Study on inflammatory cytokines, renin angiotensin aldosterone system and lung function in chronic obstructive pulmonary disease and hypertension patients treated with angiotensin converting enzyme 2 inhibitor and angiotensin receptor blocker drugs

Chronic obstructive pulmonary disease also known as COPD is one of the three most common causes of death. Its chronic nature and association with comorbidities lead to an increased economic burden on countries. This problem is expected to increase in future due to rising smoking trends even in females additionally due to the ageing of the population in most countries of the world. The renin angiotensin aldosterone system, also known as RAAS, is a vital system of the human body, which maintains plasma sodium concentration, arterial blood pressure and extracellular volume.

The RAAS is a hormonal system for which the primary effector is angiotensin 2, derived from stepwise proteolytic cleavage of angiotensinogen. Angiotensin 2 then, is a stimulator of aldosterone synthesis. Therefore, angiotensin 2 and aldosterone are the primary endpoints of the hormonal system. Angiotensin II is a versatile effector peptide hormone. Every organ is affected by RAAS activation resulting in hypertension, cell proliferation, inflammation, and fibrosis. Imbalance of renin and angiotensin II can result in an overwhelming number of chronic and acute diseases. RAAS is influenced by other enzymes, hormones, pumps and signalling pathways. Thus RAAS can cause systemic inflammation and vice versa.

Raas is well studied in hypertension but not well-studied in the context of COPD. In this study, we will compare whether any difference in the baseline inflammatory markers and RAAS in the control, COPD and COPD with hypertension group. Additionally, if these groups (except controls) treated with ACE inhibitor and ARB lead to improvement in the level of inflammatory markers, RAAS and lung function

RESEARCH GAP

1.  The association between RAAS and Hypertension has been studied well as compared to the association between RAAS and COPD.

Studies related to these have been conducted more in the Western population.

Very few studies, related to this in India have been done mainly in the South Indian population.

None of the studies, related to the effect of ACE inhibitors and ARB on respiratory inflammation and lung function have been conducted.

OBJECTIVES

1.  To study various inflammatory markers like Interleukin 2, Interleukin 4, Interleukin 6, INF alpha, TNF gamma, hS CRP, renin, angiotensin, aldosterone, ACE 2, and lung function among COPD and COPD with Hypertension patients as compared to control.

2. To evaluate the effect of ACE Inhibitors and ARB on various inflammatory markers like Interleukin 2, Interleukin 4, Interleukin 6, INF alpha, TNF gamma, hS CRP, renin, angiotensin, aldosterone and ACE 2 in COPD and COPD with hypertension group.

To evaluate the effect of ACE Inhibitors and ARB on lung functions in COPD and COPD with hypertension group.

This clinical trial will be conducted on healthy volunteer, patients of COPD and COPD with hypertension at the Department of Respiratory Medicine and Department of Medicine, School of Medical Sciences and Research and Sharda Hospital for 12 months

there will be a total of 80 individuals in each limb

INCLUSION CRITERIA FOR EACH GROUP

A. CONTROLSThe control healthy individuals will comprise volunteers with no apparent history and signs of any cardio-pulmonary disease. Both male and female volunteers with age more than years and of the same ethnicity will be recruited for the study. They will be recruited in the study after fulfilling inclusion and exclusion criteria. Medical history will be taken with prior written informed consent from all the volunteers. Volunteers with any cardio-pulmonary ailment will be excluded from the study.

B. COPD  Patients reporting to Sharda Hospital with COPD of all 3 groups that is, A, B and E according to GOLD guideline 2024 will be recruited for the study after various clinical investigations. Previously diagnosed patients and newly diagnosed patients treated with standard protocol for COPD, for at least 2 months will be recruited.

C. COPD WITH HYPERTENSION Patients of COPD as per criteria mentioned in para B with newly diagnosed or previously diagnosed patients of hypertension, not treated with ACE II inhibitors and ARBs, reporting to Sharda Hospital with any grade of hypertension according to the American College of Cardiology/American Heart Association will be recruited for the study.

EXCLUSION CRITERIA Patients with bronchial asthma, active tuberculosis, signs and symptoms of clinically significant neurological, psychiatric, renal, immunological, gastrointestinal and urinogenital disorders; endocrine disorders (uncontrolled diabetes or thyroid disease) or uncontrolled haematological disease, unstable liver disease and unstable or life-threatening heart disease, cancer patients and patients with any drug, substance or alcohol abuse will be excluded

SCREENING PARAMETERS Blood sugar (random), CBC, LFT, KFT, ECG and X ray chest (PA view) will be done to fulfil the inclusion criteria

STUDY PARAMETERS Pre-application of the drug, Renin, Angiotensin, Aldosterone, ACE 2,  Interleukin 2, Interleukin 4, Interleukin 6, INF alpha, TNF gamma, hS CRP and lung function will be performed and comparison will be made between various values in controls, COPD and COPD with hypertension.

RANDOMIZATION In this trial, randomization will not be done as most of the COPD patients with advanced disease were diagnosed several years ago and on standard treatment since then, hence any effects of drugs used as standard care for COPD would occur by that time

Patients of groups B and C, that is COPD and COPD with hypertension will be treated with capsule Ramipril 5.0 mg, an angiotensin converting enzyme and tablet Telmisartan 40 mg, an angiotensin receptor blocker for 90 days

Then, all the parameters that is, Renin, Angiotensin, Aldosterone, ACE 2 Interleukin 2, Interleukin 4, Interleukin 6, INF alpha, TNF gamma

EXPECTED OUTCOMESThis study on its successful completion will provide new insight into the treatment of COPD and COPD with hypertension.