Polyamine Treatment in Elderly Patients With Coronary Artery Disease

Study Overview
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Brief Summary
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The present study is testing spermidine treatment in elderly patients with coronary artery disease. The study is a randomized, double-blind, placebo-controlled, two-armed, parallel-group, single centre, clinical study.

Detailed Description
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Life expectancy has increased tremendously over the past century and as populations age, chronic diseases such as cardiovascular disease and diabetes have become more prevalent. Healthy aging is therefore of paramount importance to further promote longevity and quality of life. In humans, a high concentration of whole-blood spermidine is associated with longevity, and individuals with a high dietary spermidine intake have improved cardiovascular health and less obesity. Spermidine is essentially a polyamine found in all plant-derived foods, particularly in whole grains, soybeans, nuts, and fruit. Its favorable effects may act via several mechanisms. In an experimental model of hypertensive heart disease, spermidine reduced cardiac hypertrophy and improved diastolic and mitochondrial function. Spermidine also induces cytoprotective autophagy in skeletal muscle and alters body fat accumulation by metabolically modulating glucose and lipid metabolism. The clinical data on spermidine dietary supplementation are scarce. In elderly subjects with cognitive problems, spermidine supplement was well tolerated and had potential blood-pressure-lowering effects. The reported beneficial effects of spermidine raise the question whether elderly patients with cardiovascular disease can benefit from a dietary supplement of this polyamine. The central hypothesis of the current proposal is that a twelve-month spermidine treatment regimen in elderly patients with cardiovascular disease will yield positive effects on heart and skeletal muscle function, whole body composition and inflammation. The secondary hypotheses are that spermidine reduces blood pressure and has a beneficial impact on cognitive function, daily activity level, quality of life, biomarker risk profile, skeletal muscle cellular metabolism and lastly but not least gut microbiota. The study design is a randomized, double-blind, placebo-controlled trial to investigate the effects of a 24 mg daily oral spermidine dietary supplement vs. matching placebo in elderly patients with cardiovascular disease. A total of 220 patients will be included and randomized 1:1 to either spermidine 24 mg x 1 daily or matching placebo for one year. At baseline and after one year of intervention the patients will undergo study procedures. Changes from baseline to follow-up will be compared between the active and placebo treated patient groups.

Official Title
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Polyamine Treatment in Elderly Patients With Coronary Artery Disease - a Randomized Controlled Trial

Conditions
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Hypertension, Ischemic Heart Disease, Myocardial Infarction, Cardiovascular Diseases, Vascular Diseases, Hypertensive Heart Disease, Diastolic Dysfunction, Obesity, Metabolic Syndrome, Diabetes Mellitus, Type 2, Dietary Habits, Inflammation, Quality of Life, Cognition Disorder, Cognitive Impairment

Intervention / Treatment
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* Dietary Supplement: Spermidine
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 65 years Chronic ischemic heart disease (previous revascularization or myocardial infarction) Left ventricular ejection fraction of > 40% And at least two of the following risk factors: Type 2 diabetes, Obesity (BMI ≥ 30 kg/m2), Hypertension, Previous LVEF < 40%, Left atrial volume index ≥ 30 mL/m2 Left ventricular wall thickness ≥ 1.1 cm. Exclusion Criteria: Unstable coronary syndrome Significant and severe cardiac valve disease Severe peripheral artery disease Permanent atrial fibrillation Pacemaker treatment Chronic kidney disease with eGFR <45 ml/min/1,73m2 Severe comorbidity as judged by the investigator (such as severe pulmonary, neurological, or musculoskeletal disease) Inability to give informed consent. Exclusion criteria for MRI: Some metallic implants Claustrophobia Exclusion criteria for muscle biopsy: Treatment with either two antiplatelet drugs (aspirin and ADP-receptor antagonists) Anticoagulants (warfarin, NOACs)

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled, two-armed, parallel-group, single centre, clinical study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Spermidine<br>Spermidine will be given orally as capsules of cellulose with spermedine (24 mg/day) and rice flour. | Dietary Supplement: Spermidine<br>* Spermidine capsule of 8 mg x 3 capsules daily.<br>* Other names: Polyamine;|
| Placebo Comparator: Placebo<br>Placebo will be given orally as capsules of cellulose and rice flour (same size and visual appearance as spermidine capsules) | Other: Placebo<br>* Placebo capsule. 3 capsules daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in left ventricular mass | Measured with Cardiac Magnetic Resonance Imaging (CMR). | From randomization (month 0) to 12 months | 
| Change in High-sensitivity C-reactive Protein (hs-CRP) | Measured from blood samples. | From randomization (month 0) to 12 months | 
| Change in lean body mass | By a whole-body dual-energy X ray absorptiometry (DXA) scan. | From randomization (month 0) to 12 months | 
| Change in Physical performance, peak oxygen consumption (VO2max) | By cardiopulmonary exercise capacity (CPET) will be performed using a cycle ergometer test. Peak oxygen uptake measured in ml O2/kg/min. | From randomization (month 0) to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Handgrip strengh | Hand-held dynamometer for measuring handgrip strength in kilograms-force. | From randomization (month 0) to 12 months | 
| Knee-extension strength | Measured using a dynamometer in Newton meters. | From randomization (month 0) to 12 months | 
| Knee-flexion strength | Measured using a dynamometer in Newton meters. | From randomization (month 0) to 12 months | 
| Skeletal muscle mass | MRI. | From randomization (month 0) to 12 months | 
| Skeletal muscle cross sectional area and fibers | Microscopy of skeletal muscle biopsy. | From randomization (month 0) to 12 months | 
| Fluorescence-activated Cell Sorting (FACS) of fat biopsy | Sorting cell types and calculating ratios. | From randomization (month 0) to 12 months | 
| Fluorescence-activated Cell Sorting (FACS) of muscle biopsy | Sorting cell types and calculating ratios. | From randomization (month 0) to 12 months | 
| Cell proliferation Assay | Stem cells proliferation. | From randomization (month 0) to 12 months | 
| Skeletal muscle mitochondrial function | High-resolution respirometry by Oroboros. | From randomization (month 0) to 12 months | 
| Appendicular lean mass | DXA scan. | From randomization (month 0) to 12 months | 
| Muscle quality assesment | MRI DIXON method. | From randomization (month 0) to 12 months | 
| Evaluation of Intramuscular fat | MRI DIXON method. | From randomization (month 0) to 12 months | 
| Evaluation of Intermuscular fat | MRI DIXON method. | From randomization (month 0) to 12 months | 
| Free fatty acids | Measured from blood samples. | From randomization (month 0) to 12 months | 
| HOMA-IR | Measured from blood samples with the formula: (fasting glucose (mmol/L) x fasting insulin (mU/L)) / 22.5). | From randomization (month 0) to 12 months | 
| Markers of autophagy | Proteomics. | From randomization (month 0) to 12 months | 
| Polyamine content in muscle biopsy | Measured with liquid chromatography mass spectrometry (LC-MS). | From randomization (month 0) to 12 months | 
| Polyamine content in blood | Plasma samples obtained from blood. Measured with liquid chromatography mass spectrometry (LC-MS). | From randomization (month 0) to 12 months | 
| Change in 24-hour ambulatory blood pressure measurements (24h ABPM) | Measured with the Spacelabs Healthcare 90217A device in an out-of-hospital setting. | From randomization (month 0) to 12 months | 
| Change in daily physical activity | Assessed by 14-day activity monitoring with an accelerometer (AX3, Axivity). | From randomization (month 0) to 12 months | 
| Change in cardiac extracellular volume fraction | Assessed using Cardiac Magnetic Resonance Imaging (CMR) with intravenous gadolinium-based agent. | From randomization (month 0) to 12 months | 
| Change in myocardial strain | Assessed using Cardiac Magnetic Resonance Imaging (CMR) with intravenous gadolinium-based agent. | From randomization (month 0) to 12 months | 
| Change in Carotid-femoral pulse wave velocity | Measured non-invasively through applanation tonometry using a SphygmoCor system. The unit of measure is m/s. | From randomization (month 0) to 12 months | 
| Change in Aortic pulse wave velocity | Magnetic resonance imaging (MRI) assessment. The unit of measure is m/s. | From randomization (month 0) to 12 months | 
| Change in general cognitive function and memory performance | Evaluated using the Montreal Cognitive Assessment (MoCA). It will be administered in a clinical setting using a tablet. MoCA score ranges from 0-30 and a score of 26 or higher is considered normal. | From randomization (month 0) to 12 months | 
| Change in specific domains of cognitive function | Evaluated using Cambridge Cognition (CANTAB) digital assessment software in a clinical setting using a tablet. The cognitive tests are MOT, RTI, SWM, DMS and PAL. These tests will objectively measure psychomotor speed, executive function and memory. | From randomization (month 0) to 12 months | 
| HeartQol | HeartQol measures health-related quality of life (HRQL) and is a disease-specific health status instrument for ischemic heart disease. It consists of 14 items and provides two subscales; a 10-item physical subscale and a 4-item emotional subscale, which are scored on a four-point Likert scale (0 to 3). Higher scores indicate a better HRQL. Measured as global, physical and emotional score. | From randomization (month 0) to 12 months | 
| Cytokines | Changes in cytokines are evaluated through the utilization of multiplex cytokine assays. Measured from plasma blood samples. | From randomization (month 0) to 12 months | 
| White blood cells | Changes in white blood cell differential count. | From randomization (month 0) to 12 months | 
| Immune cells | Changes in specific immune cell populations are measured using peripheral blood mononuclear cells (PBMCs) isolated from blood samples. | From randomization (month 0) to 12 months | 
| Vascular inflammatory markers | Measured from plasma blood samples with a multiplex assay. | From randomization (month 0) to 12 months | 
| Time to first occurrence of Composite cardiovascular endpoint: Cardiovascular death, heart failure hospitalizations, non-fatal myocardial infarction, non-fatal stroke, and coronary revascularization | Measured in months. | From randomization (month 0) to 12 months | 
| Days alive and out of hospital | Measured in months. | From randomization (month 0) to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spermidine, Dietary supplement, Polyamine, Prevention, Treatment, Lifestyle, Coronary artery disease, Ischemic heart disease, Cardiovascular disease, Heart disease, Hypertension, Obesity, Diabetes Mellitus, Type 2, Insulin resistance, Inflammation, Quality of life, Cognitive function, Memory, Autophagy