Heart and Blood Diseases

All Conditions

Hypertension

Thrombosis

Ninian Lang, MBChB PhD

Recent developments in chemotherapy, particularly VEGF-inhibitor (VEGFI) drugs, have markedly improved the prognosis of patients with cancer. However, these drugs frequently cause high blood pressure (hypertension) which can lead to heart attacks, heart failure and stroke and can limit their use for cancer treatment.

Endothelin-1 is a hormone that causes blood vessels to tighten and may contribute to high blood pressure associated with VEGFI drugs. Blocking the effects of endothelin-1 may therefore reduce or prevent VEGFI-associated blood pressure changes, although this has never been tested in humans.

Our long-term goal is to assess the protective effects of endothelin-1 blocker drugs in patients treated with VEGFI. Before doing so, we must better explore whether VEGFIs cause blood vessel narrowing and if endothelin-1 blockers prevent this. We will assess this in healthy volunteers using a special technique called 'forearm plethysmography'. We will examine the effect of VEGFI on blood flow and also the effect of simultaneous administration of endothelin-1 blockers. These will be given at doses that produce local effects in the arm without affecting the rest of the body.

These studies study will show whether endothelin-1 blockers may help treat VEGFI-associated hypertension to enable more patients safely to receive vital cancer treatments.

Developments in chemotherapy have improved the prognosis for patients with cancer.1,2 Angiogenesis is essential for tumour growth and metastasis and vascular endothelial growth factor (VEGF) is fundamental to this process.3,4 Chemotherapeutic VEGF inhibitor (VEGFI) drugs have revolutionised therapy and improved the prognosis and survival of patients with previously untreatable malignancies.1,2 Blood pressure elevation is a common complication that occurs in up to 80% of patients treated with VEGFI and almost all patients have an absolute increase in blood pressure, with 30-60% developing frank hypertension.1,5 Patients are at risk of acute hypertensive complications, including stroke, acute coronary syndrome or reversible leukoencephalopathy and the development of VEGFI-associated hypertension may mandate the premature discontinuation of these important anti-cancer therapies. Those who survive their cancer are at risk of developing end-organ damage leading to ischaemic heart disease, heart failure, renal failure and stroke.1,5 Indeed, with substantially increased cancer survivorship patients often survive long enough to allow cardiovascular morbidity to take precedence over their initial cancer diagnosis.

Mechanisms contributing to the development of VEGFI-associated hypertension may include endothelial dysfunction, capillary rarefaction and vascular remodelling.1,5 Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor and is strongly implicated in the pathogenesis of hypertension and endothelial dysfunction. 3,6,7 However, the effects of VEGFI on endothelial function and the role of ET-1 in VEGFI-associated hypertension are incompletely defined. Indeed, there is a paucity of information on mechanisms contributing to VEGFI-induced hypertension and our study will address this key issue.

Endothelial Effects of VEGF Inhibition In Vivo in Man

Novel Cancer Chemotherapeutics and the Vasculature: Endothelial Effects of VEGF Inhibition In Vivo in Man

Study drugs will be infused intra-arterially and forearm arterial blood flow assessed using forearm venous occlusion plethysmography expressed as ml per 100 ml of forearm volume per minute

Change in plasma concentration of t-PA measured as units/mL

Change in plasma concentration of PAI-1 measured as units/mL

University of Glasgow

NHS Greater Glasgow and Clyde

Respiratory Tract (Lung and Bronchial) Diseases

Immune System Diseases

Symptoms and General Pathology

Infections

Digestive System Diseases

Diseases and Abnormalities at or Before Birth

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Asthma

Hypersensitivity

Lung Diseases

Fibrosis

Pneumonia

Cystic Fibrosis

Lung Diseases, Interstitial

Lymphangioleiomyomatosis

Respiration Disorders

Respiratory Tract Diseases

Alveolitis, Extrinsic Allergic

Pancreatic Diseases

Gastrointestinal Diseases

Genetic Diseases, Inborn

Infant, Newborn, Diseases

Bronchial Diseases

Lung Diseases, Obstructive

Respiratory Hypersensitivity

Hypersensitivity, Immediate

Communicable Diseases

Respiratory Tract Infections

Lymphangiomyoma

Neoplasms by Histologic Type

Perivascular Epithelioid Cell Neoplasms

Neoplasms, Connective and Soft Tissue

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Chronic Graft Versus Host Disease

Hypersensitivity Pneumonitis

Included patients, aged ≥ 18 years, with chronic respiratory diseases: COPD, bronchial asthma, cystic fibrosis, lymphangioleiomyomatosis, hypersensitivity pneumonitis and other interstitial lung diseases.

Intervention: breath analysis using the Compact PTR-MS proton mass spectrometer by Ionicon (Austria); electrocardiogram (ECG) in one lead with an assessment of the pulse wave using a portable cardiac monitor "CardioQvark"; assessment of arterial stiffness using the VaSera VS-1500N Fukuda Denshi device by non-invasive measurement of blood pressure in four limbs with simultaneous recording of electrocardiogram (ECG), phonocardiogram (PCG) and pulse waves on the carotid, femoral arteries, as well as on the arteries of four limbs.

Interventions:

Diagnostic Test: Breath analysis using the Compact PTR-MS proton mass spectrometer; Diagnostic Test: Portable cardiac monitor "CardioQvark"; Diagnostic Test: Assessment of arterial stiffness using the VaSera VS-1500N.

Included subjects, aged ≥ 18 years.

Intervention: breath analysis using the Compact PTR-MS proton mass spectrometer by Ionicon (Austria); electrocardiogram (ECG) in one lead with an assessment of the pulse wave using a portable cardiac monitor "CardioQvark"; assessment of arterial stiffness using the VaSera VS-1500N Fukuda Denshi device by non-invasive measurement of blood pressure in four limbs with simultaneous recording of ECG, phonocardiogram (PCG) and pulse waves on the carotid, femoral arteries, as well as on the arteries of four limbs.

Interventions:

Diagnostic Test: Breath analysis using the Compact PTR-MS proton mass spectrometer; Diagnostic Test: Portable cardiac monitor "CardioQvark"; Diagnostic Test: Assessment of arterial stiffness using the VaSera VS-1500N.

Breath samples will be analyzed with a proton-transfer reaction mass spectrometer (Compact PTR-MS, Ionicon, Austria) to obtain eVOCs profiles listed as ions at various mass-to-charge ratios (m/z).

Breath test using the Compact PTR-TOF-MS

Record an electrocardiogram (ECG) in one lead with an assessment of the pulse wave using a portable cardiac monitor "CardioQvark" (Russia, LLC "L Card" , RU No. RZN 2019/8124 dated February 15, 2019) once. Devices automatically transfer data to the A\&D Connect app paired with it (link). When transferring data, they are completely protected. The data obtained using the application must be sent to the specialists of the research group in a depersonalized form.

Portable cardiac monitor "CardioQvark"

Assessment of arterial stiffness using the VaSera VS-1500N Fukuda Denshi device by non-invasive measurement of blood pressure in four limbs with simultaneous recording of ECG, PCG and pulse waves on the carotid, femoral arteries, as well as on the arteries of four limbs.

Assessment of arterial stiffness using the VaSera VS-1500N

Assessment of cardiovascular disorders using echocardiography and arterial stiffness; comparative noninvasive assessment of volatile organic compound (eVOC) exhale breath patterns in patients with different chronic respiratory diseases with age and gender-matched healthy adults in order to identify a disease-specific exhaled eVOCs profiles and markers of respiratory and cardiovascular disorders.

Evaluating of eVOCs profiles by proton mass spectrometry with a time-of-flight (PTR-TOF) in patients with different chronic respiratory diseases is of great interest for assessing the prognosis and development of severe ventilation and cardiovascular disorders.

The aim of our study is to determine the diagnostic significance of PTR-TOF analysis in patients with chronic respiratory diseases and to identify specific eVOC markers of a severe ventilation and cardiovascular disorders in patients with different chronic respiratory diseases.

Breath Analysis and Arterial Stiffness in Patients With Respiratory Diseases

Exhaled Breath Proton Mass Spectrometry and Assessment of Endothelial Dysfunction in Patients With Respiratory Diseases

Exhaled volatile organic compounds (eVOCs) profiles listed as ions at various mass-to-charge ratios (m/z)

Pulse wave velocity, augmentation index, pulse wave type (A, B or C) analysed by a portable cardiac monitor "CardioQvark"

Cardio-ankle vascular index and ankle-brachial index analysed with using the VaSera VS-1500N

Clinical data are assessed via questionaire according to the Modified Medical Research Council (mMRC) Dyspnea Scale, Borg Dyspnea scale, standard examination of respiratory function (spirometry, body plethysmography, diffusion test), echocardiography, CT scan of the chest, if necessary, sputum culture results

I.M. Sechenov First Moscow State Medical University

Neoplasms, Germ Cell and Embryonal

Germ Cells Tumors

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Cisplatin

GCT patients who are planned to start cisplatin-based chemotherapy will be identified within the genitourinary oncology service clinics and offered inclusion in the trial.

GCT patients who have been treated with surgery and who do not require chemotherapy or radiation will be used as a comparison group to confirm that there is not a significant change in endothelial function among GCT patients treated with surgery alone.

Endo-PAT2000 testing is done six times during the study. Baseline Assessment Time 1 Cycle 1, Day 1 (Pre-chemotherapy)Time 2 Cycle 1, Day 1 (After 1st dose of cisplatin), Time 3 Cycle 1, Day 2 (Before second cisplatin dose of cycle 1), Time 4 Cycle 1, Day 5 (After last cisplatin dose of cycle 1), End-of-Study Assessment Time 5 (14-34 weeks from Time 1; e.g., 1-12 weeks following completion of the last cycle of first-line chemotherapy) Long-Term Follow Up Assessment Time 6 (24-30 months from Time 1)

Endo-PAT2000 testing

Time 1: A baseline assessment will be performed in the fasting state including Endo-PAT2000, vital signs, waist circumference, fasting blood draw, \& urine sample. This will be considered Day 1 of the study for this group of patients. Time 2 (2-5 hours from Time 1): Two to five hours after Time 1, patients will undergo assessment of blood pressure \& heart rate, including orthostatics \& Endo-PAT2000 testing. Time 5 -- End of Study visit (14-34 weeks from Time 1): At a time point 14 to 34 weeks later than Time 1 patients will undergo study testing in the fasting state. This includes Endo-PAT2000 testing, vital signs including orthostatics, waist circumference, fasting blood draw, \& urine sample. The Surgery-Only Group will not have any assessment at Time 3 (Day 2) or Time 4 (Day 5) due to logistical concerns. Long-Term Follow Up Assessment Time 6 (24-30 months following Time 1)

Darren Feldman, MD

Cisplatin is one of the most common chemotherapy drugs used to treat many different cancers, including germ cell tumors (GCT). Cisplatin is very effective in treating GCT, but there are side effects. One of the possible long-term side effects of cisplatin is thought to be heart disease. The way that cisplatin causes heart disease is not well understood. One possibility is that cisplatin may damage the inside layer of blood vessels called the endothelium. The purpose of this study is to measure changes in the endothelium that happen when patients with GCT get cisplatin chemotherapy and to compare these changes with a group of patients not receiving chemotherapy.

Acute Changes in Endothelial Function in Germ Cell Tumor Patients Treated With Cisplatin and Untreated Germ Cell Tumor Controls

A Pilot Study Measuring Acute Changes in Endothelial Function in Germ Cell Tumor Patients Treated With Cisplatin and Untreated Germ Cell Tumor Controls

The Endo-PAT quantifies the endothelium-mediated changes in vascular tone, elicited by a 5-minute occlusion of the brachial artery (using a standard BP cuff).

Other laboratory studies being assessed in this trial will include lipid profile, testosterone, LH, FSH, and hemoglobin A1C. These tests are being evaluated to determine if there are concurrent comorbidities

at Time 6 (Long-Term Follow Up Assessment) in the Cisplatin-Based Chemotherapy Group and evaluate long term changes in PATRH index.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Endothelial Effects of VEGF Inhibition In Vivo in Man	NCT03557190	Cardiovascular ...		18 Years - 64 Years	NHS Greater Glasgow and Clyde
Endothelial Effects of VEGF Inhibition In Vivo in Man	NCT03557190	Cardiovascular ...		18 Years - 64 Years	NHS Greater Glasgow and Clyde
Breath Analysis and Arterial Stiffness in Patients With Respiratory Diseases	NCT05727852	Chronic Respira... Cystic Fibrosis Lymphangioleiom... Hypersensitivit... Interstitial Lu... COPD Bronchial Asthm...	Breath test usi... Portable cardia... Assessment of a...	18 Years -	I.M. Sechenov First Moscow State Medical University
Acute Changes in Endothelial Function in Germ Cell Tumor Patients Treated With Cisplatin and Untreated Germ Cell Tumor Controls	NCT01453660	Germ Cell Cance...	Endo-PAT2000 te... Endo-PAT2000 te...	18 Years -	Memorial Sloan Kettering Cancer Center

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