Cardiac Denervation Research Articles

Impact of body mass index on cardiac adrenergic derangement in heart failure patients: a 123I-mIBG imaging study.

To assess the impact of body mass index (BMI) on cardiac adrenergic derangement, measured by iodine-123 meta-iodobenzylguanidine (123I-mIBG) imaging in heart failure (HF) patients. Overweight and obesity represent relevant health issues, and augmented sympathetic tone has been described in patients with increased BMI. An extensive literature supports that HF-dependent cardiac denervation, measured through mIBG parameters, is an independent predictor of cardiovascular outcomes and mortality. However, the influence of BMI on cardiac mIBG uptake has not been largely investigated. We prospectively enrolled patients with systolic HF, collecting demographic, clinical, echocardiographic data, and mIBG imaging parameters. In order to detect the factors associated with mIBG parameters, a model building strategy, based on the Multivariable Fractional Polynomial algorithm, has been employed. We studied 249 patients with systolic HF, mean age of 66.4 ± 10.6years, and mean left ventricular ejection fraction (LVEF) of 30.7% ± 6.4, undergoing cardiac 123I-mIBG imaging to assess HF severity and prognosis. Seventy-eight patients (31.3%) presented a BMI ≥ 30kg/m2 and obese patients showed a significant reduction in early heart to mediastinum (H/M) ratio (1.66 ± 0.19 vs. 1.75 ± 0.26; p = 0.008) and a trend to reduction in washout rate (33.6 ± 18.3 vs. 38.1 ± 20.1; p= 0.092) compared with patients with BMI < 30kg/m2. Multiple regression analysis revealed that BMI, age, and LVEF were significantly correlated with early and late H/M ratios. Results of the present study indicate that BMI, together with LVEF and age, is independently correlated with cardiac mIBG uptake in HF patients.

Reliable quantification of myocardial sympathetic innervation and regional denervation using [11C]meta-hydroxyephedrine PET.

Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [11C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF). Dynamic HED PET-CT scans were performed 47 ± 22days apart in 20 patients with stable heart failure and reduced ejection fraction. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (VT), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC). Intra- and inter-observer correlations of both VT and RI were excellent (ICC = 0.93-0.99). Observer reproducibility (NPC = 3-13%) was lower than test-retest repeatability (NPC = 12-61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to VT (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or VT. Regional partial-volume correction degraded repeatability of both the global and regional VT measures by 2-12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30-61%) compared with the RI. Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex VT. Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure.

In This Issue of the Journal

In This Issue of the Journal

P2733Prognostic value of cardiac dysautonomia in AL amyloidosis

Abstract Introduction Cardiac involvement is the major prognostic factor in patients with light chain amyloidosis (AL). Cardiac dysautonomia can occur early in amyloidosis and can be assess by Iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy. Its prognostic value has been shown in TTR amyloidosis but is unknown in AL amyloidosis. We aimed to evaluate the prognosis impact of cardiac dysautonomia in patients with AL amyloidosis. Methods We carried out a prospective study in consecutive patients with biopsy-proven AL amyloidosis. All patients underwent clinical examination, EKG, echocardiography, cardiac MRI and biological tests. The 2012 Mayo clinic prognostic classification was calculated by using blood levels of NT-proBNP, cardiac T troponin and the differential of free light chains as recommended. The sympathetic cardiac innervation was assessed by using 123I-MIBGscintigraphy and measurement of the heart-to-mediastinum uptake ratio (late H/M) in the anterior view of the chest. A cardiac denervation was defined by late H/M &lt;1.8 4h after injection of 3 MBq/kg of 123I-MIBG. The primary end-point was all-cause mortality during follow-up. Results Fifty consecutive patients with AL amyloidosis were included. The median age was 68 years old [58–73]. By using both echocardiography and MRI, cardiac involvement was diagnosed in 33 patients (66%) and thirteen of these patients were NYHA class III or IV. By using Mayo clinic classification, patients were I, II, III and IV classes in 9 (18%), 14 (28%), 16 (32%) and 11 (22%) cases respectively. According to echocardiographic data, the median wall thickness of left ventricle was 13 mm [12–15]. The late H/M was 1.51 [1.33–1.67]. Cardiac denervation was found in 44 patients (88%). The 6 patients (12%) with a normal late H/M had no cardiac amyloidosis involvement. During a median follow-up of 24 months, 9 patients (18%) died. The area under the ROC curve of late H/M for predicting death was 0.74 (CI 95% 0.58–0.86). According to this curve, the best threshold was 1.44 and 7 of the 9 patients who died had late H/M ≤1.44. The figure shows the 2 year-survival according to late H/M. Late H/M ≤1.44 predicted all-cause death irrespective of the Mayo clinic classification: HR 8.0 (CI 95% 2.1–63) after adjustment on the Mayo clinic score (p=0.005). In addition, unplanned hospitalization for heart failure occurred in 8 patients with late H/M ≤1.44 versus 3 patients with late H/M &gt;1.44 (p=0.03). Survival according to late H/M Conclusion Late H/M ≤1.44 is predictive of adverse outcomes in patients with AL amyloidosis, independently of the Mayo Clinic prognostic classification.

262Circulating muscle-derived mir-206 links skeletal muscle dysfunction to cardiac autonomic denervation

Abstract Purpose Recent studies and our preliminary data demonstrate that muscle-specific ablation of the autophagy-related protein Atg7, leads to block of autophagy, sarcopenia and destabilization of the neuro-muscular junction (NMJ). In addition, Atg7 knock-out (Atg7 KO) muscle fibers release exosomes containing the muscle specific, miR-206, which is consistently elevated in the plasma. Interestingly, we found that miR-206 content was elevated in the heart, suggesting cardiac uptake of the miR-carrying circulating exosomes. We thus aimed at defining the effects of miR-206 on heart homeostasis. Methods Here, we analyzed the cardiac phenotype of adult (12mo.) and aged (24mo.) Atg7 KO mice, as well as of adult C57BL/6J mice injected, via tail vein, with scramble- or miR-206-loaded exosomes. Exosomes were isolated from EDL muscle of control and Atg7 KO mice, as well as from HEK293 cells. Heart function was assessed by echocardiography and ECG-telemetry. Confocal IF, whole-mount IF on heart blocks and multiphoton imaging were used to assess heart structure and sympathetic innervation. Bioinformatics, molecular and biochemical analyses were performed to identify novel targets of miR-206. IF, BRET assay and imaging of TrKA translocation were performed in cultured sympathetic neurons (SNs). Results We demonstrate that circulating exosomes, containing miR-206, are taken up by the heart leading to sympathetic dysinnervation, accompanied to reduction in the neurogenic control of cardiac rhythm and increased arrhythmogenesis. In vitro assays demonstrated that exosome-carried miR-206 targets cardiac SNs (cSNs), compromising cell structure and function. Indeed, increased miR-206 expression is accompanied by cSN atrophy, irregular axonal distribution of the active neurotransmitter release sites, and reduction in axonal sprouting. These effects are likely attributed to the miR-206-mediated down-regulation of the NGF receptor p75, as demonstrated by bioinformatics, luciferase assay, molecular and biochemical analyses in vitro and ex vivo. BRET assay, performed in cultured SNs treated with exosomes carrying miR-206, showed reduced formation of p75/TrkA complexes, which generate high-affinity binding sites for NGF and enhance neurotrophin responsiveness. Consistent with impaired NGF retrograde transport, miR-206 over-expressing SNs displayed reduced NGF protein content and decreased phosphorylation of Akt, which is an NGF downstream target, regulating neuronal survival. Interestingly, these latter results were confirmed in the stellate ganglia from Atg KO and miR-206 treated mice. miR-206 causes heart dysinnervation Conclusions We identify miR-206 as a key molecular player in the “muscle-to-heart” communication. miR-206 may participate to the pathogenesis of secondary cardiac dysfunction in skeletal muscle diseases associated to increased circulating levels of miR-206, ranging from ageing to neurodegenerative disorders (i.e. ALS, DMD).

How do we establish cardiac sympathetic nervous system imaging with 123I-mIBG in clinical practice? Perspectives and lessons from Japan and the US

Cardiac denervation is associated with progressive left ventricular (LV) dysfunction, ventricular arrhythmias, and sudden cardiac death (SCD) in heart failure (HF). In this regard, it is important to evaluate cardiac-specific sympathetic nervous system (SNS) function. The radiotracer Iodine-123 meta-iodobenzylguanidine (123I-mIBG) can noninvasively evaluate pre-synaptic SNS function. Recent multicenter trials have shown 123I-mIBG to have strong predictive value for fatal arrhythmias and cardiac death in HF. 123I-mIBG was initially developed in the USA in the 1970s. In 1992, the Japanese Ministry of Health and Labour approved 123I-mIBG for the assessment of cardiac function. Following approval, the Japanese nuclear cardiology community developed 123I-mIBG imaging services in various medical centers. Japanese groups have been trying to establish the clinical utility of 123I-mIBG and standardize parameters for data acquisition and image analysis. The US Food and Drug Administration (FDA) has approved clinical use of 123I-mIBG for cardiac and non-cardiac imaging. However, clinical use of 123I-mIBG in the US has been very limited. The number of 123I-mIBG studies in Japan has also been limited. There are similarities and differences between the two countries. To establish the clinical utility of 123I-mIBG in both countries, it is important to characterize the situations of 123I-mIBG in each.

Profil évolutif de la dénervation cardiaque sympathique dans l’amylose héréditaire à transthyrétine

IntroductionCardiac amyloidosis is a rare disease with poor prognosis, requiring an early diagnosis. I123-MIBG plays an important role in early evaluation of sympathetic cardiac innervation, which is decreased due to amyloid infiltration. The aim of this study was to assess the temporal evolution of cardiac denervation in patients with hereditary amyloidosis, particularly the rate of progression and regional abnormalities; and to identify progression markers. MethodsForty-six patients were included. All of them were carriers of a TTR mutation or received domino liver transplantation, and underwent at least two evaluations of cardiac innervation with MIBG, between February 2011 and February 2018. Progression of cardiac denervation was determined by comparing the H/M ratio at first and final assessment. Regional abnormalities were evaluated using the perfusion/innervation mismatch on a 17 segments model. Logistic regression analysis was used to identify predictors of progression. ResultsTwenty-two patients were stable and 24 were progressive. The mean delay between two MIBG scans was 3.2±1.3 years. Late H/M decreased by 3.9%/year in progressive group, and tended to accelerate after symptoms onset (−1.4±5.4 vs−0.49±2.9, P=0.03). Regional abnormalities were initally located in the infero-latéral segments and extended to the inferior and lateral walls at final assessment. LVEF (OR: 0.90, P=0.003) and initiation of amyloidosis targeted treatment (OR=5,35, P=0.003) were independent predictors of sympathetic denervation progression. ConclusionProgression of myocardial sympathetic denervation in hereditary amyloidosis is slow, but accelerates after symptoms onset. LVEF and treatment are potential progression markers. Regional abnormalities are mainly located in the inferolateral segments and tend to extend at the borders of the denervated area.

Cardiac Afferent Denervation Abolishes Ganglionated Plexi and Sympathetic Responses to Apnea: Implications for Atrial Fibrillation.

Background The autonomic nervous system response to apnea and its mechanistic connection to atrial fibrillation (AF) are unclear. We hypothesize that sensory neurons within the ganglionated plexi (GP) play a role. We aimed to delineate the autonomic response to apnea and to test the effects of ablation of cardiac sensory neurons with resiniferatoxin (RTX), a neurotoxic TRPV1 (transient receptor potential vanilloid 1) agonist. Methods Sixteen dogs were anesthetized and ventilated. Apnea was induced by stopping ventilation until oxygen saturations decreased to 80%. Nerve recordings from bilateral vagal nerves, left stellate ganglion, and anterior right GP were obtained before and during apnea, before and after RTX injection in the anterior right GP (protocol 1, n=7). Atrial effective refractory period and AF inducibility on single extrastimulation were assessed before and during apnea, and before and after intrapericardial RTX administration (protocol 2, n=9). GPs underwent immunohistochemical staining for TRPV1. Results Apnea increased anterior right GP activity, followed by clustered crescendo vagal bursts synchronized with heart rate and blood pressure oscillations. On further oxygen desaturation, a tonic increase in stellate ganglion activity and blood pressure ensued. Apnea-induced effective refractory period shortening from 110.20±31.3 ms to 90.6±29.1 ms ( P<0.001), and AF induction in 9/9 dogs versus 0/9 at baseline. After RTX administration, increases in GP and stellate ganglion activity and blood pressure during apnea were abolished, effective refractory period increased to 126.7±26.9 ms ( P=0.0001), and AF was not induced. Vagal bursts remained unchanged. GP cells showed cytoplasmic microvacuolization and apoptosis. Conclusions Apnea increases GP activity, followed by vagal bursts and tonic stellate ganglion firing. RTX decreases sympathetic and GP nerve activity, abolishes apnea's electrophysiological response, and AF inducibility. Sensory neurons play a role in apnea-induced AF.

The effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mice myocardial morphology

ABSTRACT: Studies have demonstrated sympathetic cardiac denervation in the MPTP mouse model. MPTP toxicity causes sympathetic nerve damage and depletion of heart norepinephrine. Previous evaluations of impairments in heart innervation have been based on imaging, electrophysiological and biochemical methods. However, these studies lacked information that can be obtained from morphoquantitative analyses. Thus, this study aimed to apply a design-based stereological method for evaluating the morphoquantitative alterations of myocardium following treatment with the neurotoxin MPTP in the C57/BL mouse. Our results showed that MPTP reduced the number of cardiomyocytes in the left ventricle.

Cardiovascular Responses to the Exercise Pressor Reflex in Pediatric Heart Transplant Recipients

Pediatric heart transplant recipients (HTR) have reduced exercise tolerance despite normal systolic ventricular function. A slower heart rate adaptation to exercise in HTR due to cardiac denervation is commonly observed in HTR patients, which explains, in part, the exercise intolerance. We tested the hypothesis that the cardiovascular response to exercise pressor reflex activation from handgrip exercise would be blunted in HTR.MethodsSix pediatric HTR (3f/3m; mean±SD, 10±3 yrs) and five healthy‐matched controls (CTL; 3f/2m; 10±2 yrs) were studied. After 3 min of resting baseline, subjects performed 2 min of isometric handgrip (HG) exercise at 40% maximal voluntary contraction, followed by 3 min post‐exercise circulatory occlusion (PECO). Beat‐by‐beat mean arterial pressure, heart rate, and modelflow stroke volume and cardiac output were recorded. Data were analysed as the change (Δ) from rest using two‐way repeated measures ANOVA (2 × 3; group × condition) and Holm‐Sidak multiple comparisons analysis. Significance was accepted at P&lt;0.05.ResultsMean arterial pressure increased in HTR (Δ17±15 mmHg) and CTL (Δ13±16 mL) during HG (P&lt;0.001) and remained elevated above baseline during PECO (HTR: Δ10±10 mmHg; CTL: Δ11±9 mmHg; P&lt;0.05), with no between group differences. Heart rate did not significantly increase during HG in HTR (Δ4±5 bpm, P=0.235) but did in CTL (Δ14±11 bpm, P&lt;0.001), and was 9 bpm lower in HTR vs CTL (P=0.005). Heart rate was not different during PECO from rest in HTR and CTL. Stroke volume increased in HTR (Δ3±1 mL) and CTL (Δ3±3 mL) during HG (P&lt;0.001) and remained elevated above baseline during PECO (HTR: Δ3±2 mL; CTL: Δ4±3 mL; P&lt;0.001), with no between group differences. Cardiac output did not significantly increase during HG in HTR (Δ0.34±0.21 L/min, P=0.074) but did in CTL (Δ0.71±0.54 L/min, P&lt;0.001), and was 0.37 L/min lower in HTR vs CTL (P=0.035). Cardiac output was not different during PECO from rest in HTR and CTL.ConclusionsOwing to the impaired heart rate response during handgrip exercise, cardiac output was lower in pediatric HTR compared to healthy‐matched controls in response to exercise pressor reflex activation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Quantification of acute parasympathetic denervation during cryoballoon ablation by using extracardiac vagal stimulation.

The purpose of this study was to systematically quantify the level of acute parasympathetic denervation in a stepwise fashion by means of extracardiac vagal stimulation (ECVS) by positioning a quadripolar catheter in the internal jugular vein, in a cohort of patients undergoing second-generation cryoballoon ablation for paroxysmal atrial fibrillation. Fifty patients with symptomatic paroxysmal atrial fibrillation, having undergone extracardiac vagal stimulation before and after ablation by means of second-generation cryoballoon second-generation cryoballoon ablation, were included. The extracardiac vagal stimulation performed preablation provoked cardioinhibitory responses in all patients with mean pause duration of 10130.6 ± 3280.0 ms. At the end of the procedure, the VRs were significantly diminished with mean pause of 1687.5 ms ± 2183.7 ms (P = 0.00 compared with the pause before the procedure). The ECVS proved to be a reproducible, feasible and reliable method to quantify the degree of parasympathetic denervation during CB-A. In all patients, significant cardiac parasympathetic denervation could be observed at the end of the procedure. Responses to ECVS were more specific to quantify the vagal denervation than the increase in the heart rate. However larger studies are needed to confirm this observation.

Cardiac 123I-MIBG Scintigraphy in Neurodegenerative Parkinson Syndromes: Performance and Pitfalls in Clinical Practice.

Purpose: Cardiac [123I]metaiodobenzylguanidine scintigraphy (123I-MIBG), reflecting postganglionic cardiac autonomic denervation, is proposed for early detection of Parkinson's disease (PD; reduced tracer uptake) and separation from Multiple System Atrophy (MSA; preserved tracer uptake). However, several recent studies report on frequent unexpected 123I-MIBG results in PD and MSA. We sought to determine, whether 123I-MIBG is feasible to discriminate PD from MSA in unselected geriatric patients in clinical practice.Materials and Methods: We screened consecutive patients, that underwent 123I-MIBG for diagnostic reasons. Delayed 123I-MIBG uptake (heart/mediastinum ratio; H/M ratio) was verified by clinical diagnosis of PD, MSA, and ET based on a two-stage clinical assessment: comprehensive baseline (including autonomic testing and additional neuroimaging) and confirmatory clinical follow-up.Results: 28 patients with clinical diagnosis of PD (N = 11), MSA (N = 9), and Essential Tremor (ET, N = 8) were identified. In one third (9/28) nuclear medical diagnosis deviated from clinically suspected syndrome. Visual interpretation of 123I-MIBG identified two cases (MSA and ET) with indeed normal 123I-MIBG uptake. Detailed review of clinical phenotypes provided only in two cases (PD and ET) an adequate explanation (correction of initial diagnosis and confounding drug history) for unexpected 123I-MIBG. In conclusion, 123I-MIBG did not match initial clinical phenotype in 27% PD, 44% MSA, and 25% ET patients.Conclusion: 123I-MIBG scintigraphy is a known specific and valuable technique in scientific approaches and well-defined and highly selected samples. However, predictability of 123I-MIBG based nuclear medical diagnosis for individual cases and thus, feasibility in routine clinical practice is limited. Our clinical series emphasize clinical verification of 123I-MIBG results on an individual basis in clinical routine.

Video-assisted thoracoscopic cardiac denervation of refractory ventricular arrhythmias and electrical storms: a single-center series

BackgroundThe combined treatment of beta-blockers with ablation and Implanted cardioverter defibrillation therapy, continues to be the mainstay treatment for ventricular arrhythmias (VAs). Despite treatment, some patients remain refractory. Recent studies have shown success rates using video-assisted thoracoscopic (VATS) cardiac denervation as an effective therapeutic option for these patients.Case series presentationDuring a period of three years, from 2015 through 2017, twenty patients (N = 20) failed traditional medical and interventional treatment for the management of ventricular arrhythmias and electrical storms. After remaining refractory, the patients were referred to our thoracic surgery department for a VATS based treatment. The patients all had ventricular arrhythmias and electrical storms secondary to different cardiomyopathies. The patients were refractory to combined medical (beta-blockers), Implanted Cardioverter defibrillation (ICD) and ablation therapy. All twenty patients agreed to surgery and were taken to cardiac denervation using a bilateral VATS approach by two thoracic surgeons at a single Cardiothoracic center. During the month prior to bilateral VATS denervation a combined total of twenty-nine (N = 29) ICD shocks were registered in addition to six (N = 6) cases of electrical storms averaging three (N = 3) shocks per day. Mean shocks per patient was 2.3. During the first three months following VATS, the patients had a 90% (N = 18/20) total resolution of ICD registered shocks, a 100% (N = 6/6) resolution of electrical storms, and a 92% (N = 11/12) resolution of shocks in patients having previous ablation therapy. No complications were documented following surgery except for one case of pneumothorax as a result of the procedure, and there were no peri-operative mortalities.ConclusionsBilateral thoracoscopic cardiac denervation can be a safe and seemingly effective therapeutic option for patients presenting with life-threatening refractory ventricular arrhythmias and electrical storms in a variety of cardiomyopathies including Chagas disease.

Chapter 8 - Autonomic dysfunction: Diagnosis and management

The autonomic nervous system is designed to maintain physiologic homeostasis. Its widespread connections make it vulnerable to disruption by many disease processes including primary etiologies such as Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, and pure autonomic failure and secondary etiologies such as diabetes mellitus, amyloidosis, and immune-mediated illnesses. The result is numerous symptoms involving the cardiovascular, gastrointestinal, and urogenital systems. Patients with autonomic dysfunction (AUD) often have peripheral and/or cardiac denervation leading to impairment of the baroreflex, which is known to play a major role in determining hemodynamic outcome during orthostatic stress and low cardiac output states. Heart rate and plasma norepinephrine responses to orthostatic stress are helpful in diagnosing impairment of the baroreflex in patients with orthostatic hypotension (OH) and suspected AUD. Similarly, cardiac sympathetic denervation diagnosed with MIBG scintigraphy or 18F-DA PET scanning has also been shown to be helpful in distinguishing preganglionic from postganglionic involvement and in diagnosing early stages of neurodegenerative diseases. In this chapter, we review the causes of AUD, the pathophysiology and resulting cardiovascular manifestations with emphasis on the diagnosis and treatment of OH.

Cardiac Denervation for Arrhythmia Treatment with Transesophageal Ultrasonic Strategy in Canine Models

Stellate ganglion (SG) modification has been investigated for arrhythmia treatment. In this study, transesophageal SG imaging and intervention were explored using a homemade 30F integrated focused ultrasonic catheter in healthy mongrel canines in vivo. Anatomic details of SGs were ultrasonically imaged and evaluated. SG had a heterogeneous echoic structure and characteristic profiles sketched by hyper-echoic outlines in an ultrasonogram. Left SGs in the experimental group were successfully ablated through the esophagus under ultrasonic guidance provided by the catheter itself. Two weeks after the ablation, the QT and QTc of the experimental group decreased compared with those of the sham group and at baseline (both p values < 0.001). Histologic examination revealed that left SGs were destroyed. No major complications were observed. This approach may be further explored as a method for ganglia remodeling evaluation and as a strategy of ganglia modification for arrhythmia and for other diseases.

Non‐Val30Met mutation, septal hypertrophy, and cardiac denervation in patients with mutant transthyretin amyloidosis

AimsMutant transthyretin (ATTRm) amyloidosis is a systemic disease caused by the deposition of amyloid fibrils derived from mutated transthyretin. Although cardiac involvement impacts the prognosis of patients with ATTRm amyloidosis, the incidence of cardiac events, such as bradyarrhythmia, ventricular tachycardia, and heart failure, has not been fully elucidated. The aim of this study was to evaluate the prognosis and predictors of clinical outcomes, including cardiac events, in patients with ATTRm amyloidosis in Japan.Methods and resultsWe evaluated 90 consecutive patients with ATTRm amyloidosis at Kumamoto University. ATTRm amyloidosis was diagnosed by the observation of both amyloid fibril deposition on tissue biopsy and a transthyretin mutation on sequential analysis. Sympathetic nerve activity was evaluated in 59 patients using 123‐iodine metaiodobenzylguanidine (123I‐MIBG) imaging. The endpoint was a composite of all‐cause death, hospitalization for heart failure, and implantation of a pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization therapy defibrillator. Sixty‐seven patients had the Val30Met mutation (74%). The composite endpoint occurred in 23 patients (26%): all‐cause death (n = 6), hospitalization for worsening heart failure (n = 1), and implantation of an implantable cardioverter defibrillator (n = 6), cardiac resynchronization therapy defibrillator (n = 3), or pacemaker (n = 7). The 5‐year incident rate for clinical outcomes was 19%. In a multivariate Cox hazard analysis, age [hazard ratio (HR): 1.07, 95% confidence interval (95% CI): 1.01–1.12, P = 0.015], PQ interval (HR: 1.01, 95% CI: 1.00–1.02, P = 0.042), interventricular septum thickness in diastole (HR: 1.25, 95% CI: 1.09–1.42, P = 0.001), and non‐Val30Met mutation (HR: 4.31, 95% CI: 1.53–12.16, P = 0.006) were independent predictive factors of clinical outcomes. Kaplan–Meier analysis demonstrated a significantly higher probability of the composite endpoint in the non‐Val30Met group than in the Val30Met group (log‐rank test: P = 0.002) and in patients with left ventricular hypertrophy than in patients without left ventricular hypertrophy (log‐rank test: P < 0.001). In patients who underwent 123I‐MIBG imaging, a delayed heart‐to‐mediastinum (HM) ratio <1.6 was a significant predictive factor of the composite endpoint (HR: 4.98, 95% CI: 1.73–14.37, P = 0.003) in the univariate Cox hazard analyses. Kaplan–Meier curve analysis showed that a delayed HM ratio <1.6 was associated with a poor prognosis (log‐rank test: P = 0.001).ConclusionsNon‐Val30Met mutation, septal hypertrophy, and a delayed HM ratio are useful predictors of clinical outcomes in patients with ATTRm amyloidosis in Japan. These results suggest that it is important to evaluate cardiac involvement in terms of morphological (left ventricular hypertrophy) and functional (cardiac denervation) perspectives using echocardiography and 123I‐MIBG imaging, respectively.

EARLY DETECTION OF CORONARY ARTERY THICKENING IN PEDIATRIC HEART TRANSPLANT RECIPIENTS USING OPTICAL COHERENCE TOMOGRAPHY

Cardiac allograft vasculopathy (CAV) is the leading cause of graft failure and mortality in pediatric heart transplant recipients, characterized by diffuse and concentric coronary intimal thickening. CAV is most successfully treated at mild stages. Thus, early CAV detection is critical because it permits earlier intervention, ultimately prolonging graft and patient longevity. Coronary angiography is the standard for CAV screening and diagnosis; however, it can underestimate disease extent, severity, and prevalence in pediatric patients, and lacks the sensitivity to detect early thickening because early vascular remodeling does not necessarily restrict luminal diameter. In addition, because of cardiac denervation during transplantation, CAV disease progression often occurs silently and may not be discovered until advanced stages. Thus, higher definition imaging modalities are required to identify early vascular changes. Coronary optical coherence tomography (OCT) is a high-definition intravascular imaging technique that may aid early diagnosis. We used OCT to investigate coronary intimal thickening in pediatric transplant recipients and examined its: 1) location (i.e. vessel type and location), and 2) nature (i.e. characteristics of cross-sectional and longitudinal thickening). Coronary angiography and OCT images from pediatric cardiac transplant recipients were collected (N=152 from 73 individuals; median age: 11.5 y (8.4-15.3); 54.1% male). OCT images were collected from the left anterior descending, left circumflex, and right coronary arteries, and classified by location (i.e. proximal, medial, and distal) using coronary angiography. OCT identified significant intimal thickening (intimal thickness >0.25 mm) in 31 pullbacks, 88% of which were angiographically silent. 88% of longitudinal thickening was segmental rather than global. 50% of cross-sectional thickening was eccentric rather than concentric (Figure 1). Thickness severity did not differ between coronary artery type, but intimal thickness was increased proximally (P=0.004). Increased age at transplant was associated with increased intimal thickness (P=0.036), and left circumflex artery thickening (P=0.004). Our study supports the efficacy and feasibility of OCT in detecting otherwise angiographically-silent intimal thickening in pediatric heart transplant patients. Early CAV detection optimizes patient outcomes. Our study also highlights the restricted description of CAV thickening as being strictly global and concentric. We postulate that the eccentric and segmental thickening detectable by OCT may represent pathophysiological processes earlier in the natural history of CAV, though further study is needed to test this hypothesis. In conclusion, OCT offers a safe, high-definition means of detecting coronary vascular changes in pediatric heart transplant recipients that may otherwise be angiographically silent.

Minimally invasive transtracheal cardiac plexus block for sympathetic neuromodulation

Bilateral thoracoscopic stellectomy has antiarrhythmic effects, but the procedure is invasive with associated morbidity. Sympathetic nerves from both stellate ganglia form the deep cardiac plexus (CP) in the aortopulmonary window, anterior to the trachea. The purpose of this study was to demonstrate a novel and minimally invasive transtracheal approach to block the CP in porcine models. In 12 Yorkshire pigs, right (RSG) and left (LSG) stellate ganglia were electrically stimulated and sympathetic baseline response recorded (hemodynamic parameters and T-wave pattern). Aortopulmonary window was accessed transtracheally with endobronchial ultrasound guidance, and local stimulation of CP confirmed the location. Injection of 1% lidocaine (n = 10) or saline solution (n = 2) was performed, and RSG and LSG responses were re-evaluated and compared with baseline. Transtracheal lidocaine injection into the CP successfully blocked bilateral sympathetic induced changes (%) in T-wave amplitude (282.8% ± 152.2% vs 20.1% ± 16.5%; P <.001 [LSG]; 338.9% ± 189.8% vs 28% ± 18.3%; P <.001 [RSG]), Tp-Te interval (87.9% ± 37.2% vs 6.9% ± 6.7%; P <.001 [LSG]; 32.6% ± 27.4% vs 6.9% ± 4.7%; P <.035 [RSG]), and left ventricular dP/dTmax (148.3% ± 108.5% vs 16.5% ± 13.4%; P <.001 [LSG]; 243.1% ± 105.2% vs 19.0% ± 12.4%; P <.001 [RSG]). RSG-induced elevations of systemic, left ventricular, and pulmonary arterial pressures were blocked by lidocaine injection into CP (P <.005 for all comparisons). Stellate ganglia response was not affected in sham studies. No complications were observed during the procedures. Minimally invasive transtracheal injection of lidocaine into the CP blocked the sympathetic response of either RSG and LSG. Transtracheal assessment of CP may allow for minimally invasive and selective ablation of cardiac innervation, extending the cardiac sympathectomy denervation benefits to those not suitable for surgery.

Can Nuclear Imaging Techniques Predict Patient Outcome and Guide Medical Management in Hereditary Transthyretin Cardiac Amyloidosis?

Nuclear imaging recently gained a key role in the diagnosis and prognostic assessment of transthyretin (TTR)-related cardiac amyloidosis. This review aims at summarizing the state-of-the art regarding the implementation of nuclear imaging in the management of hereditary mutated TTR-cardiac amyloidosis (mTTR-CA). Although cardiac uptake of bone tracers is acknowledged as a specific marker of TTR amyloid cardiac burden, recent studies validated the implementation of bone scan in the flow chart for non-invasive diagnosis and follow-up of CA in multicenter trials. Simultaneously, cardiac denervation evidenced by MIBG scintigraphy proved to be a strong and independent prognostic marker of poor outcome in mTTR-CA. By its unique ability to assess both amyloid burden and cardiac denervation, nuclear imaging may prove useful as part of multimodality imaging tools to trigger treatment initiation and monitoring in patients with mTTR-CA.

Cardiac denervation evidenced by MIBG occurs earlier than amyloid deposits detection by diphosphonate scintigraphy in TTR mutation carriers.

Cardiac involvement in familial transthyretin (TTR) amyloidosis is of major prognostic value, and the development of early-diagnostic tools that could trigger the use of new disease-modifying treatments is crucial. The aim of our study was to compare the respective contributions of 99mTc-diphosphonate scintigraphy (DPD, detecting amyloid deposits) and 123I-MIBG (MIBG, assessing cardiac sympathetic denervation) in patients with genetically proven TTR mutation referred for the assessment of cardiac involvement. We prospectively studied 75 consecutive patients (classified as symptomatic or asymptomatic carriers), using clinical evaluation, biomarkers (troponin and BNP), echocardiography, and nuclear imaging. Patients were classified as having normal heart-to-mediastinum (HMR) MIBG uptake ratio 4h after injection (defined by HM4 ≥ 1.85) or abnormal HM4 < 1.85, and positive DPD uptake (grade ≥ 1 of Perugini classification) or negative DPD uptake. Among 75 patients, 49 (65%) presented with scintigraphic sympathetic cardiac denervation and 29 (39%) with myocardial diphosphonate uptake. When MIBG was normal, DPD was negative except for two patients. Age was an independent predictor of abnormal scintigraphic result of both MIBG and DPD (HR 1.08 and 1.15 respectively), whereas echocardiographic-derived indicators of increased left ventricular filling pressure (E/e' ratio) was an independent predictor of abnormal MIBG (HR 1.33) and global longitudinal strain of positive DPD (HR 1.45). In asymptomatic patients (n = 31), MIBG was abnormal in 48% (n = 15) among whom 50% had a normal DPD; all those with a normal MIBG (n = 16) had a normal DPD. In TTR mutation carriers, cardiac sympathetic denervation evidenced by decreased MIBG uptake is detected earlier than amyloid burden evidenced by DPD. These results raise the possibility of a diagnostic role for MIBG scintigraphy at an early stage of cardiac involvement in TTR-mutated carriers, in addition to its well-established prognostic value.