Clinical trial NCT04625036: NO-mediated Vascular Function in Covid-19 Patient
Official title: Pilot Study on Peripheral Vascular Function in Covid-19 Patient
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: COVID-19 Pneumonia
Keywords: COVID -19
Vascular function
Endothelial function
Lead sponsor: Istituti Clinici Scientifici Maugeri SpA
Sponsor class: OTHER
Collaborators: name: Universita di Verona
First posted: 2020-11-12
Enrollment: 22
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients, from acute care hospitals, diagnosed with COVID-19 pneumonia, with documented positive throat swab, within one month from discharge.

Brief summary: The 2019 coronavirus-induced infection (COVID-19) has caused a pandemic that has spread worldwide. Up to date, many subjects affected by the virus report important sequelae on different organs increasing morbidity and exacerbating previous pathological conditions. Mortality is also increased in cases of comorbidities such as cardiovascular disease, hypertension and diabetes. COVID-19 infection is caused by Coronavirus-2 (SARS-CoV-2). Concerning the specific interaction of SARS-CoV-2 with the cardiovascular system, we know that this virus enters the body through the receptors for the conversion of angiotensin II (ACE2r) that are present in the lungs, heart, intestinal epithelium and vascular endothelium. This receptor's availability suggests a multi-organ involvement with a consequent multi-organ dysfunction, as found in patients affected by SARS-CoV-2 infection.

Furthermore, poor vascular peripheral function -usually correlated with old age and long periods of bed rest or hypomobility- is a distinguishing characteristic of the population affected by COVID-19, as well. Thus, it is reasonable to expect that peripheral vascular function, already deteriorated by aging and common age-related diseases, can be further compromised by COVID-19 and by the forced hypomobility, typically experienced during the acute phase of the disease.

The main aim of this project will be to investigate the peripheral NO-mediated vascular function in the leg of patients recovering from Covid-19 pneumonia.

A significant vascular dysfunction is expected to be found in post COVID individuals and to be correlated to the relevant clinical variables.

Detailed description: The 2019 coronavirus-induced infection (COVID-19) has caused a pandemic that has spread worldwide, causing approximately 250,000 deaths to date. Even if the contagion curves seem to stabilize, many subjects have been affected by the virus and report important sequelae on the cardiovascular system. This can be explained by the assumption that COVID-19 interacts with the cardiovascular system at different levels, increasing morbidity and exacerbating previous pathological conditions. Mortality is, in fact, increased in cases of comorbidities such as cardiovascular disease, hypertension and diabetes.

COVID-19 infection is caused by Coronavirus-2 (SARS-CoV-2). This virus enters the body through the receptor for the conversion of angiotensin \[angiotensin-converting enzyme 2, ACE2\]. This receptor is present in the lungs, heart, intestinal epithelium and vascular endothelium. The receptor's availability suggests a multi-organ dysfunction, as found in patients affected by SARS-CoV-2 infection. In particular, the infection of endothelial cells or pericytes, as well as the cytokine-mediated inflammatory cascade induced by the infection, can lead to severe microvascular and macrovascular dysfunctions.

It is important to underline that endothelial damage is one of the precursors of the atherosclerosis and endothelial dysfunction is related to pulmonary, cardiac and neurological diseases. Furthermore, poor vascular function is related to old age and long periods of bed rest or hypomobility, those characteristics are present in the population affected by COVID-19, as well. Thus, it is reasonable to expect that peripheral vascular function, already deteriorated by aging and common age-related diseases, can be further compromised by COVID-19 and by the forced hypomobility typically experienced during the acute phase of the disease.

Recently, the endothelial function mediated by nitric oxide (NO) has been easily and non-invasively investigated on common femoral artery with the ultrasound technique of Single Passive Leg Movement. The main aim of this project will be to investigate the NO-mediated vascular function in patients recovering from Covid-19 pneumonia, within one month from discharge in order to verify the presence of endothelial dysfunction acutely induced by the viral infection.

The secondary aim will be to evaluate the correlation between NO-mediated vascular function (evaluated by ultrasound technique) and age, anthropometric parameters (height, weight, Body Mass Index), clinical parameters, oxygenation status, physical performance and pharmacology.

The data will be analysed with the Shapiro-Wilk test to evaluate their "normality" and will be presented as mean ± standard deviation (sd) or median (interquartile range) depending on the type of distribution detected. Correlation tests (Pearson/Spearman) between ultrasound evaluation on peripheral blood flow and vessels and oxygenation levels, clinical, anthropometric and physical performance measures will then be performed. Values of p \<0.05 will be considered significant.

A significant peripheral vascular dysfunction is expected to be found in post COVID individuals and to be correlated to relevant clinical variables (i.e. muscle strength, respiratory parameters, oxygenation status).

Eligibility criteria: Inclusion criteria:

* Diagnosis of COVID-19 pneumonia
* Clinical stability condition (temperature \<37.5 ° C, Respiratory Rate (RR) \<22 breaths/min, Heart Rate (HR)\> 50 beats/minute and \<120 beats/minute, absence of major arrhythmias, hemodynamic stability)
* Possibility to reach the sitting position independently

Exclusion criteria:

-Previous cardiovascular, respiratory, neurological or orthopaedic diseases.

Primary outcomes:
measure: Leg Blood Flow
timeFrame: Baseline
Secondary outcomes:
measure: Clinical evaluations
timeFrame: Baseline
measure: Clinical characteristics
timeFrame: Baseline
measure: Presence of device
timeFrame: Baseline
measure: Therapy
timeFrame: Baseline
measure: Clinical characteristics
timeFrame: Baseline
measure: Biochemical evaluations - ProBNP
timeFrame: Baseline
measure: Biochemical evaluations - D-dimer
timeFrame: Baseline
measure: Biochemical evaluations - PCR
timeFrame: Baseline
measure: Functional evaluations - 1-Minute Sit To Stand
timeFrame: Baseline
measure: Functional evaluations - 6-Minute Walking Test
timeFrame: Baseline
measure: Functional evaluations - Biceps' muscle strength with dynamometer
timeFrame: Baseline
measure: Functional evaluations - Quadriceps' muscle strength with dynamometer
timeFrame: Baseline
Other outcomes:
Locations:
city: Lumezzane
country: Italy
facility: ICS Maugeri IRCCS, U.O. Emergenza Coronavirus di Lumezzane
state: Brescia
Study officials:
affiliation: Istituti Clinici Scientifici Maugeri IRCCS
name: Mara Paneroni, PT
role: PRINCIPAL_INVESTIGATOR
References:
citation: Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, Madhur MS, Tomaszewski M, Maffia P, D'Acquisto F, Nicklin SA, Marian AJ, Nosalski R, Murray EC, Guzik B, Berry C, Touyz RM, Kreutz R, Wang DW, Bhella D, Sagliocco O, Crea F, Thomson EC, McInnes IB. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res. 2020 Aug 1;116(10):1666-1687. doi: 10.1093/cvr/cvaa106.
citation: Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.
citation: Venturelli M, Layec G, Trinity J, Hart CR, Broxterman RM, Richardson RS. Single passive leg movement-induced hyperemia: a simple vascular function assessment without a chronotropic response. J Appl Physiol (1985). 2017 Jan 1;122(1):28-37. doi: 10.1152/japplphysiol.00806.2016. Epub 2016 Nov 10.
citation: Broxterman RM, Trinity JD, Gifford JR, Kwon OS, Kithas AC, Hydren JR, Nelson AD, Morgan DE, Jessop JE, Bledsoe AD, Richardson RS. Single passive leg movement assessment of vascular function: contribution of nitric oxide. J Appl Physiol (1985). 2017 Dec 1;123(6):1468-1476. doi: 10.1152/japplphysiol.00533.2017. Epub 2017 Aug 31.
citation: Trinity JD, Groot HJ, Layec G, Rossman MJ, Ives SJ, Runnels S, Gmelch B, Bledsoe A, Richardson RS. Nitric oxide and passive limb movement: a new approach to assess vascular function. J Physiol. 2012 Mar 15;590(6):1413-25. doi: 10.1113/jphysiol.2011.224741. Epub 2012 Feb 6.
citation: Gifford JR, Richardson RS. CORP: Ultrasound assessment of vascular function with the passive leg movement technique. J Appl Physiol (1985). 2017 Dec 1;123(6):1708-1720. doi: 10.1152/japplphysiol.00557.2017. Epub 2017 Sep 7.
citation: Strassmann A, Steurer-Stey C, Lana KD, Zoller M, Turk AJ, Suter P, Puhan MA. Population-based reference values for the 1-min sit-to-stand test. Int J Public Health. 2013 Dec;58(6):949-53. doi: 10.1007/s00038-013-0504-z. Epub 2013 Aug 24.
citation: Casanova C, Celli BR, Barria P, Casas A, Cote C, de Torres JP, Jardim J, Lopez MV, Marin JM, Montes de Oca M, Pinto-Plata V, Aguirre-Jaime A; Six Minute Walk Distance Project (ALAT). The 6-min walk distance in healthy subjects: reference standards from seven countries. Eur Respir J. 2011 Jan;37(1):150-6. doi: 10.1183/09031936.00194909. Epub 2010 Jun 4.
citation: Andrews AW, Thomas MW, Bohannon RW. Normative values for isometric muscle force measurements obtained with hand-held dynamometers. Phys Ther. 1996 Mar;76(3):248-59. doi: 10.1093/ptj/76.3.248.
citation: Paneroni M, Pasini E, Vitacca M, Scalvini S, Comini L, Pedrinolla A, Venturelli M. Altered Vascular Endothelium-Dependent Responsiveness in Frail Elderly Patients Recovering from COVID-19 Pneumonia: Preliminary Evidence. J Clin Med. 2021 Jun 9;10(12):2558. doi: 10.3390/jcm10122558.