metabolism – The Early Career Voice

Live Streaming Into Scientific Sessions 2018

December 12, 2018March 28, 2019 Trupti Shetty

AHA Scientific Sessions 2018 was a unique experience for me – unable to attend the meeting, I live-streamed the sessions (first time ever for a conference!). Two of my most favorite sessions this year were the panel discussion for advanced heart failure (HF) patients, “The Metabolic Face of Heart Failure,” and the mini-symposium on “Cutting Edge in Cardiovascular Science.”

One of the main highlights in the session Metabolic Face of HF, moderated by Dr Lynne Stevenson, was the talk by cardiovascular stalwart Dr. E. Braunwald, Brigham and Women’s Hospital. Dr. Braunwald spoke of the significance and latest practices in the use of Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors, a class of FDA-approved drugs for type-2 diabetes. He indicated how SGLT2 inhibitors should be explored beyond diabetes treatment and these class of drugs can benefit HF patients as well. “I had to learn about blood clotting 30 years ago, which was difficult,” he modestly admitted as he clarified the renal effects of SGLT2 inhibition. His views also seemed to resonate with Dr. Subodh Verma, St. Michael’s Hospital, Toronto and Dr. John McMurray, Glasglow University, as they covered SGLT2 inhibitors in HF, as well.

Other speakers at this session, Dr. Neha Pagidipati, Duke University and Dr. Lewandowski, Ohio State University, touched upon aspects of stroke and metabolism regulating HF, respectively. While Dr. Pagidipati compared the risk of cardiovascular diseases and stroke with the risks of diabetes, Dr. Lewandowski explained how metabolic regulator PPAR-a (transcriber of genes in fat metabolism) could be a player explored in targeted therapy.

The session ‘Cutting Edge in Cardiovascular Science’ had presenters covering diverse strategies in dealing with cardiovascular therapy, ranging from computational screening to identifying small molecule compounds, to decoding neurovascular networks and the gut microbiome. Dr. Stanley Hazen from Cleveland Clinic presented his work on understanding the microbes in the gut and their role in driving cardiovascular diseases. Dr. Hazen explained how food like red meat, which are rich in components like phosphatidyl serine, activates the gut microbiome. He described the significance of trimethylamine N-oxide (TMAO) pathway in liver and its association with HF, stroke and cardiovascular diseases. He also strategized the use of enzyme in TMAO pathway as targets of small molecule inhibitors.

Dr. Joseph Loscalzo, Brigham and Women’s Hospital, explained how repurposing drugs and finding drug targets computationally could help precision medicine vastly. He also offered his expertise and tools as open access to AHA members. Finally, Dr. Costantino Iadecola, Cornell, elaborated on the heart-brain connectome. He brought attention to the fact that dementia, known to cause hardening of arteries, led to Alzheimer’s, but we all forgot about the vascular complications of this. He bridged this connection between neurovascular dysfunction and cognitive impairment and went on to explain his research on the intake of high salt in diet caused dementia in mice models. To learn of such versatile range of topics in a session was illuminating, to say the least!

Researchers must spend time thinking about applications of their current projects beyond their own niche – this is the only way we can widen our horizons with existing tools.

Natural Supplements Can Be A Pain In The Kidneys

May 1, 2018 Wei Ling Lau, MD

Mrs. M presented with a list of 20 natural supplements that she was taking to boost her immune system and fight off a lingering fatigue attributed to Lyme disease. She was in nephrology clinic to evaluate a 30% decline in kidney function over the recent 3 months.

She got straight to the point. “Are the supplements hurting my kidneys?” The best answer I could come up with was: “Maybe”. Which led to a discussion about why side effects can happen with herbal or other dietary supplements:

Metabolism of any drug or supplement involves several enzymatic pathways. Due to genetic variability, an individual may not be able to metabolize a certain supplement, and accumulation of byproducts leads to off-target effects. As an example, the “Asian flush” after alcohol intake is due to deficiency of acetaldehyde dehydrogenase, a key enzyme needed to break down booze in the body. The resulting acetaldehyde accumulation causes facial redness, headache, and heart palpitations.
Supplements contain more than just the pure natural product. Excipients (inactive ‘other ingredients’) are added to serve as filler, flavoring, coating, preservative, etc.¹ The inactive ingredients would typically pose little to no health risk, however, again due to genetic variability some people experience side effects. For example, potassium sorbate is sometimes used to prolong the shelf life of herbal products; sensitivity to this compound induces nausea and stomach cramps.
The optimal beneficial dose of many natural supplements is unknown. Any supplement taken in excess will overwhelm metabolic pathways and result in toxicity. Of note, many herbal products evolved as plant defenses against being eaten by insects or animals,² thus large amounts can be viewed as natural poisons.
In the setting of liver or kidney disease, byproducts can accumulate and cause adverse effects.
Interactions with prescribed medications can be problematic. One example is St. John’s wort which is consumed for its anti-anxiety and anti-inflammatory properties; this herb is known to inhibit warfarin and thus increases clotting risk in patients on warfarin anticoagulation.

The use of herbal supplements is growing. In a national U.S. survey of approximately 26,000 people, more than one-third of respondents reported using herbal supplements.³ Older age and higher education were associated with higher use of herbal supplements.

Even vitamins or minerals, when over-supplemented, can cause problems. The recommended daily vitamin C intake is 90 mg for men and 75 mg for women; these needs are easily met by a balanced diet. Many people take vitamin C (usually 1000 mg daily) to boost the immune system. Vitamin C supplementation in men is associated with increased kidney stones,⁴ likely due to increased urine levels of oxalate (a metabolite of vitamin C) and formation of calcium oxalate stones. Vitamin D calcium combination supplements, commonly taken for prevention of bone fractures, are also associated with increased risk of kidney stones⁵ as high body calcium levels leads to high urine calcium. It is interesting to note that the prevalence of kidney stones in the U.S. increased from 1 in 20 persons to 1 in 11 persons in the past 2 decades (NHANES data from 1994 and 2007-2010).⁶ One wonders if this trend is partly driven by use of vitamin and mineral supplements.

Research is ongoing to examine how natural supplements can be used to derive health benefits without causing harm. For example, our group and other researchers are investigating the antioxidant effects of curcumin derivatives (from the spice turmeric) in kidney disease.⁷ Studies in cancer cell lines discovered that curcumin at high concentrations has a paradoxical effect of increasing oxidative stress (overwhelming the antioxidant benefits), emphasizing the importance of correct dosing to avoid harm.

So what is the best approach if you have decided to take a natural supplement? Definitely let your doctor know so that the medication list is checked for potential interactions and blood tests can be monitored (if necessary). Avoid taking amounts in excess of the manufacturer’s instructions. If you have chronic kidney disease, herbal supplements should be avoided per National Kidney Foundation recommendations⁸ (until more data is available) given concerns for high potassium or phosphorus content, diuretic effects, or direct kidney toxicity.

In the case of Mrs. M, she decided to quit the 20 natural supplements and her kidney function returned to normal a few weeks later.

Suggested reading:

1. Natural Healthy Concepts blog on inactive ingredients in supplements (2014).
2. Advances in Nutrition review paper about herbal extracts that evolved as plant defenses against herbivores and insects (2011).
3. Journal of Patient Experience report on prevalence of herbal supplements use in the U.S. (2017).
4. JAMA Internal Medicine report of increased kidney stones in Swedish men taking vitamin C supplements (2013).
5. JAMA meta-analysis noting increased incidence of kidney stones in persons taking vitamin D with calcium (2018).
6. European Urology article reporting increasing occurrence of kidney stones in the U.S. from analysis of National Health and Nutrition Examination Survey data (2012).
7. PubMed list of published research papers about curcumin effects in kidney disease (as of April 2018).
8. National Kidney Foundation website advising against use of herbal supplements in chronic kidney disease patients (2015).

Wei Ling Lau, MD is Assistant Professor in Nephrology at University of California-Irvine, where she studies vascular calcification and brain microbleeds in chronic kidney disease. She is currently funded by an AHA Innovative Research Grant, and has been a speaker for CardioRenal University and the American Society of Nephrology.

Microbiota Alterations In Obesity And Sister Complications

March 13, 2018March 28, 2019 Shayan Mohammadmoradi

In my previous blog post, I briefly discussed the importance of microbiome research and how to take the first steps in conducting a microbiome study. In today’s post, I will continue to discuss the importance of this area of research with a focus on obesity.

The worldwide epidemic of metabolic syndrome and obesity in different age groups both in the United States and around the world is considered as a major public health concern. Moreover, the human gut microbiome has been linked to metabolic disease and adiposity and it is not only a marker of disease, but also contributes to pathology.

Intestinal microbiota plays a critical role in the host metabolism and immune system that extents its related physiological functions to other organs including brains, liver and adipose tissue. Metagenomic-wide association studies indicate significant changes between gut microbiota metagenome of metabolically healthy versus unhealthy individuals. Such microbiota changes are thought to be a possible cause of obesity and therefore, intestinal microbiota represents a potential therapeutic target to manage obesity.

Overview of gut microbiota role in host metabolism

Overview of gut microbiota role in host metabolism. The shift in gut bacteria can affect host metabolism via several pathways in different tissues.

Study results have illustrated alterations in the dominant gut phyla of obese subjects/animals, reporting significant reduction in Bacteroidetes and significant increase in Firmicuts and Actinobacteria. The consequence of this shift in gut microbiota is the increased potential of harvesting energy from food and a low-level inflammation. Obesity leads to a low level inflammation, specifically in adipose tissue, that results in the production of several inflammatory cytokines, which may lead to insulin resistance as well. TNF-α, IL-1β and CCL2/MCP1 are among the important inflammatory cytokines that are induced in obese state accompanied by increased macrophages, T cells and mast cells. Presence of the aforementioned cells not only correlates with the gene expressions that control inflammation, but also indicates the possible role of innate immunity in obesity and insulin resistance. Moreover, Pattern recognition receptors such as Toll-like receptors (TRLs) are activated by bacterial endotoxins such as lipopolysaccharide (LPS), which results in innate immune response and inflammation. Also, gut microbiota produce wide range of molecules, such as flagellins and peptidoglycans, which activate inflammatory pathways leading to obesity and insulin resistance. Recent data from mice genetically deficient in TLR5 reported significant changes in their microbiota and development of metabolic syndrome characteristics. Results from germ free mice also illustrated possible effects of gut microbiota on host metabolism. High fat – high sugar diet fed mice did not show same metabolic disturbance in comparison with not germ free littermates. Microbiota transplantation from obese mice also resulted in greater adiposity in comparison with lean donor recipients. It is also suggested that short chain fatty acids (SCFAs) may contribute to regulation of gut dysbiosis. These compounds such as butyrate, acetate and propionate are produced by intestinal microbiota as a result of diet-derived fibers fermentation. SCFAs are thought to be the energy source for intestinal epithelium and liver, whereas they can also play a modulatory role in immune response via reducing gut permeability.

Shayan is a caffeine-dependent Ph.D. Candidate at the Saha Cardiovascular Research Center, University of Kentucky. His research area is focused on vascular biology and lipid metabolism. He tweets @MoradiShayan, blogs at shayanmoradi.com and he is the Winner of World’s Best Husband Award (Category: nagging).