 100% and 94% for the delayed images, respectively. Patients with MSA or PSP has a significantly lower WR compared with those with PD. (WR = 0.15 ± 0.23 and 0.48 ± 0.17, respectively; P < 0.001). Conclusion131I-MIBG scintigraphy is a feasible method to depict cardiac sympathetic activity. The diagnostic performance is comparable to that of 123I-MIBG.

A Comparative Assessment of Cardiovascular Autonomic Reflex Testing and Cardiac 123I-Metaiodobenzylguanidine Imaging in Patients with Type 1 Diabetes Mellitus without Complications or Cardiovascular Risk Factors.

Aim To compare the cardiovascular autonomic reflex tests (CARTs) with cardiac sympathetic innervation imaging with 123I-metaiodobenzylguanidine (MIBG) in patients with type 1 diabetes mellitus (T1DM). Patients and Methods Forty-nine patients (29 males, mean age 36 ± 10 years, mean T1DM duration 19 ± 6 years) without cardiovascular risk factors were prospectively enrolled. Participants were evaluated for autonomic dysfunction by assessing the mean circular resultant (MCR), Valsalva maneuver (Vals), postural index (PI), and orthostatic hypotension (OH). Within one month from the performance of these tests, patients underwent cardiac MIBG imaging and the ratio of the heart to upper mediastinum count density (H/M) at 4 hours postinjection was calculated (abnormal values, H/M < 1.80). Results Twenty-nine patients (59%) had abnormal CARTs, and 37 (76%) patients had an H/M_4 < 1.80 (p = 0.456). MCR, PI, Vals, and OH were abnormal in 29 (59%), 8 (16%), 5 (10%), and 11 (22%) patients, respectively. When using H/M_4 < 1.80 as the reference standard, a cutoff point of ≥2 abnormal CARTs had a sensitivity of 100% but a specificity of only 33% for determining CAN. Conclusions CARTs are not closely associated with 123I-MIBG measurements, which can detect autonomic dysfunction more efficiently than the former. In comparison to semiquantitative cardiac MIBG assessment, the recommended threshold of ≥2 abnormal CARTs to define cardiovascular autonomic dysfunction is highly sensitive but of limited specificity and is independently determined by the duration of T1DM.

Investigation into cardiac sympathetic innervation during the commencement of haemodialysis in patients with chronic kidney disease

BackgroundPatients with chronic kidney disease (CKD) who undergo chronic haemodialysis (HD) show altered sympathetic tone, which is related to a higher cardiovascular mortality. The purpose of this study was to investigate the effect of transition from pre-HD to HD on cardiac sympathetic innervation.MethodsEighteen patients aged 58 ± 18 years (mean ± standard deviation [SD]), 13 males and five females, with stage 5 CKD and nine healthy control subjects aged 52 ± 17 (mean ± SD), three males and six females, were included in this prospective study between May 2010 and December 2013. All patients underwent 123I-labelled meta-iodobenzylguanidine (123I-MIBG) scintigraphy for cardiac sympathetic innervation and electrocardiographically gated adenosine stress and rest 99mTc-labelled tetrofosmin single-photon emission computed tomography for myocardial perfusion imaging prior to (pre-HD) and 6 months after the start of HD. Results of 123I-MIBG scans in patients were compared to controls. Impaired cardiac sympathetic innervation was defined as late heart-to-mediastinum ratio (HMR) < 2.0.ResultsMean late HMR was lower in patients during HD (2.3) than in controls (2.9) (p = 0.035); however, in patients it did not differ between pre-HD and after the start of HD. During HD, two patients showed new sympathetic innervation abnormalities, and in three patients innervation abnormalities seemed to coincide with myocardial perfusion abnormalities.ConclusionsCKD patients show cardiac sympathetic innervation abnormalities, which do not seem to progress during the maintenance HD. The relationship between sympathetic innervation abnormalities and myocardial perfusion abnormalities in HD patients needs further exploration.

The heart of PD: Lewy body diseases as neurocardiologic disorders

This review provides an update about cardiac sympathetic denervation in Lewy body diseases. The family of Lewy body diseases includes Parkinson’s disease (PD), pure autonomic failure (PAF), and dementia with Lewy bodies (DLB). All three feature intra-neuronal cytoplasmic deposits of the protein, alpha-synuclein. Multiple system atrophy (MSA), the parkinsonian form of which can be difficult to distinguish from PD with orthostatic hypotension, involves glial cytoplasmic inclusions that contain alpha-synuclein. By now there is compelling neuroimaging, neuropathologic, and neurochemical evidence for cardiac sympathetic denervation in Lewy body diseases. In addition to denervation, there is decreased storage of catecholamines in the residual terminals. The degeneration develops in a centripetal, retrograde, “dying back” sequence. Across synucleinopathies the putamen and cardiac catecholaminergic lesions seem to occur independently of each other, whereas non-motor aspects of PD (e.g., anosmia, dementia, REM behavior disorder, OH) are associated with each other and with cardiac sympathetic denervation. Cardiac sympathetic denervation can be caused by synucleinopathy in inherited PD. According to the catecholaldehyde hypothesis, 3,4-dihydroxyphenylacetaldehyde (DOPAL), an intermediary metabolite of dopamine, causes or contributes to the death of catecholamine neurons, especially by interacting with proteins such as alpha-synuclein. DOPAL oxidizes spontaneously to DOPAL-quinone, which probably converts alpha-synuclein to its toxic oligomeric form. Decreasing DOPAL production and oxidation might slow the neurodegenerative process. Tracking cardiac sympathetic innervation over time could be the basis for a proof of principle experimental therapeutics trial targeting DOPAL.

Diagnosis and Management of Cognitive and Behavioral Changes in Dementia With Lewy Bodies.

Proper diagnosis of dementia with Lewy bodies (DLB) in clinical practice remains suboptimal as many cases are misdiagnosed, usually as Alzheimer disease (AD) or Parkinson's disease (PD) and, in rare cases, psychosis. Therefore, it is important for patients with dementia to be thoroughly evaluated by a specialist who is familiar with current diagnostic tests and treatment options. New diagnostic criteria from the Dementia with Lewy Bodies Consortium have been developed to increase diagnostic sensitivity for DLB (Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium; McKeith et al.; Neurology, 89(1): 88-100). REM sleep behavior disorder (RBD) has been studied more thoroughly in correlation with DLB and is now considered a core feature. D2 receptor blocking antipsychotics, which can cause severe antipsychotic sensitivity, are now rarely prescribed for treatment. Therefore, severe antipsychotic sensitivity, which was a suggestive criterion for DLB diagnosis, is now listed as a supportive feature. Reduced DAT uptake in basal ganglia demonstrated by SPECT or PET imaging has high specificity (90%) for distinguishing DLB from AD. Reduced uptake on metaiodobenzylguanidine myocardial scintigraphy correlates with reduced postganglionic sympathetic cardiac innervation in Lewy body diseases, which can increase specificity for discriminating probable DLB from probable AD in milder cases of dementia. However, the latter is more commonly used in Japan and is not used in the USA. The evidence supporting the benefit of other therapeutic modalities is limited in DLB due to lack of extensive studies. There are no FDA-approved medications for the treatment of DLB, although some effective drugs have been used off label to treat various symptoms.

Cardiac sympathetic denervation predicts PD in at-risk individuals

IntroductionBy the time a person develops the motor manifestations of Parkinson's disease (PD), substantial loss of nigrostriatal dopamine neurons has already occurred. There is great interest in identifying biomarkers that can detect pre-clinical PD. Braak's neuropathological staging concept imputes early autonomic involvement. Here we report results from a small prospective cohort study about the utility of neuroimaging evidence of cardiac sympathetic denervation in predicting PD among individuals with multiple PD risk factors. MethodsSubjects provided information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. From this pool, 27 people with at least 3 risk factors confirmed underwent cardiac 18F-dopamine positron emission tomographic scanning and were followed for at least 3 years. Interventricular septal and left ventricular free wall concentrations of 18F-dopamine-derived radioactivity were measured. ResultsOf the 27 subjects, 4 were diagnosed with PD within the 3-year follow-up period (Pre-Clinical PD group); 23 risk-matched (mean 3.2 risk factors) subjects remained disease-free (No-PD group). Compared to the No-PD group, the Pre-Clinical PD group had lower initial values for septal and free wall concentrations of 18F-dopamine-derived radioactivity (p = 0.0248, 0.0129). All 4 Pre-Clinical PD subjects had evidence of decreased cardiac sympathetic innervation in the interventricular septum or left ventricular free wall, in contrast with 3 of 23 (13%) No-PD subjects (p = 0.0020 by Fisher's exact test). ConclusionPeople with multiple PD risk factors and diagnosed with PD within 3 years have evidence of antecedent cardiac sympathetic denervation. The findings fit with Braak's staging concept.

073_16284-H5 Visualization of Left Atrial Sympathetic Innervation Activity and the Effect of Catheter Ablation on Activity Patterns in Patients With Atrial Fibrillation

A novel cardiac gamma camera utilises the radiopharmaceutical Iodine-123 Meta- iodobenzylguanidine (123I –m IBG) to visualise cardiac sympathetic innervation. Physiologic uptake of 123I –m IBG provides anatomical quantification of autonomic nervous system (ANS) structures, with discrete uptake

073_16731-A1 Visualisation of Left Atrial Sympathetic Activity Distribution and Its Physiological Variation Over Time in Healthy Individuals

A novel cardiac gamma camera utilises physiologic uptake of Iodine-123 Meta -iodobenzylguanidine (123I –m IBG) to visualise cardiac sympathetic innervation. Physiologic uptake of 123I – m IBG provides anatomical quantification of autonomic nervous system (ANS) structures with discrete uptake

Changes in Sympathetic Innervation of the Heart in Rats with Experimental Myocardial Infarction. Effect of Semax.

The effect of peptide Semax on remodeling of cardiac sympathetic innervation was examined in rats with experimental myocardial infarction. In 28 days after ischemia/reperfusion injury, Semax diminished the growth of sympathetic innervation of ventricular septum, although it produced no effect on the density of β1 and β2 adrenoceptors.

Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease.

Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by 123I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. Cardiac sympathetic innervation was assessed by 123I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n=10); (2) unmatched, with MIBG defect but without fibrosis (n=5); and (3) matched abnormal, with MIBG defect and fibrosis (n=10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p=0.008), LV hypertrophy (p=0.05), and enzyme replacement therapy (p=0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r2=0.98, p<0.001), MIBG defect size was larger than fibrosis size (26±23 vs. 18±13%LV, p=0.02). Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, 123I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD.

Cardiac sympathetic innervation, from a different point of (re)view.

The audience of basic and clinical scientists is familiar with the notion that the sympathetic nervous system controls heart function during stresses. However, evidence indicates that the neurogenic control of the heart spans from the maintenance of housekeeping functions in resting conditions to the recruitment of maximal performance, in the fight-or-flight responses, across a whole range of intermediate states. To perform such sophisticated functions, sympathetic ganglia integrate both peripheral and central inputs, and transmit information to the heart via 'motor' neurons, directly interacting with target cardiomyocytes. To date, the dynamics and mode of communication between these two cell types, which determine how neuronal information is adequately translated into the wide spectrum of cardiac responses, are still blurry. By combining the anatomical and structural information brought to light by recent imaging technologies and the functional evidence in cellular systems, we focus on the interface between neurons and cardiomyocytes, and advocate the existence of a specific 'neuro-cardiac junction', where sympathetic neurotransmission occurs in a 'quasi-synaptic' way. The properties of such junctional-type communication fit well with those of the physiological responses elicited by the cardiac sympathetic nervous system, and explain its ability to tune heart function with precision, specificity and elevated temporal resolution.

Exploring the Pathophysiology of Takotsubo Cardiomyopathy.

The purpose of this review is to explore the pathophysiology of Takotsubo cardiomyopathy by appraising the interplay between myocardial perfusion, function, metabolism, and, particularly, sympathetic innervation. A number of hypotheses have been proposed to explain the pathogenesis of Takotsubo cardiomyopathy, which include (1) catecholamine cardiac toxicity, (2) myocardial sympathetic innervation disruption, (3) coronary vasospasm, (4) myocardial microvascular dysfunction, and (5) aborted myocardial infarction. These proposals are primarily derived from findings of nuclear myocardial perfusion, metabolism, and cardiac sympathetic innervation imaging. Although data in the literature are not necessarily uniform, the two most plausible working postulates for explaining the phenomenon are (1) regional myocardial stunning (due to coronary vasospasm, microvascular dysfunction, or aborted myocardial infarction) and (2) cardiac sympathetic innervation disruption or toxicity. Current data suggest that disturbances of both coronary circulation and neural innervation are associated with the Takotsubo cardiomyopathy: myocardial stunning from transient ischemic attack and sympathetic innervation disruption. It remains to be determined, however, whether the observed leading mechanistic explanations that have gained momentum are merely the sequelae of the disease rather than its primary etiology.

The utility of the combination of a SPECT study with [123I]-FP-CIT of dopamine transporters and [123I]-MIBG myocardial scintigraphy in differentiating Parkinson disease from other degenerative parkinsonian syndromes.

ObjectiveMolecular imaging of nigrostriatal dopamine transporters (DAT) and sympathetic cardiac innervation with single-photon emission computed tomography (SPECT) are useful tools for differentiating idiopathic Parkinson disease (PD) from other degenerative parkinsonian syndromes (non-PD). Nevertheless, these modalities are often insufficient for achieving a definite diagnosis. The aims of this study were to evaluate the diagnostic accuracy of the combination of these tools.Materials and methodsThe SPECT radiotracers [123I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)-nortropane (FP-CIT) and meta-[123I]-iodobenzylguanidine (MIBG) were used to research presynaptic dopaminergic projections (DAT SPECT) and myocardial adrenergic innervation (MIBG scintigraphy), respectively. PD patients (n=15; age: 61.5±13.6 years) and non-PD patients (n=19; age: 62.6±14.2 years) who underwent both tests were enrolled in this study. Receiver-operating characteristic analyses were used to set the cutoff values of the specific binding ratio in DAT SPECT and the heart to mediastinum ratio in delayed scan in MIBG scintigraphy for differentiating PD from non-PD. We calculated the sensitivity, specificity, and test accuracy of the individual methods and also the combination of these two modalities.ResultsWhen DAT SPECT and MIBG scintigraphy were used individually, they showed mild accuracy in differentiating PD from non-PD (DAT, 67.6%; MIBG, 67.6%). The combination of the two approaches using cutoff values of less than 3.24 for the specific binding ratio and less than 2.745 for the delayed heart to mediastinum ratio enabled more accurate differentiation between PD and non-PD. The accuracy of these indices in distinguishing PD from non-PD was 79.4%.ConclusionThese results suggested that the combination of DAT SPECT and MIBG scintigraphy may improve the diagnostic accuracy in differentiating PD from non-PD.

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

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.

Asymmetric sympathetic output: The dorsomedial hypothalamus as a potential link between emotional stress and cardiac arrhythmias.

The autonomic response to emotional stress, while involving several target organs, includes an important increase in sympathetic drive to the heart. There is ample evidence that cardiac sympathetic innervation is lateralized, and asymmetric autonomic output to the heart during stress is postulated to be a causal factor that precipitates cardiac arrhythmias. Recent animal studies provided a new picture of the central pathways involved in the cardiac sympathetic response evoked by emotional stress, pointing out a key role for the region of dorsomedial hypothalamus. However, how much of this information can be extrapolated to humans? Analysis of human functional imaging data at rest or during emotional stress shows some consistency with the components that integrate these pathways, and attention must be given to the asymmetric activation of subcortical sites. In this short review, we will discuss related findings in humans and animals, aiming to understand the neurogenic background for the origin of emotional stress-induced cardiac arrhythmias.

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis.

The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n = 12) or anterior myocardial infarction (MI, n = 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CVL) was increased by RSGS (0.98 ± 0.11 vs. 1.2 ± 0.14m/s, P < 0.001) but not transverse CV (CVT). This increase was abrogated by β-adrenergic receptor and gap junction (GJ) blockade. Neither CVL nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 ± 37 vs. 322 ± 30 ms, P < 0.001, and 423 ± 36 vs. 398 ± 36 ms, P = 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 ± 1.2 vs. 17.3 ± 1.6 ms, P = 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals (P < 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic peri-infarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis.NEW & NOTEWORTHY This study demonstrates regional control of conduction velocity in normal hearts by sympathetic nerves. In infarcted hearts, however, not only is modulation of propagation heterogeneous, some regions showed paradoxical conduction slowing. Sympathoexcitation altered propagation in all infarcted hearts studied, and we describe the temporal arrhythmogenic potential of these findings.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/sympathetic-nerves-and-cardiac-propagation/.

Renal denervation in male rats with heart failure improves ventricular sympathetic nerve innervation and function.

Heart failure is characterized by the loss of sympathetic innervation to the ventricles, contributing to impaired cardiac function and arrhythmogenesis. We hypothesized that renal denervation (RDx) would reverse this loss. Male Wistar rats underwent myocardial infarction (MI) or sham surgery and progressed into heart failure for 4 wk before receiving bilateral RDx or sham RDx. After additional 3 wk, left ventricular (LV) function was assessed, and ventricular sympathetic nerve fiber density was determined via histology. Post-MI heart failure rats displayed significant reductions in ventricular sympathetic innervation and tissue norepinephrine content (nerve fiber density in the LV of MI+sham RDx hearts was 0.31 ± 0.05% vs. 1.00 ± 0.10% in sham MI+sham RDx group, P < 0.05), and RDx significantly increased ventricular sympathetic innervation (0.76 ± 0.14%, P < 0.05) and tissue norepinephrine content. MI was associated with an increase in fibrosis of the noninfarcted ventricular myocardium, which was attenuated by RDx. RDx improved LV ejection fraction and end-systolic and -diastolic areas when compared with pre-RDx levels. This is the first study to show an interaction between renal nerve activity and cardiac sympathetic nerve innervation in heart failure. Our findings show denervating the renal nerves improves cardiac sympathetic innervation and function in the post-MI failing heart.

Iodine-123 metaiodobenzylguanidine scintigraphy for the assessment of cardiac sympathetic innervation and the relationship with cardiac autonomic function in healthy adults using standardized methods.

Global iodine-123 metaiodobenzylguanidine (I-MIBG) uptake is predictive of cardiovascular events and mortality in patients with heart failure. Normal variations in global and regional uptake, however, are not well defined and few studies have addressed the functional relevance of I-MIBG uptake and distribution in healthy individuals. We performed I-MIBG scintigraphy and cardiac autonomic function testing using the standardized methodology in 15 healthy individuals (mean age 54.6±5.3 years, male : female 10 : 5) with no evidence of previous myocardial infarction or ischaemic heart disease. Early heart to mediastinum ratio (HMR) was 1.67±0.13, late HMR was 1.73±0.16 and washout rate was 19.09±7.63% (4.20-31.30). Regional analysis showed reduced tracer uptake at the apex, base and inferior wall in all individuals. Early and late HMR correlated negatively with RFa (r=-0.603; P=0.05 and r=-0.644; P=0.033) and expiration and inspiration ratio (r=-0.616; P=0.043 and r=-0.676; P=0.022) and positively with LFa/RFa (r=0.711; P=0.014 and r=0.784; P=0.004). Washout rate correlated only with RFa (r=0.642; P=0.033). Healthy adults show a heterogeneous pattern of cardiac innervation with reduced regional uptake of I-MIBG. Furthermore, HMR correlates with indices of cardiac sympathetic function, suggesting that it might not only be a useful prognostic marker but may also provide insight into the functional integrity of the cardiac autonomic nervous system.