Clinical trial NCT05752760: Pilot Study Lp299v Supplementation in Chronic Heart Failure
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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Heart Failure
Heart Failure With Reduced Ejection Fraction
Heart Failure, Systolic
Heart Failure With Preserved Ejection Fraction
Heart Failure, Diastolic
Keywords: Endothelial Function
Microbiome
Heart Failure
Ejection Fraction
Lead sponsor: Medical College of Wisconsin
Sponsor class: OTHER
Collaborators: name: Advancing a Healthier Wisconsin
First posted: 2023-03-03
Enrollment: 20
Sex: ALL
Minimum age (years): 21
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximal Oxygen Consumption (VO2Max)
timeFrame: 12 weeks
measure: Brachial Artery Flow Mediated Dilation (FMD%)
timeFrame: 12 weeks
measure: Carotid-Femoral Pulse Wave Velocity (cfPWV)
timeFrame: 12 weeks
Secondary outcomes:
measure: Brachial Artery Absolute Flow Mediated Dilation (FMDmm)
timeFrame: 12 weeks
measure: Resting shear stress of brachial artery
timeFrame: 12 weeks
measure: Resting velocity
timeFrame: 12 weeks
measure: Change in serum Soluble Suppression Tumorigenesis (SST2)
timeFrame: 12 weeks
measure: Peak flow velocity
timeFrame: 12 weeks
measure: Peak Hyperemic Shear Stress of Brachial Artery
timeFrame: 12 weeks
measure: Change in Galectin-3
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Medical College of Wisconsin
name: Michael E Widlansky, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
citation: Wisconsin Heart Disease and Stroke Prevention Program, February 2010. www.dhs.wisconsin.gov/publications/p0/p00146.pdf
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.
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.
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.
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.
citation: Spertus, J., Kansas City Cardiomyopathy Questionnaire MDDT decision summary. <fda.gov>
citation: Thomas, R, Cohn, J., Minnesota Living with Heart Failure Questionnaire <license.umn.edu/product/minnesota-living-with-heart-fialure-questionnaire-mlhfq>