On the Utility of MIBG SPECT/CT in Evaluating Cardiac Sympathetic Dysfunction in Lewy Body Diseases

BackgroundAbnormal cardiac uptake of ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) is a diagnostic marker of Lewy body diseases (LBDs), e.g., Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Planar imaging is generally used to assess cardiac sympathetic dysfunction in ¹²³I-MIBG scintigraphy; however, its clinical utility requires further improvement. We hypothesized that the co-registration of single-photon emission tomography (SPECT) and computed tomography (CT) images would improve the diagnostic accuracy of ¹²³I-MIBG cardiac scintigraphy for LBDs. This study sought to evaluate the effects of SPECT/CT imaging on ¹²³I-MIBG cardiac scintigraphy for diagnosing LBDs.MethodsWe retrospectively investigated data of 54 patients (consecutive 18 patients in each PD, DLB, and idiopathic normal pressure hydrocephalus [iNPH] groups) who underwent ¹²³I-MIBG cardiac scintigraphy (planar and SPECT/CT) because of suspected LBDs at the Tohoku University hospital from June 2012 to June 2015. We compared the diagnostic accuracies of the conventional planar ¹²³I-MIBG method and SPECT/CT methods (manual and semi-automatic).ResultsIn the conventional planar analysis, ¹²³I-MIBG uptake decreased only in the DLB group compared with the iNPH group. In contrast, the SPECT/CT analysis revealed significantly lower ¹²³I-MIBG uptake in both the PD and DLB groups compared with the iNPH group. Furthermore, a receiver operating characteristic analysis revealed that both the manual and semi-automatic SPECT/CT methods were superior to the conventional planar method in differentiating the 3 disorders.ConclusionsSPECT/CT ¹²³I-MIBG cardiac scintigraphy can detect mild cardiac sympathetic dysfunction in LDBs. Our results suggest that the SPECT/CT technique improves diagnostic accuracy for LBDs.     

La scintigraphie myocardique à la 123I-métaiodobenzylguanidine dans les arythmies

Metaiodobenzylguanidine-iode 123 (¹²³I-MIBG) myocardial scintigraphy is one of only the few methods available for the objective evaluation of cardiac sympathetic function at the clinical level. Disorders of cardiac sympathetic function play an important role in a variety of heart diseases and particularly arrhythmic disease. MIBG abnormalities have been described in various arrhythmic diseases. Their signification and their prognostic value are still not clear. This article focuses on reviewing the characteristics of ¹²³I-MIBG myocardial scintigraphy in different arrhythmic diseases.     

Scintigraphie cardiaque à la 123I-métaiodobenzylguanidine et cardiomyopathies : « le retour »: (Insuffisance cardiaque et scintigraphie à la 123I-MIBG)

Congestive heart failure is a often associated with an impairment of sympathetic nervous system, i.e., global hyperactivity and regional impairment of adrenergic system. Cardiac 123I-métaiodobenzylguanidine (MIBG) scintigraphy is a radionuclide technique which can explore the presynaptic adrenergic function. Cardiac fixation of MIBG is decreased in congestive heart failure, reflecting a reduction of norepinephrine uptake by the myocardial presynaptic ending nerves. The impairment of presynaptic function is early and actually involved in the pathogenesis of cardiac failure. Cardiac MIBG scintigraphy is a useful tool to explore the myocardial adrenergic stores in patients with congestive heart failure.     

Évaluation de l’innervation sympathique cardiaque par la scintigraphie myocardique à la 123I-métaiodobenzylguanidine

Metaiodobenzylguanidine-iode 123 (¹²³I-MIBG) myocardial scintigraphy is one of the few methods available for the objective evaluation of cardiac sympathetic function at the clinical level. Disorders of cardiac sympathetic function play an important role in a variety of heart diseases and particularly in heart failure. MIBG myocardial scintigraphy provides abundance of useful information for evaluation of severity therapeutic effects and prognosis.     

Autres applications de la MIBG : « applications de la scintigraphie de l’innervation myocardique à la 123-I-MIBG en neurologie »

Myocardial 123-I-metaiodobenzylguanidine (MIBG) imaging enables the assessment of postganglionic sympathetic cardiac innervation. Recently myocardial 123-I-MIBG scintigraphy has been found to be useful to distinguishing Parkinsońs disease (PD) from other akinetic rigid syndromes. The absence of published guidelines for cardiac 123-I-MIBG imaging makes standardization of procedures among individual users of this technique even more important. Cardiac MIBG study showed markedly decreased uptake in PD, dementia with Lewy bodies (DLB) and pure autonomic failure, which is a common feature of Lewy body disease. The cardiac MIBG uptake is severely impaired even in the early disease stage. Atypical parkinsonian syndromes, including Multiple System Atrophy, Progressive Supranuclear Palsy, and other, show modest reduction of cardiac MIBG uptake. The MIBG study can be used for differentiating patients with extrapyramidal signs and dementia, and might provide useful diagnostic information to discriminate DLB and Alzheime?s disease.     

Simultaneous dual-isotope 123I/99mTc acquisition using CZT-based cameras: Toward a one-stop-shop SPECT in heart failure patients

The CZT-cameras (DNM 530c and DSPECT) have only recently been introduced, and the impact of the increased energy resolution remains unknown. This paper summarizes the evidence on the assessment of: (i) the left ventricular function, (ii) the ¹²³I/^99mTc mismatch, and (iii) the heart-to-mediastinum ratio (HMR) of ¹²³I-metaiodobenzylguanidine (MIBG) uptake under dual-isotope conditions (^99mTc and ¹²³I) using cadmium-zinc-telluride (CZT) technology. The diagnostic accuracy of CZT cameras for myocardial sympathetic innervation imaging, left ventricular function and perfusion assessment using perfusion-gated SPECT have only been established in a few studies, under single-isotope conditions. Limited evidence is available regarding simultaneous dual-isotope acquisition using CZT-cameras. However, recently reported data have shown that CZT cameras allow, in dual-isotope (¹²³I and ^99mTc) acquisitions and under routine conditions: (i) a simultaneous and accurate segmental study of myocardial innervation and perfusion (match and mismatch), (ii) the ventricular function assessment (EDV, ESV and LVEF), and (iii) the determination of the late HMR of cardiac ¹²³I-MIBG uptake in patients with heart failure. However, this latter should be performed using transaxial reconstructed images and a linear correction based on phantom data acquisitions.

Cardiac sympathetic activity in chronic heart failure: cardiac <Superscript>123</Superscript>I-<Emphasis Type="Italic">m</Emphasis>IBG scintigraphy to improve patient selection for ICD implantation

Heart failure is a life-threatening disease with a growing incidence in the Netherlands. This growing incidence is related to increased life expectancy, improvement of survival after myocardial infarction and better treatment options for heart failure. As a consequence, the costs related to heart failure care will increase. Despite huge improvements in treatment, the prognosis remains unfavourable with high one-year mortality rates. The introduction of implantable devices such as implantable cardioverter defibrillators (ICD) and cardiac resynchronisation therapy (CRT) has improved the overall survival of patients with chronic heart failure. However, after ICD implantation for primary prevention in heart failure a high percentage of patients never have appropriate ICD discharges. In addition 25–50?% of CRT patients have no therapeutic effect. Moreover, both ICDs and CRTs are associated with malfunction and complications (e.?g. inappropriate shocks, infection). Last but not least is the relatively high cost of these devices. Therefore, it is essential, not only from a clinical but also from a socioeconomic point of view, to optimise the current selection criteria for ICD and CRT. This review focusses on the role of cardiac sympathetic hyperactivity in optimising ICD selection criteria. Cardiac sympathetic hyperactivity is related to fatal arrhythmias and can be non-invasively assessed with ¹²³I-meta-iodobenzylguanide (¹²³I-mIBG) scintigraphy. We conclude that cardiac sympathetic activity assessed with ¹²³I-mIBG scintigraphy is a promising tool to better identify patients who will benefit from ICD implantation.     

Diagnostic Accuracy of 123I-Meta-Iodobenzylguanidine Myocardial Scintigraphy in Dementia with Lewy Bodies: A Multicenter Study

Background and Purpose

Dementia with Lewy bodies (DLB) needs to be distinguished from Alzheimer’s disease (AD) because of important differences in patient management and outcome. Severe cardiac sympathetic degeneration occurs in DLB, but not in AD, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the diagnostic accuracy, in the ante-mortem differentiation of probable DLB from probable AD, of cardiac imaging with the ligand ¹²³I-meta-iodobenzylguanidine (MIBG) which binds to the noradrenaline reuptake site, in the first multicenter study.

Methods

We performed a multicenter study in which we used ¹²³I-MIBG scans to assess 133 patients with clinical diagnoses of probable (n = 61) or possible (n = 26) DLB or probable AD (n = 46) established by a consensus panel. Three readers, unaware of the clinical diagnosis, classified the images as either normal or abnormal by visual inspection. The heart-to-mediastinum ratios of ¹²³I-MIBG uptake were also calculated using an automated region-of-interest based system.

Results

Using the heart-to-mediastinum ratio calculated with the automated system, the sensitivity was 68.9% and the specificity was 89.1% to differentiate probable DLB from probable AD in both early and delayed images. By visual assessment, the sensitivity and specificity were 68.9% and 87.0%, respectively. In a subpopulation of patients with mild dementia (MMSE ≥ 22, n = 47), the sensitivity and specificity were 77.4% and 93.8%, respectively, with the delayed heart-to-mediastinum ratio.

Conclusions

Our first multicenter study confirmed the high correlation between abnormal cardiac sympathetic activity evaluated with ¹²³I-MIBG myocardial scintigraphy and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from AD, especially in patients with mild dementia.     

Dietary cholesterol affects sympathetic nerve function in rabbit hearts

In order to assess the effect of hypercholesterolemia on cardiac sympathetic nerve function, New Zealand white rabbits were fed a normal diet (the control group) or one enriched with 0.5% cholesterol [the hypercholesterol (HC) group] for 3 months. Before and after the 3-month diet treatment, we performed serial imaging examinations and analyzed the uptake and washout ratio of¹²³I-meta-iodobenzylguanidine (¹²³I-MIBG) from the myocardium by administration of¹²³I-MIBG through an ear vein. At the end of the experiments, the rabbits were sacrificed, and right ventricular strips were taken from their hearts. The inotropic response of the right ventricular strips to isoproterenol (ISO) and norepinephrine (NE) were evaluated. The cardiac MIBG uptake of the HC group, which was evaluated using the heart to mediastinum ratio, was higher than that of the age-matched control group. However, the washout ratios of¹²³I-MIBG did not differ statistically between the two groups. On pretreatment with cocaine, NE-enhanced contractility was greater in papillary muscles isolated from the HC group. The concentration-response curve to ISO was shifted to the right in the HC group, compared with that in the control group. In conclusion, hypercholesterolemia in rabbits resulted in an increase in sympathetic nerve density in the myocardium, a decrease in the inotropic response to ISO and an increase in the inotropic response to NE in cocaine-treated myocardium. Both the in vivo and in vitro studies demonstrated the functional significance of neural remodeling induced by hypercholesterolemia.     

Cardiac Iodine-123-Meta-Iodo-Benzylguanidine Uptake in Carotid Sinus Hypersensitivity

Background

Carotid sinus syndrome is the association of carotid sinus hypersensitivity with syncope, unexplained falls and drop attacks in generally older people. We evaluated cardiac sympathetic innervation in this disorder in individuals with carotid sinus syndrome, asymptomatic carotid sinus hypersensitivity and controls without carotid sinus hypersensitivity.

Methods

Consecutive patients diagnosed with carotid sinus syndrome at a specialist falls and syncope unit were recruited. Asymptomatic carotid sinus hypersensitivity and non-carotid sinus hypersensitivity control participants recruited from a community-dwelling cohort. Cardiac sympathetic innervation was determined using Iodine-123-metaiodobenzylguanidine (123-I-MIBG) scanning. Heart to mediastinal uptake ratio (H:M) were determined for early and late uptake on planar scintigraphy at 20 minutes and 3 hours following intravenous injection of 123-I-MIBG.

Results

Forty-two subjects: carotid sinus syndrome (n = 21), asymptomatic carotid sinus hypersensitivity (n = 12) and no carotid sinus hypersensitivity (n = 9) were included. Compared to the non- carotid sinus hypersensitivity control group, the carotid sinus syndrome group had significantly higher early H:M (estimated mean difference, B = 0.40; 95% confidence interval, CI = 0.13 to 0.67, p = 0.005) and late H:M (B = 0.32; 95%CI = 0.03 to 0.62, p = 0.032). There was, however, no significant difference in early H:M (p = 0.326) or late H:M (p = 0.351) between the asymptomatic carotid sinus hypersensitivity group and non- carotid sinus hypersensitivity controls.

Conclusions

Cardiac sympathetic neuronal activity is increased relative to age-matched controls in individuals with carotid sinus syndrome but not those with asymptomatic carotid sinus hypersensitivity. Blood pressure and heart rate measurements alone may therefore represent an over simplification in the assessment for carotid sinus syndrome and the relative increase in cardiac sympathetic innervation provides additional clues to understanding the mechanisms behind the symptomatic presentation of carotid sinus hypersensitivity.     

Heart rate variability analysis in general medicine

Autonomic nervous system plays an integral role in homeostasis. Autonomic modulation can frequently be altered in patients with cardiac disorders as well as in patients with other critical illnesses or injuries. Assessment of heart rate variability is based on analysis of consecutive normal R-R intervals and may provide quantitative information on the modulation of cardiac vagal and sympathetic nerve input. The hypothesis that depressed heart rate variability may occur over a broad range of illness and injury, and may inversely correlated with disease severity and outcome has been tested in various clinical settings over the last decade. This article reviews recent literature concerning the potential clinical implications and limitations of heart rate variability assessment in general medicine.     

Atrial natriuretic peptides in heart failure: pathophysiological significance, diagnostic and prognostic value

Neurohormonal activation in patients with heart failure is dominated by the deleterious long-term effects of activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. The natriuretic peptides, including brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP), are also upregulated in heart failure, and partially counteract these deleterious effects by promoting vasodilation, natriuresis, and diuresis. Although BNP has been established as an important biomarker in the diagnosis and prognosis of heart failure, growing evidence suggests that measurement of plasma ANP, specifically its metabolite mid-regional pro-ANP, has similar diagnostic and prognostic value. Furthermore, its measurement may provide incremental diagnostic value when BNP levels fall into "grey zone" levels and may be a more potent prognostic marker of mortality.     

Pharmacologic tools for assessment of adrenergic nerve activity in human hypertension

Measurement of plasma norepinephrine concentration (plasma NE) has not resolved the role of the adrenergic system in the pathogenesis or maintenance of hypertension. A better picture is gained if plasma NE measurement is combined with the assessment of sympathetic drive and reactivity by the use of specific sympathetic antagonists and agonists. In mild hypertension, the decrease in heart rate and cardiac output after beta-adrenoceptor blockade correlates with the level of plasma NE. In established hypertension, the fall in blood pressure or peripheral vascular resistance after alpha-adrenoceptor blockade is related to plasma NE levels. Similarly, changes in forearm vascular resistance induced by local alpha-adrenoceptor blockage correlates with plasma NE in hypertension. Cardiovascular responsiveness to adrenergic agonists is altered in hypertension. The response to cardiac beta-receptor stimulation decreases during the course of the disease. To the contrary, vascular responses to exogenous NE increase with the progression of the hypertensive disease. Results with total autonomic blockade indicate that in some patients with early or borderline hypertension, increased sympathetic tone is involved in the maintenance of blood pressure. In established hypertension, there is no definite indication of increased sympathetic tone, but the sympathetic nervous system may nevertheless play a prominent role in the maintenance of the blood pressure. A vascular hyperreactivity to adrenergic stimulation is characteristically associated with established hypertension. The nature of this hyperreactivity has not been fully elucidated, but it is very likely that it reflects structural vascular changes in hypertension.     

Efficacy and safety of [131I]metaiodobenzylguanidine therapy for patients with refractory neuroblastoma.

Metaiodobenzylguanidine (MIBG) is a guanethidine derivative that is selectively concentrated in sympathetic nervous tissue. MIBG labeled with 123I or 131I has proven to be a specific and sensitive tool for detection of primary and metastatic pheochromocytoma and neuroblastoma. Eleven patients, with refractory stage IV neuroblastoma were treated with a total of 23 courses of 131I-MIBG, 100-400 mCi/m2/course. Total activity administered per course ranged from 90-550 mCi; maximum cumulative radioactivity per patient was 1356 mCi. The 131I-MIBG was given as a 2 hour infusion. Total body dose was calculated from whole body activity measurements, ranging from 73-250 cGy. The main toxicity was thrombocytopenia, with platelet nadirs to less than 25,000/microL in 5/23 courses (5 patients), all occurring in patients with greater than 25% replacement by tumor in the bone marrow. Neutropenia to a nadir of less than 500/microL was seen in only 2 patients, both with greater than 50% bone marrow replacement after 2 and 4 courses of 131I-MIBG, respectively. Tumor doses were calculated in patients with an evaluable measurable lesion, and ranged from 312-6329 cGy per course. Two of the eleven patients had partial responses, with one long-term survivor with stage IV neuroblastoma with no evidence of active disease now 4 years off treatment. Two other patients survive with stable disease after 3 treatments, at 3+ and 5+ months. Seven patients died with progressive disease. This study shows that treatment with 131I-MIBG is safe and can be effective in refractory neuroblastoma, particularly in patients who do not have extensive bone and bone marrow involvement.     

Effect of stellate ganglionectomy on basal cardiovascular function and responses to beta1-adrenoceptor blockade in the rat

Cardiac sympathetic nerve activity is an important short-term controller of cardiac function and arterial pressure. Studies also suggest that long-term increases in cardiac sympathetic nerve activity may contribute to hypertension, coronary artery disease, and cardiac remodeling in heart failure. However, our understanding of the role of cardiac sympathetic nerves in chronic models of cardiovascular disease has been limited by inadequate experimental approaches. The present study was conducted to develop a surgical method to surgically denervate the sympathetic nerves of the rat heart for long-term cardiovascular studies. We characterized the effect of cardiac sympathetic denervation on basal levels of mean arterial pressure (MAP) and heart rate (HR) and the responses to a chronic administration of atenolol, a beta1-adrenoceptor antagonist. Rats were instrumented with telemetry transmitters for continuous recording of MAP and HR. After a 4-day baseline period, the rats were subjected to bilateral stellate ganglionectomy (SGX; n=9) or sham surgery (Sham; n=8). Seven days following SGX or Sham, the rats were administered atenolol for 5 days, followed by a 7-day recovery period. Following a transient decrease, SGX had no effect on basal MAP but decreased HR compared with baseline and Sham rats. Five days of atenolol treatment decreased MAP similarly in SGX and Sham rats. Atenolol resulted in a marked bradycardia in Sham rats but had a neglible effects on HR in SGX rats. The measurement of the content of cardiac catecholamines in all cardiac chambers at the end of the study verified a successful sympathetic denervation. This study confirms that bilateral SGX is a useful method to study the contribution of cardiac sympathetic nerves on the regulation of cardiac function. Moreover, these results suggest that cardiac sympathetic nerves are relatively unimportant in maintaining the basal level of MAP or the depressor response to atenolol in conscious, unrestrained rats.     

心脏彩超检查联合血清BNP、ALB、CysC在慢性心力衰竭患者预后评估中的临床价值分析

摘要 目的：分析心脏彩超检查联合血清B型钠尿肽（BNP）、白蛋白（ALB）、胱抑素C（CysC）在慢性心力衰竭（CHF）患者预后评估中的临床价值。方法：选取2017年6月-2018年5月我院收治的123例CHF患者,心脏彩超检查左心室射血分数（LVEF）、左心房内径（LAD）和左心室内径（LVD）,实验室检测血清BNP、ALB、CysC水平。按照3年随访后患者是否死亡分为死亡组35例和存活组88例,收集临床资料,采用多因素Logistic回归分析CHF患者预后的影响因素。采用受试者工作特征（ROC）曲线分析心脏彩超检查联合血清BNP、ALB、CysC对CHF患者预后的评估价值。结果：死亡组患者的LAD、LVD及血清BNP、CysC水平高于存活组患者,而LVEF及血清ALB水平低于存活组患者（P＜0.05）。心脏彩超指标LVEF、LAD、LVD及血清BNP、ALB、CysC是CHF患者预后的影响因素（P＜0.05）。心脏彩超指标LVEF、LAD、LVD联合血清BNP、ALB、CysC检测对CHF患者预后评估的ROC曲线下面积（AUC）（0.95CI）为0.857（0.771～0.938）,灵敏度及特异度分别为0.914（32/35）、0.795（70/88）,均明显高于上述各指标单独检测。结论：心脏彩超指标LVEF、LAD、LVD和血清BNP、ALB、CysC均为CHF患者预后的影响因素,且联合检测对患者预后的评估价值较高,具有一定的临床应用价值。     

Effect of berberine on catecholamine levels in rats with experimental cardiac hypertrophy

The aim of this study is to investigate the effect of berberine on catecholamine level (adrenaline and noradrenaline) in rats with experimental cardiac hypertrophy. Cardiac hypertrophy(CH) was induced by suprarenal abdominal aorta constriction, and the drugs were administered for 8 weeks starting from 4 weeks after surgery. The degree of cardiac hypertrophy was determined by heart and left ventricular weight. The level of adrenaline(AD) and noradrenaline(NA) was detected by HPLC. The data showed that in the CH model rats, the level of plasma and left ventricular tissue AD, and the level of NA in plasma were higher than that of the age-matched controls(indicating increased "total" sympathetic activity). The level of NA in left ventricular tissue of CH model rats was however lower than the age-matched controls. Berberine and captopril showed significant effect on inhibiting the development of cardiac hypertrophy. Berberine decreased plasma NA level and the AD level both in plasma and left ventricular tissue, but had no effect on improving the cardiac NA depletion. Captopril showed significant effect on increasing the depleted cardiac NA and in reducing the elevated plasma NA level. These findings show the efficacy of berberine on modulating the sympathetic nervous activity of rats with experimental cardiac hypertrophy, and reflect the therapeutic potentials of berberine in patients with cardiac hypertrophy and chronic heart failure.     

Functional and molecular effects of imidazoline receptor activation in heart failure

AimsHeart failure is a progressive deterioration in heart function associated with overactivity of the sympathetic nervous system. The benefit of inhibition of sympathetic activity by moxonidine, a centrally acting imidazoline receptor agonist, was questioned based on the outcome of a failing clinical trial. The following studies measured cardiac structure and hemodynamics and mechanisms underlying moxonidine-induced changes, in cardiomyopathic hamsters, where the stage of the disease, dose, and compliance were controlled.Main methodsMale BIO 14.6 hamsters (6 and 10 months old, with moderate and advanced heart failure, respectively) received moxonidine at 2 concentrations: low (2.4 mg/kg/day) and high (9.6 mg/kg/day), or vehicle, subcutaneously, for 1 month. Cardiac function was measured by echocardiography, plasma and hearts were collected for histological determination of fibrosis and apoptosis, as well as for measurement cytokines by Elisa and cardiac proteins by Western blotting.Key findingsCompared to age-matched vehicle-treated BIO 14.6, moxonidine did not reduce blood pressure but significantly reduced heart rate and improved cardiac performance. Moxonidine exerted anti-apoptotic effect with differential inflammatory/anti-inflammatory responses that culminate in attenuated cardiac apoptosis and fibrosis and altered protein expression of collagen types. Some effects were observed regardless of treatment onset, although the changes were more significant in the younger group. Interestingly, moxonidine resulted in upregulation of cardiac imidazoline receptors.SignificanceThese studies imply that in addition to centrally mediated sympathetic inhibition, the effects of moxonidine may, at least in part, be mediated by direct actions on the heart. Further investigation of imidazolines/imidazoline receptors in cardiovascular diseases is warranted.     

Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure

Cardiac overstimulation by the sympathetic nervous system (SNS) is a salient characteristic of heart failure, reflected by elevated circulating levels of catecholamines. The success of beta-adrenergic receptor (betaAR) antagonists in heart failure argues for SNS hyperactivity being pathogenic; however, sympatholytic agents targeting alpha2AR-mediated catecholamine inhibition have been unsuccessful. By investigating adrenal adrenergic receptor signaling in heart failure models, we found molecular mechanisms to explain the failure of sympatholytic agents and discovered a new strategy to lower SNS activity. During heart failure, there is substantial alpha2AR dysregulation in the adrenal gland, triggered by increased expression and activity of G protein-coupled receptor kinase 2 (GRK2). Adrenal gland-specific GRK2 inhibition reversed alpha2AR dysregulation in heart failure, resulting in lowered plasma catecholamine levels, improved cardiac betaAR signaling and function, and increased sympatholytic efficacy of a alpha2AR agonist. This is the first demonstration, to our knowledge, of a molecular mechanism for SNS hyperactivity in heart failure, and our study identifies adrenal GRK2 activity as a new sympatholytic target.