Sympathetic Nerve Activity Predictors in Patients With Chronic Obstructive Pulmonary Disease

NCT ID: NCT04849806

Last Updated: 2023-11-22

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Total Enrollment

80 participants

Study Classification

OBSERVATIONAL

Study Start Date

2022-05-10

Study Completion Date

2024-08-31

Brief Summary

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The project will be pursued in our respiratory, autonomic nervous system physiology laboratory (Respiratory, autonomic nervous system physiology laboratory, Department of Pneumology and Intensive Care Medicine, RWTH Aachen University Hospital; Head of Department: Professor Michael Dreher).

Overactivity of the sympathetic nerve activity (SNA) axis with "centrally" increased heart rate and peripheral vasoconstriction is a known phenomenon in patients with systolic heart failure (HF) and has recently been described in patients with primary lung disease as seen in chronic obstructive pulmonary disease (COPD).

However, systematic analyses on this clinically relevant topic are currently lacking.

Thus, using a comprehensive, multimodal approach and state-of-the-art technology, this research project is designed to determine the extent and nature of increased SNA in COPD (AIM 1) and evaluate the underlying mechanisms (AIM 2).

The project will address the following hypotheses:

1. In COPD, concomitant obstructive sleep apnea is independently associated with increased SNA.
2. Precapillary pulmonary hypertension (PH), inspiratory muscle dysfunction and systemic inflammation describe a COPD phenotype characterised by increased SNA with a different subtype.

Detailed Description

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The project will be pursued in our respiratory, autonomic nervous system physiology laboratory (Respiratory, autonomic nervous system physiology laboratory, Department of Pneumology and Intensive Care Medicine, RWTH Aachen University Hospital; Head of Department: Professor Michael Dreher).

Overactivity of the sympathetic nerve activity (SNA) axis is a known phenomenon in patients with systolic heart failure (HF) and has recently been described in patients with primary lung disease as seen in chronic obstructive pulmonary disease (COPD).

Thus, insights into the nature of and factors involved in increased SNA in COPD are urgently needed.

Potentially obstructive sleep apnea (OSA) with not only repetitive obstructions but also additional hypoxia and poor sleep quality additively increase SNA in COPD. In addition, inspiratory muscle dysfunction (if adequately measured by magnetic diaphragm stimulation studies and comprehensive diaphragm ultrasound) with related hypercapnia, pulmonary hypertension (PH) and systemic inflammation all likely also impact on SNA in COPD.

However, systematic analyses on this clinically relevant topic are currently lacking.

Thus, using a comprehensive, multimodal approach and state-of-the-art technology, this research project is designed to determine the extent and nature of increased SNA in COPD (AIM 1) and evaluate the underlying mechanisms (AIM 2). The project will address the following hypotheses:

1. In COPD, concomitant OSA with poor sleep is independently associated with increased SNA,.
2. PH, inspiratory muscle dysfunction and systemic inflammation describe a COPD phenotype characterised by increased SNA, manifesting differently.

To test these hypotheses COPD patients without an established cardiovascular disease will be enrolled and the extent, nature and mechanism of SNA increase compared with healthy controls matched in a 3:1 ratio for age, sex and body mass index (BMI).

Invasive assessment of muscle SNA to the point of single unit recordings with analysis of single postganglionic sympathetic firing, and hence SNA drive to the peripheral vasculature, is the gold standard for quantification of SNA in humans but is only available in a few centres worldwide because it is costly, time consuming and requires a high level of training.

A small substudy will investigate the short term acute treatment effects of non-invasive ventilation and oxygen supplementation on SNA in patients with COPD.

Conditions

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COPD Sympathetic Nervous System Diseases Catecholamine; Overproduction

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

PROSPECTIVE

Study Groups

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COPD patients (n=60)

The following parameters will be determined in 60 consecutive patients with COPD without established cardiovascular disease (i.e. without an indication for beta blocker therapy or other pharmacological treatments attacking on the neurohormonal pathways like angiotensin-converting enzyme inhibitors or mineralocorticoid receptor antagonists).

1. OSA severity.
2. Determination of PH and right HF severity (defined as tricuspid annular plane systolic excursion ≤14 mm) and pulmonary arterial pressure (PAsys) using transthoracic echocardiography;
3. Comprehensive lung function and inspiratory muscle function testing ;Assessment of daytime hypoxia (PaO2 \<55 mmHg) and hypercapnia (PaCO2 \>45 mmHg) using capillary blood gas analysis;
4. Assessment of systemic inflammation

Assessments of the sympathetic nerve activity axis

Intervention Type DIAGNOSTIC_TEST

For assessment sympathovagal balance (SVB), HRV and dBPV will be analysed using a 3-lead electrocardiogram (sampling rate 1000Hz) and a continuous non-invasive arterial blood pressure signal (CNAP® technology, sampling rate 100Hz). HRV (ms2 based on continuously recorded variability in RR intervals) and (diastolic) BPV (expressed as mmHg2 based on continuously recorded variability in diastolic BP) will be computed by time domain analysis and by frequency domain analysis and presented as the high frequency component (HF; 0.15-0.4 Hz), low frequency component (LF; 0.04-0.15 Hz), their relative ratio (LF/HF), and the very low frequency component (VLF; 0.0-0.04 Hz) for both HRV and dBPV .

Muscle SNA will be recorded via a tungsten microelectrode carefully placed in the peroneal nerve. Plasma catecholamines will also be assessed.

OSA severity

Intervention Type DIAGNOSTIC_TEST

OSA is defined as apnoea-hypopnoea index \[AHI\] \>15/h and obstructive apnoea index \[OAI\] \>5/h) and sleep architecture

Determination of PH and right HF severity

Intervention Type DIAGNOSTIC_TEST

(defined as tricuspid annular plane systolic excursion ≤14 mm) and pulmonary arterial pressure (PAsys) using transthoracic echocardiography

Comprehensive lung function and inspiratory muscle function testing.

Intervention Type DIAGNOSTIC_TEST

Respiratory Muscle strength and function testing as previously established by our group and Assessment of daytime hypoxia (PaO2 \<55 mmHg) and hypercapnia (PaCO2 \>45 mmHg) using capillary blood gas analysis.

Assessment of systemic inflammation

Intervention Type DIAGNOSTIC_TEST

Based on blood samples taken.

Controls (n=20)

(and in a group of healthy controls \[3:1\] matched for age, sex and BMI).

Assessments of the sympathetic nerve activity axis

Intervention Type DIAGNOSTIC_TEST

For assessment sympathovagal balance (SVB), HRV and dBPV will be analysed using a 3-lead electrocardiogram (sampling rate 1000Hz) and a continuous non-invasive arterial blood pressure signal (CNAP® technology, sampling rate 100Hz). HRV (ms2 based on continuously recorded variability in RR intervals) and (diastolic) BPV (expressed as mmHg2 based on continuously recorded variability in diastolic BP) will be computed by time domain analysis and by frequency domain analysis and presented as the high frequency component (HF; 0.15-0.4 Hz), low frequency component (LF; 0.04-0.15 Hz), their relative ratio (LF/HF), and the very low frequency component (VLF; 0.0-0.04 Hz) for both HRV and dBPV .

Muscle SNA will be recorded via a tungsten microelectrode carefully placed in the peroneal nerve. Plasma catecholamines will also be assessed.

OSA severity

Intervention Type DIAGNOSTIC_TEST

OSA is defined as apnoea-hypopnoea index \[AHI\] \>15/h and obstructive apnoea index \[OAI\] \>5/h) and sleep architecture

Determination of PH and right HF severity

Intervention Type DIAGNOSTIC_TEST

(defined as tricuspid annular plane systolic excursion ≤14 mm) and pulmonary arterial pressure (PAsys) using transthoracic echocardiography

Comprehensive lung function and inspiratory muscle function testing.

Intervention Type DIAGNOSTIC_TEST

Respiratory Muscle strength and function testing as previously established by our group and Assessment of daytime hypoxia (PaO2 \<55 mmHg) and hypercapnia (PaCO2 \>45 mmHg) using capillary blood gas analysis.

Assessment of systemic inflammation

Intervention Type DIAGNOSTIC_TEST

Based on blood samples taken.

Interventions

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Assessments of the sympathetic nerve activity axis

For assessment sympathovagal balance (SVB), HRV and dBPV will be analysed using a 3-lead electrocardiogram (sampling rate 1000Hz) and a continuous non-invasive arterial blood pressure signal (CNAP® technology, sampling rate 100Hz). HRV (ms2 based on continuously recorded variability in RR intervals) and (diastolic) BPV (expressed as mmHg2 based on continuously recorded variability in diastolic BP) will be computed by time domain analysis and by frequency domain analysis and presented as the high frequency component (HF; 0.15-0.4 Hz), low frequency component (LF; 0.04-0.15 Hz), their relative ratio (LF/HF), and the very low frequency component (VLF; 0.0-0.04 Hz) for both HRV and dBPV .

Muscle SNA will be recorded via a tungsten microelectrode carefully placed in the peroneal nerve. Plasma catecholamines will also be assessed.

Intervention Type DIAGNOSTIC_TEST

OSA severity

OSA is defined as apnoea-hypopnoea index \[AHI\] \>15/h and obstructive apnoea index \[OAI\] \>5/h) and sleep architecture

Intervention Type DIAGNOSTIC_TEST

Determination of PH and right HF severity

(defined as tricuspid annular plane systolic excursion ≤14 mm) and pulmonary arterial pressure (PAsys) using transthoracic echocardiography

Intervention Type DIAGNOSTIC_TEST

Comprehensive lung function and inspiratory muscle function testing.

Respiratory Muscle strength and function testing as previously established by our group and Assessment of daytime hypoxia (PaO2 \<55 mmHg) and hypercapnia (PaCO2 \>45 mmHg) using capillary blood gas analysis.

Intervention Type DIAGNOSTIC_TEST

Assessment of systemic inflammation

Based on blood samples taken.

Intervention Type DIAGNOSTIC_TEST

Eligibility Criteria

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Inclusion Criteria

* Age ≥ 18
* Ability and willingness to give informed consent to participate in the study

Exclusion Criteria

* Atrial fibrillation
* Active pacing of the heart by a cardiac pacemaker (i.e. no intrinsic heart rate)
* Clinically pre-established cardiovascular disease (e.g. arterial hypertension or systolic heart failure)
* In-patient stay in the hospital within the last 4 weeks prior to the study examination date
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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RWTH Aachen University

OTHER

Sponsor Role lead

Responsible Party

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Jens Spießhöfer

Jens Spiesshoefer, MD, PhD Candidate, Group head Respiratory Physiology

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Michael Dreher, Professor

Role: STUDY_DIRECTOR

RWTH Aachen University

Jens Spiesshoefer, MD

Role: PRINCIPAL_INVESTIGATOR

RWTH Aachen University

Binaya Regmi, MD

Role: STUDY_CHAIR

RWTH Aachen University

Locations

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RWTH Aachen University

Aachen, , Germany

Site Status RECRUITING

Countries

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Germany

Central Contacts

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Michael Dreher, Professor

Role: CONTACT

+492418088763 ext. 88763

Jens Dr. Spiesshoefer, MD

Role: CONTACT

+492418037036

Facility Contacts

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Michael Dreher, Professor

Role: primary

+4924180 ext. 88763

Jens Spiesshoefer, MD

Role: backup

+4924180 ext. 37036

References

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Spiesshoefer J, Becker S, Tuleta I, Mohr M, Diller GP, Emdin M, Florian AR, Yilmaz A, Boentert M, Giannoni A. Impact of Simulated Hyperventilation and Periodic Breathing on Sympatho-Vagal Balance and Hemodynamics in Patients with and without Heart Failure. Respiration. 2019;98(6):482-494. doi: 10.1159/000502155. Epub 2019 Aug 28.

Reference Type BACKGROUND
PMID: 31461730 (View on PubMed)

Spiesshoefer J, Herkenrath S, Henke C, Langenbruch L, Schneppe M, Randerath W, Young P, Brix T, Boentert M. Evaluation of Respiratory Muscle Strength and Diaphragm Ultrasound: Normative Values, Theoretical Considerations, and Practical Recommendations. Respiration. 2020;99(5):369-381. doi: 10.1159/000506016. Epub 2020 May 12.

Reference Type BACKGROUND
PMID: 32396905 (View on PubMed)

Spiesshoefer J, Henke C, Herkenrath S, Brix T, Randerath W, Young P, Boentert M. Transdiapragmatic pressure and contractile properties of the diaphragm following magnetic stimulation. Respir Physiol Neurobiol. 2019 Aug;266:47-53. doi: 10.1016/j.resp.2019.04.011. Epub 2019 Apr 25.

Reference Type BACKGROUND
PMID: 31029769 (View on PubMed)

Dreher M, Neuzeret PC, Windisch W, Martens D, Hoheisel G, Groschel A, Woehrle H, Fetsch T, Graml A, Kohnlein T. Prevalence Of Chronic Hypercapnia In Severe Chronic Obstructive Pulmonary Disease: Data From The HOmeVent Registry. Int J Chron Obstruct Pulmon Dis. 2019 Oct 18;14:2377-2384. doi: 10.2147/COPD.S222803. eCollection 2019.

Reference Type BACKGROUND
PMID: 31695357 (View on PubMed)

Other Identifiers

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CTCA 20-423

Identifier Type: -

Identifier Source: org_study_id