Sympathetic Heart Innervation in Patients With Tako-Tsubo Cardiomyopathy

Apical Ballooning Syndrome Clinical Trial

Official title:

Sympathetic Heart Innervation in Patients With Previous Experience of Transient Stress-induced Cardiomyopathy (Tako-Tsubo): Effects of α-lipoic Acid and L-acetyl Carnitine Therapies.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01524861
• Other study ID #: IT 278354
• Status: Completed
• Phase: Phase 4
• First received: January 23, 2012
• Last updated: January 26, 2016
• Start date: December 2011
• Est. completion date: January 2016

Study information

• Verified date: January 2016
• Source: Second University of Naples
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

Stress (tako-tsubo) cardiomyopathy (SC) is a rapidly reversible form of acute heart failure reported to be triggered by stressful events and associated with a distinctive left ventricular (LV) contraction pattern.

SC mimics acute coronary syndrome and is accompanied by reversible left ventricular apical ballooning in the absence of angiographically significant coronary artery stenosis. sympathetic activity dysfunction appears to play a very important role in the pathophysiology of takotsubo cardiomyopathy.

In most cases, myocardial scintillography with 123Imetaiodobenzylguanidine (MIBG) showed altered captation of the radiotracer in several heart segments. In particular, the apical myocardium has poor sympathetic innervations and an uptake reduction in MIBG tracer.

A hypothesis for this finding could be that the intense discharge of adrenalin, acting on heart segment with different and abnormal innervation, may produce a transient heart failure characterized by a particular shape of the left ventricle.

While studies have shown that heterogeneous MIBG distribution, decreased MIBG uptake and increased norepinephrine content were completely prevented by α-lipoic acid or by L-acetyl carnitine administrations in diabetic cardiomyopathy, no studies have examined the effects of these therapies on tako-tsubo cardiomyopathy.

On this basis, the investigators study will evaluate whether the dysfunction of adrenergic cardiac innervation, evaluated by MIBG, persist after previous experience of transient stress-induced cardiac dysfunction. Moreover, the investigators will assess whether the medications that restore sympatho-vagal alterations in diabetic cardiomyopathy, such as α-lipoic acid and L-acetyl carnitine, will improve the adrenergic cardiac innervation, in patients with SC.

Description:

Study design Each patient will be assessed with history and physical examination, 12-lead ECG, serum troponin, coronary arteriography, and LV angiogram (an average of 6 hours after admission to the hospital), with echocardiography and 123Imetaiodobenzylguanidine (MIBG) myocardial scintillography. All patients were admitted to the cardiac care unit after coronary angiography. Currently recommended treatments for acute coronary syndromes (ACS), with therapy directed at relieving myocardial ischemia and preventing thrombotic complications, were provided to all patients. For each patient, the Charlson score index, 8 which represents the most studied and evaluated comorbidity index, will be calculated. At discharge, surviving patients with established SC will be managed and followed for 12 month after the event, as outpatients. At discharge, the surviving patients will be randomly assigned to alpha-lipoic acid 800 mg/day treatment (ALA group), or L-acetyl carnitine 1000 mg/day treatment (LAC group) or placebo (control group). With regard to the full medical therapy, the protocol stated that the use of concomitant treatment should be uniform, between the groups, and according to evidence-based international guidelines for ACS in all patients. Following discharge, patients were asked to return to our outpatient clinic for follow-up evaluation at 6 and 12 months after the initial event of SC.

Coronary Angiography Coronary angiograms at baseline, immediately after percutaneous coronary intervention (PCI) will be performed in at least 2 orthogonal views after intracoronary nitroglycerin. The analyses of all angiographic data will be performed by operators who were unaware of the study groups (Toshiba, Infinix CS-i).

Echocardiography LV function will be evaluated in all patients by two-dimensional echocardiography at admission, 6 and 12 months after the discharge.

MIBG imaging. MIBG imaging will be performed in all patients shortly after admission and at 6 and 12 months after the discharge. MIBG will be performed with a The standard protocol for 123I-MIBG cardiac imaging requires that drugs that interfere with 123I-MIBG uptake be withheld. A comprehensive listing of prescription and over-the-counter drugs that interfere with 123I-MIBG biodistribution, and the time for which they should be withheld, has been published . Thyroid uptake of unbound 123I is blocked with 500 mg of potassium perchlorate given orally 30 min before 123I-MIBG injection. Between 148 MBq and 370 MBq of 123I-MIBG are injected intravenously at rest. Both planar and SPECT images are acquired 15 min after injection (early) and 4 h after injection (delayed). A dual head gammacamera (ECAM Siemens, Erlangen - Germany) equipped with a low-energy - high resolution collimator was used. A 20% window is usually centered over the 159-keV photopeak of 123I for imaging. Anterior planar images of the chest are acquired using a 256 x 256 matrix. single photon emission computed tomography (SPECT) images are acquired using a 64 x 64 matrix over 180°, from the right anterior oblique position to the left posterior oblique position. Planar imaging allows for global assessment of cardiac innervation, whereas SPECT allows for regional evaluation. Quantitative evaluations will be performed with a standard protocol previously described.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: January 2016
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• acute onset of a cardiovascular event, usually associated with substernal chest pain, initially regarded as ST-segment elevation myocardial infarction/evolving coronary syndrome;

• systolic dysfunction, predominantly characterized by akinesia/hypokinesia of the mid-to-distal portion of the LV chamber, with hypercontractile basal LV;

Exclusion Criteria:

• presence, by angiography, of significant atherosclerotic luminal narrowing in each of the 3 epicardial coronary arteries (0 to < 25%) (- presence of pheochromocytoma, myocarditis, or hypertrophic cardiomyopathy.

• coexisting conditions that limited life expectancy to less than 12 months or that could affect a patient's compliance with the protocol

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Apical Ballooning Syndrome
• Autonomic Nervous System Diseases
• Cardiomyopathies
• Nervous System Diseases
• Nervous System Diseases, Sympathetic
• Takotsubo Cardiomyopathy

Intervention

Drug:
• Placebo
a placebo tablet bis in die for 12 months
• alpha-lipoic acid
alpha-lipoic, tablets of acid 400 mg bis in die (800 mg/day), for 12 months
• L-acetyl carnitine
L-acetyl carnitine tablets, 500 mg bis in die (1000 mg/day), for 12 months

Locations

Country	Name	City	State
Italy	Dept Geriatric and Metabolic diseases SUN	Naples

Sponsors (1)

Lead Sponsor	Collaborator
Second University of Naples

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from Baseline in Adrenergic cardiac innervation at 6 and 12 months	The improvement of adrenergic cardiac innervation as determined by quantitative MIBG	0, 6 and 12 months	Yes
Secondary	Change from Baseline in the markers of inflammation at 6 and 12 months	Serum concentrations of IL-6 and IL-18 will be determined using a highly sensitive, quantitative sandwich enzyme assay. High-sensitivity TNF-a will assayed by immune-nephelometry. CRP will be determined using automated turbidimetry.	0, 6 and 12 months	Yes
Secondary	Change from Baseline in the markers of oxidative stress at 6 and 12 months	Nitrotyrosine plasma concentration, will be assayed by enzyme-linked immunosorbent assay.	0, 6 and 12 months	Yes
Secondary	Change from Baseline in the markers of myocardial damage at 6 and 12 months	Serum levels of Troponin I, miR-1, miR-133a, and miR-499 will be evaluated.	0, 6 and 12 months	Yes
Secondary	Change from Baseline in the markers of sympathetic tone at 6 and 12 months	Plasma levels of catecholamines and their metabolites will measured by HPLC; brain natriuretic peptide and neuropeptide Y will be measured by enzyme immunoassay.	0, 6 and 12 months	Yes