Pilot Study Lp299v Supplementation in Chronic Heart Failure

Heart Failure Clinical Trial

Official title:

Impact of Lactobacillus Plantarum 299v Probiotic Supplementation on Vascular Function and Exercise Capacity in Chronic Heart Failure With Reduced and Preserved Ejection Fraction.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05752760
• Other study ID #: 45284
• Status: Recruiting
• Phase: N/A
• Start date: February 20, 2023
• Est. completion date: March 1, 2025

Study information

• Verified date: March 2024
• Source: Medical College of Wisconsin
• Contact: Michael E Widlansky, MD
• Phone: 414-955-6759
• Email: mwidlans[@]mcw.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this study is to determine the impact of 12 weeks of Lp299v supplementation (20 million cfu/day vs. placebo) on exercise capacity, circulating biomarkers of cardiac remodeling, quality of life, and vascular endothelial function in humans with heart failure and reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) who have evidence of residual inflammation based on an elevated C-reactive protein level. This will be done in the setting of a randomized, double-blind, placebo-controlled trial.

Description:

Heart failure (HF) has significant morbidity and mortality and is one of the leading causes of hospital admissions in the United States. In 2017, almost 1 million people were affected and responsible for 1.2 million hospitalizations in the United States alone. Prognosis is poor for patients with HF despite significant medical therapy regimens and device therapy. Worldwide, mortality is as high as 17% during initial hospitalization, as high as 45% within one year of admission, and greater than 50% within five years. According to the Wisconsin Department of Health Services, mortality rates for HF have been increasing in the state since 1980. Wisconsin also consistently had higher rates of HF compared to the remaining states. Emerging data suggest targeting the gut microbiota in HF could be a safe and effective alternative for mitigating inflammation. HF patients have increased systemic circulating endotoxins and lipopolysaccharides due to impaired gut-barrier function, secondary to gut congestion and reduced cardiac output, which drives systemic inflammation. The gut flora of patients with HF also includes more pathogenic bacteria species (candida, campylobacter, shigella, and yersinia) compared to patients with normal heart function. Previous studies by the lab showed that supplementation of 20 billion cfu/day of Lactobacillus plantarum 299v (Lp299v) probiotic decreases systemic inflammation in men with stable coronary artery disease (CAD), and also improves vascular endothelial function (measured by endothelium-dependent vasodilation in the brachial artery and by nitric-oxide dependent vasodilation of resistance arterioles from CAD patients). The investigators have shown that there are significantly decreased levels of IL-8, IL-12 and Leptin in Lp299v-supplemented patients with CAD. Leptin is known to increase IL-6 (which drives increased C-reactive protein expression), IL-8, IL-12 and TNF-α levels, all which activate pro-inflammatory immune responses leading to vasoconstriction and vascular stiffness. Further, our data suggests Lp299v has a significant, favorable anti-inflammatory effect on signaling pathways (NLRP3, IL-6, IL-1β) shown to be important to chronic inflammation in heart failure. Therefore, the investigators plan to perform a pilot study targeting the gut microbiota of patients with HF with oral supplementation with 20 billion cfu/day of Lp299 and determine if Lp299v improves peak oxygen consumption (measured by VO2 max testing), endothelial function (measured by brachial artery flow-mediated dilation), and vascular stiffness (measured by peak wave velocity). We plan to test the hypothesis that Lp299v will improve these measures in the setting of a randomized, double-blind, placebo-controlled clinical trial of 20 subjects. The investigators will additionally test if Lp299v supplementation improves circulating biomarkers of inflammation and cardiac remodeling in chronic heart failure, as well as if it improves the quality of life in patients using the Minnesota Living with Heart Failure Questionnaire and the Kansas City Cardiomyopathy Questionnaire.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: March 1, 2025
• Est. primary completion date: October 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 89 Years

Eligibility

Inclusion Criteria:

• Age between 21-89 years old
• Clinical diagnosis of Congestive Heart Failure (CHF) in the six months prior to enrollment along with an echocardiogram documenting systolic dysfunction with ejection fraction =40%
• Clinical diagnosis of CHF in the six months prior to enrollment along with an echocardiogram documenting diastolic dysfunction with an ejection fraction =50%, and a H2FpEFF score of =6
• New York Heart Association (NYHA) Class II-IIID heart failure symptoms with either ischemic or non-ischemic etiology OR similar diagnosis with congestive heart failure (CHF) along with an echocardiogram documenting an LV ejection fraction of 50% or more with similar NYHA classification as those with LVEF of 40% or less
• Evidence of systemic inflammation at baseline (C-reactive protein = 2 mg/L at the time of screening)

Exclusion Criteria:

• Heart failure due to severe valve disease such as Aortic Stenosis, Mitral Regurgitation, or Mitral Stenosis
• Cancer besides non-melanoma skin carcinomas or localized prostate and breast cancer at the time of enrollment with life expectancy <1 year
• Lung disease such as Chronic Obstructive Pulmonary Disease (COPD), emphysema, or Pulmonary fibrosis
• Active inflammatory disease or infectious disease at the time of enrollment
• Current treatment (or use within the past 14 days) of steroids or anti-inflammatory treatments (excluding non-steroidal anti-inflammatory medications or steroids used solely for IV contrast dye allergy)
• Chronic Kidney Disease with eGFR = 30 mL/min
• Hepatic Failure (Child's Class B or C)
• Patients with Gastrointestinal (GI) tract illness such as short gut syndrome, inflammatory bowel disease, or an ileostomy, such that probiotic absorption would be altered
• Anticipated need for cardiac surgery during the projected study period for the subject
• Pregnancy
• Patients who are receiving Vitamin K antagonists such as Coumadin or Warfarin
• Neutropenia (Absolute Neutrophil Count (ANC) < 1800/mm3)
• Inability to give informed consent or follow the study protocol
• On antibiotics at the time of enrollment or within one month of enrollment
• Currently taking a Lactobacillus based probiotic as an outpatient at the time of enrollment
• Patients who are unable to walk on treadmill or use a bicycle to participate in exercise testing
• Allergy to Lp299v probiotic supplement

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction
• Heart Failure With Reduced Ejection Fraction
• Heart Failure, Diastolic
• Heart Failure, Systolic

Intervention

Other:
• Lactobacillus Plantarum 299v Freeze Dried Capsule
The intervention is a probiotic lactobacillus that is contained in food products in the US
• Freeze Dried Potato Starch Capsule
The intervention is potato starch that is freeze dried designed to mimic the lp299v capsule.

Locations

Country	Name	City	State
United States	Medical College of Wisconsin	Milwaukee	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
Medical College of Wisconsin	Advancing a Healthier Wisconsin

Country where clinical trial is conducted

United States, 

References & Publications (9)

Agarwal MA, Fonarow GC, Ziaeian B. National Trends in Heart Failure Hospitalizations and Readmissions From 2010 to 2017. JAMA Cardiol. 2021 Aug 1;6(8):952-956. doi: 10.1001/jamacardio.2020.7472. — View Citation

Dick SA, Epelman S. Chronic Heart Failure and Inflammation: What Do We Really Know? Circ Res. 2016 Jun 24;119(1):159-76. doi: 10.1161/CIRCRESAHA.116.308030. — View Citation

Hofeld BC, Puppala VK, Tyagi S, Ahn KW, Anger A, Jia S, Salzman NH, Hessner MJ, Widlansky ME. Lactobacillus plantarum 299v probiotic supplementation in men with stable coronary artery disease suppresses systemic inflammation. Sci Rep. 2021 Feb 17;11(1):3972. doi: 10.1038/s41598-021-83252-7. — View Citation

Iikuni N, Lam QL, Lu L, Matarese G, La Cava A. Leptin and Inflammation. Curr Immunol Rev. 2008 May 1;4(2):70-79. doi: 10.2174/157339508784325046. — View Citation

Pasini E, Aquilani R, Testa C, Baiardi P, Angioletti S, Boschi F, Verri M, Dioguardi F. Pathogenic Gut Flora in Patients With Chronic Heart Failure. JACC Heart Fail. 2016 Mar;4(3):220-7. doi: 10.1016/j.jchf.2015.10.009. Epub 2015 Dec 9. — View Citation

Santos-Alvarez J, Goberna R, Sanchez-Margalet V. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol. 1999 May 25;194(1):6-11. doi: 10.1006/cimm.1999.1490. — View Citation

Spertus, J., Kansas City Cardiomyopathy Questionnaire MDDT decision summary. <fda.gov>

Thomas, R, Cohn, J., Minnesota Living with Heart Failure Questionnaire <license.umn.edu/product/minnesota-living-with-heart-fialure-questionnaire-mlhfq>

Wisconsin Heart Disease and Stroke Prevention Program, February 2010. www.dhs.wisconsin.gov/publications/p0/p00146.pdf

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximal Oxygen Consumption (VO2Max)	This is a measurement of exercise capacity	12 weeks
Primary	Brachial Artery Flow Mediated Dilation (FMD%)	This is a measurement of endothelial function in the brachial artery	12 weeks
Primary	Carotid-Femoral Pulse Wave Velocity (cfPWV)	Measurement of vascular stiffness	12 weeks
Secondary	Brachial Artery Absolute Flow Mediated Dilation (FMDmm)	This is a measurement of endothelial function in the brachial artery	12 weeks
Secondary	Resting shear stress of brachial artery	This is a measurement of vascular stiffness	12 weeks
Secondary	Resting velocity	This is a measurement of vascular stiffness	12 weeks
Secondary	Change in serum Soluble Suppression Tumorigenesis (SST2)	This measures cardiac fibrosis	12 weeks
Secondary	Peak flow velocity	This is a measurement of vascular stiffness	12 weeks
Secondary	Peak Hyperemic Shear Stress of Brachial Artery	This is a measurement of vascular stiffness	12 weeks
Secondary	Change in Galectin-3	This measures cardiac fibrosis	12 weeks