Clinical trial NCT04681612: The Prognostic Role of Indices of Sympathetic Nervous System Overdrive in MINOCA
Official title: The Prognostic Role of Indices of Sympathetic Nervous System Overdrive in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Myocardial Infarction With Nonobstructive Coronary Arteries
Keywords: Myocardial infarction
MINOCA
Sympathetic overdrive
SNS
MSNA
Muscle Microneurography
CMR
Heart rate variability
Lead sponsor: Hippocration General Hospital
Sponsor class: OTHER
Collaborators: name: 401 General Military Hospital of Athens
name: 251 Hellenic Air Force & VA General Hospital
name: Athens Naval Hospital
name: Evangelismos General Hospital
name: Aleksandra General Hospital
name: Sismanoglio General Hospital
name: G.Gennimatas General Hospital
name: Tzaneio General Hospital of Pireus
name: Elpis General Hospital
name: Thriasio General Hospital of Elefsina
name: Laiko General Hospital
name: Attikon Hospital
name: KAT General Hospital
First posted: 2020-12-23
Enrollment: 150
Sex: ALL
Minimum age (years): 35
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients hospitalized with MINOCA according to working group position paper and after CMR confirmation of ischemic pattern LGE (excluding myocarditis and Takotsubo)

Brief summary: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in 1-13% of all patients with acute myocardial infarction (AMI). According to most studies MINOCA patients seem to have a more favorable prognosis compared to the obstructive AMI ones, but face a significant risk for recurrent events of angina. It has been demonstrated that sympathetic nervous system (SNS) overdrive during the acute phase of an acute coronary syndrome (ACS) has a deleterious impact on cardiovascular morbidity and mortality and this is the reason why contemporary treatment strategy of ACS aims towards the inhibition of SNS mechanisms. In the setting of MINOCA, however, data are scarce regarding the prognostic role of SNS activation and the concomitant utility of a similar therapeutical approach.

The aim of this study is to investigate the potential role of SNS in cardiovascular prognosis of MINOCA patients. In the same context, this study is the first, to the investigators' knowledge, registry where the working diagnosis of MINOCA will be confirmed with cardiac magnetic resonance (CMR) imaging.

This is an observational cohort study with a prospective follow-up of 18 months enrolling all patients aged 38-85 years old who fulfill the diagnostic criteria of MINOCA. Patients will receive treatment according to the latest guidelines and consensus documents. Assessment of SNS will include calculation of indices of heart rate and blood pressure variability, as well as the measurement of muscle sympathetic nerve activity (MSNA) during the first 14 days following the event. Follow-up will include a phone contact at 3, 6 and 12 months to record potential primary endpoints and a clinic visit at 18 months to reassess clinical and lab parameters and record primary and secondary endpoints. Definition of primary endpoints includes hospitalization for new onset of ACS, heart failure, stroke or transient ischemic attack, cardiovascular death or death from any cause. Secondary endpoints include the burden of arrythmias estimated from 24hr ECG recording, recurrent angina assessed via Seattle Angina Questionnaire (SAQ) and the general health condition and quality of life (QoL) assessed using SF-12 questionnaire.

The results of this study are expected to reveal the prognostic role of SNS assessment in patients with MINOCA with a potential clinical implication in a treatment approach towards the inhibition of SNS mechanisms.

Detailed description: BACKGROUND

Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in 1-13% of all patients with acute myocardial infarction (AMI). According to most studies MINOCA patients seem to have a more favorable prognosis compared to the obstructive AMI ones, but face a significant risk for recurrent events of angina. MINOCA consists a clinical entity characterized by a heterogeneous and poorly understood pathophysiological substrate (plaque disruption, coronary epicardial and microvascular spasm, thromboembolism, thrombophilia, spontaneous dissection, myocardial bridges, microvascular dysfunction), whereas current data leave significant knowledge gaps regarding the risk stratification and the proper therapeutical approach of these patients. Sympathetic nervous system (SNS) overdrive during the acute phase of an acute coronary syndrome (ACS) is an expected reflex mechanism aiming to maintain homeostasis. On the other hand, it has been demonstrated that it has a deleterious impact on cardiovascular morbidity and mortality and this is the reason why contemporary treatment strategy of ACS aims towards the inhibition of SNS mechanisms. In the setting of MINOCA, however, data are scarce regarding the prognostic role of SNS activation and the concomitant utility of a similar therapeutical approach.

AIM OF THE STUDY

The primary aim of this study is to investigate the potential role of SNS in cardiovascular prognosis of MINOCA patients. Furthermore, investigators will assess relations between various SNS parameters and clinical characteristics of these patients, as well as other indices of cardiovascular function (biomarkers, imaging). In the same context, this study is the first, to the investigators' knowledge, registry where the working diagnosis of MINOCA will be confirmed with cardiac magnetic resonance (CMR) imaging.

METHODS

This is an observational cohort study with a prospective follow-up of 18 months enrolling all patients aged 35-85 years old who fulfill the diagnostic criteria of MINOCA, on the condition that CMR does not reveal findings compatible with a diagnosis of myocarditis or Takotsubo. Patients will receive treatment according to the latest guidelines and consensus documents. During hospitalization, a complete medical history will be recorded and all basic clinical and lab parameters will be collected. Assessment of SNS will include calculation of indices of heart rate and blood pressure variability derived from 24hr monitoring using validated devices, as well as the measurement of muscle sympathetic nerve activity (MSNA) during the first 14 days following the event. Follow-up will include a phone contact at 3, 6 and 12 months to record potential primary endpoints and a clinic visit at 18 months to reassess clinical and lab parameters and record primary and secondary endpoints. Definition of primary endpoints includes hospitalization for new onset of ACS, heart failure, stroke or transient ischemic attack, cardiovascular death or death from any cause. Secondary endpoints include the burden of arrythmias estimated from 24hr ECG recording, recurrent angina assessed via Seattle Angina Questionnaire (SAQ) and the general health condition and quality of life (QoL) assessed using SF-12 questionnaire and Hospital Anxiety and Depression Scale (HADS).

- Sympathetic tone estimation:

Α. MSNA. After patient's stabilization the test will be performed and the derived data will be the number of bursts per min and the average bursts per 100 beats.

B. Ambulatory heart rate and blood pressure monitoring. Heart rate variability will be analyzed via Kubios software for short-term and long-term heart rate variability. Blood pressure short-term variability will be expressed as SD, wSD, ARV, CV, time rate of BP variation.

For data analysis, SPSS 24.0 software will be used. Continuous parametric data will be expressed as mean and SD. For categoric parametric data results will be presented in means of frequency and percentage. Comparisons between categoric parameters will be done with test x2. Comparisons between the mean values for continuous parameters with normal distribution will be done via unpaired student's test. Comparisons between categoric parameters will be done with Mann Whitney U test. Normal distribution will be checked with Kolmogorov-Smirnov test. Correlation analysis will be done via Pearson Phi coefficient or Spearman Rho. Statistically significant will be differences with p value \< 0.05. Evaluation of correlations between selected variables and cardiovascular events and mortality will be via Kaplan Maier curves.

STUDY LIMITATIONS

* Study will include MINOCA patients irrespective of the underlying pathophysiological mechanism. This is the result of the inablity of most centers to perform intravascular imaging (IVUS, OCT) on a routine basis and the tendency to avoid spasm provoking procedures during coronary angiography.
* Although most data will be recorded during the acute/hospitalization phase, the time frame of MSNA and CMR is expected to vary according to the clinical state of the participants and the technical capabilities of the centers. However, an effort will be made not to overlap the 14 days time limit proposed by the majority of investigators.
* CMR will be take place in different centers thus some extent of interobserver variability is expected. However results will be reassessed by a single investigator.

ESTIMATED RESEARCH OUTCOMES

* It will be the first registry, to the investigators' knowledge, that will record data of SNS activation in patients will CMR-confirmed MINOCA.
* The results of the present study are expected to reveal the prognostic role of SNS assessment in patients with MINOCA with a potential clinical implication in a treatment approach towards the inhibition of SNS mechanisms.
* Furthermore, assessment of correlations between parameters of cardiac function and CMR imaging with the level of SNS activation will provide a valuable insight towards the elucidation of the potential role of SNS overdrive during the acute phase of MINOCA.
* Last but not least, follow up assessment will provide information regarding the long-term incidence of persistent or recurrent angina as well as the impact of MINOCA in future quality of life, sentimental state and general health status.

Eligibility criteria: Inclusion Criteria:

* Patients 35-85 years old.
* Signed ICF.
* Cases fulfilling the MINOCA criteria according to working group position paper and after CMR confirmation of ischemic pattern LGE (excluding myocarditis and Takotsubo)

Exclusion Criteria:

* Age \<35 and \>85 years old
* Myocarditis or Takotsubo (CMR confirmation)
* No CMR available (CKD stage IV-V, pacemaker)
* Inability to assess SNS (polyneuropathy, peripheral neuropathy, dysautonomy, permanent AF)
* Severe valvular disease
* LVEF\<35%
* Life expenctancy less than the follow up period on recruitement
* Active cancer on treatment
* Psychiatric illness compromising follow up

Primary outcomes:
measure: Incidence (%) of Death during follow up
timeFrame: Assessed at 4 time points after the acute event: 3 months, 6 months, 12 months, 18 months
measure: Incidence (%) of Hospitalization for Major Cardiovascular Events (MACEs) during follow up
timeFrame: Assessed at 4 time points after the acute event: 3 months, 6 months, 12 months, 18 months
measure: Incidence (%) of the Composite endpoint
timeFrame: Assessed at 4 time points after the acute event: 3 months, 6 months, 12 months, 18 months
Secondary outcomes:
measure: Frequency (%) of increased long term arrythmia burden
timeFrame: Assessed at 18 months after the acute event
measure: Frequency of long term Sustained/ Reccurent Angina
timeFrame: Assessed at 18 months after the acute event
measure: Assessment of Quality of Life and General Health Status
timeFrame: Assessed at 1-14 days and 18 months after the acute event
measure: Assessment of Sentimental status
timeFrame: Assessed at 1-14 days and 18 months after the acute event
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Hippokration Hospital
Study officials:
affiliation: Hippokration Hospital
name: Emmanouil K. Mantzouranis, MD
role: STUDY_DIRECTOR
affiliation: Hippokration Hospital
name: Ioannis E. Leontsinis, MD
role: STUDY_DIRECTOR
References:
citation: Pasupathy S, Tavella R, Beltrame JF. The What, When, Who, Why, How and Where of Myocardial Infarction With Non-Obstructive Coronary Arteries (MINOCA). Circ J. 2016;80(1):11-6. doi: 10.1253/circj.CJ-15-1096. Epub 2015 Nov 20.
citation: Tamis-Holland JE, Jneid H, Reynolds HR, Agewall S, Brilakis ES, Brown TM, Lerman A, Cushman M, Kumbhani DJ, Arslanian-Engoren C, Bolger AF, Beltrame JF; American Heart Association Interventional Cardiovascular Care Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; and Council on Quality of Care and Outcomes Research. Contemporary Diagnosis and Management of Patients With Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease: A Scientific Statement From the American Heart Association. Circulation. 2019 Apr 30;139(18):e891-e908. doi: 10.1161/CIR.0000000000000670.
citation: Agewall S, Beltrame JF, Reynolds HR, Niessner A, Rosano G, Caforio AL, De Caterina R, Zimarino M, Roffi M, Kjeldsen K, Atar D, Kaski JC, Sechtem U, Tornvall P; WG on Cardiovascular Pharmacotherapy. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J. 2017 Jan 14;38(3):143-153. doi: 10.1093/eurheartj/ehw149. No abstract available.
citation: Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol. 2018 Oct 30;72(18):2231-2264. doi: 10.1016/j.jacc.2018.08.1038. Epub 2018 Aug 25. No abstract available.
citation: Pasupathy S, Air T, Dreyer RP, Tavella R, Beltrame JF. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation. 2015 Mar 10;131(10):861-70. doi: 10.1161/CIRCULATIONAHA.114.011201. Epub 2015 Jan 13.
citation: Lindahl B, Baron T, Erlinge D, Hadziosmanovic N, Nordenskjold A, Gard A, Jernberg T. Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease. Circulation. 2017 Apr 18;135(16):1481-1489. doi: 10.1161/CIRCULATIONAHA.116.026336. Epub 2017 Feb 8.
citation: Dreyer RP, Tavella R, Curtis JP, Wang Y, Pauspathy S, Messenger J, Rumsfeld JS, Maddox TM, Krumholz HM, Spertus JA, Beltrame JF. Myocardial infarction with non-obstructive coronary arteries as compared with myocardial infarction and obstructive coronary disease: outcomes in a Medicare population. Eur Heart J. 2020 Feb 14;41(7):870-878. doi: 10.1093/eurheartj/ehz403.
citation: Grodzinsky A, Arnold SV, Gosch K, Spertus JA, Foody JM, Beltrame J, Maddox TM, Parashar S, Kosiborod M. Angina Frequency After Acute Myocardial Infarction In Patients Without Obstructive Coronary Artery Disease. Eur Heart J Qual Care Clin Outcomes. 2015;1(2):92-99. doi: 10.1093/ehjqcco/qcv014. Epub 2015 Jul 23.
citation: Tsioufis C, Iliakis P, Kasiakogias A, Konstantinidis D, Lovic D, Petras D, Doumas M, Tsiamis E, Papademetriou V, Tousoulis D. Non-pharmacological Modulation of the Autonomic Nervous System for Heart Failure Treatment: Where do We Stand? Curr Vasc Pharmacol. 2017;16(1):30-43. doi: 10.2174/1570161115666170428124756.
citation: Jamali HK, Waqar F, Gerson MC. Cardiac autonomic innervation. J Nucl Cardiol. 2017 Oct;24(5):1558-1570. doi: 10.1007/s12350-016-0725-7. Epub 2016 Nov 14.
citation: Parati G, Ochoa JE, Lombardi C, Bilo G. Assessment and management of blood-pressure variability. Nat Rev Cardiol. 2013 Mar;10(3):143-55. doi: 10.1038/nrcardio.2013.1. Epub 2013 Feb 12.
citation: Stergiou GS, Kollias A, Ntineri A. Assessment of drug effects on blood pressure variability: which method and which index? J Hypertens. 2014 Jun;32(6):1197-200. doi: 10.1097/HJH.0000000000000201. No abstract available.
citation: Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996 Mar 1;93(5):1043-65. No abstract available.
citation: Arsenos P, Gatzoulis K, Dilaveris P, Manis G, Tsiachris D, Archontakis S, Vouliotis AI, Sideris S, Stefanadis C. Arrhythmic sudden cardiac death: substrate, mechanisms and current risk stratification strategies for the post-myocardial infarction patient. Hellenic J Cardiol. 2013 Jul-Aug;54(4):301-15. No abstract available.
citation: Liao D, Carnethon M, Evans GW, Cascio WE, Heiss G. Lower heart rate variability is associated with the development of coronary heart disease in individuals with diabetes: the atherosclerosis risk in communities (ARIC) study. Diabetes. 2002 Dec;51(12):3524-31. doi: 10.2337/diabetes.51.12.3524.
citation: Vallbo AB, Hagbarth KE, Wallin BG. Microneurography: how the technique developed and its role in the investigation of the sympathetic nervous system. J Appl Physiol (1985). 2004 Apr;96(4):1262-9. doi: 10.1152/japplphysiol.00470.2003.
citation: Shoemaker JK, Klassen SA, Badrov MB, Fadel PJ. Fifty years of microneurography: learning the language of the peripheral sympathetic nervous system in humans. J Neurophysiol. 2018 May 1;119(5):1731-1744. doi: 10.1152/jn.00841.2017. Epub 2018 Feb 7.