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Posts Tagged ‘TFAM’


Reversal of Cardiac mitochondrial dysfunction

Curator: Larry H Bernstein, MD, FACP

This article is the FOURTH in a four-article Series covering the topic of the Roles of the Mitochondria in Cardiovascular Diseases. They include the following;

  • Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing, Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/

  • Mitochondrial Metabolism and Cardiac Function, Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

  • Mitochondrial Dysfunction and Cardiac Disorders, Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/

https://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/

 

Mitochondrial metabolism and cardiac function

There is sufficient evidence to suggest that, even with optimal therapy, there is an

  • attenuation or loss of effectiveness of neurohormonal antagonism as heart failure worsens.

The production of oxygen radicals is increased in the failing heart, whereas

  • normal antioxidant enzyme activities are preserved.

Mitochondrial electron transport is an enzymatic source of oxygen radical generation and

  • can be a therapeutic target against oxidant-induced damage in the failing myocardium.

Therefore, future therapeutic targets

  • must address the cellular and molecular mechanisms that contribute to heart failure.

Furthermore, since  fundamental characteristics of the failing heart are 

  • defective mitochondrial energetics and
  • abnormal substrate metabolism

we might expect that substantial benefit may be derived from the development of therapies aimed at

  • preserving cardiac mitochondrial function and
  • optimizing substrate metabolism.

Nutrition and physiological function

Blockade of electron transport in isolated, perfused guinea pig hearts –
before ischaemia with the reversible complex I inhibitor amobarbital
  • decreased superoxide production and
  • preserved oxidative phosphorylation in cardiac mitochondria,
  • decreased myocardial damage.
But when ascorbic acid was administered orally to chronic heart failure patients, there were improvements
  • in endothelial function but
  • no improvement in skeletal muscle energy metabolism.
Angiotensin I-converting enzyme (ACE) inhibitors with trandolapril treatment  in models of heart failure
  • appear to preserve mitochondrial function
  • improving cardiac energy metabolism and
  • function in rats with chronic heart failure.
Similarly perindopril treatment   – in rat skeletal muscle after myocardial infarction -restored :
  • levels of the mitochondrial biogenesis transcription factors PPARg coactivator-1a and
  • nuclear respiratory factor-2a, and
  • prevented mitochondrial dysfunction
Tissue effects of ACE inhibition, such as
might activate intracellular signalling cascades that
  • stimulate mitochondrial biogenesis and
  • improve energy metabolism.
Clearly, the mechanisms of metabolic regulation by
  • existing cardioprotective agents require further investigation.

Substrate metabolism in the failing heart

Increased sympathetic drive in heart failure patients causes adipose tissue lipolysis, thus
  • elevating plasma FFA concentrations.
Myocardial FFA uptake rates are largely determined by circulating FFA concentrations.
In addition to being a major fuel in heart,
  • fatty acids are ligands for the peroxisome proliferator-activated receptors (PPARs),
    •  members of the nuclear hormone receptor (NHR) family.
One PPAR subtype, PPARa, is highly expressed in heart and skeletal muscle. PPARs regulate gene expression by
binding to response elements in the promoter region of target genes that control fatty acid metabolism, including
It has been known for many years that high plasma FFA concentrations are detrimental to the heart,
  • increasing oxygen consumption for any given workload.
Decreased myocardial oxygen efficiency could result, in part,
  • from the inherent stoichiometric inefficiency of fatty acid oxidation,
  • which accounts for the consumption of 12% more oxygen per ATP synthesized than glucose oxidation.

High levels of plasma FFAs have been associated with increased cardiac UCP3 levels in patients undergoing CABG(Fig) and

  • are believed to activate the uncoupling action of UCP3.

http://htmlimg1.scribdassets.com/8o5pfgywg0lyerj/images/4-244729cb6a.jpg

Fig .  Metabolic modulation of the failing heart can be achieved by inhibiting mitochondrial beta-oxidation with trimetazidine, or
  • free fatty acid (FFA) uptake via the carnitine palmitoyltransferase (CPT) system with perhexiline,
    • giving rise to more oxygen-efficient glucose oxidation.
Alternatively, CPT is inhibited by malonyl-coenzyme A (CoA),
  • synthesized from cytosolic acetyl-CoA by acetyl-CoA  carboxylase.
Pharmacological inhibition, or mutation, of
  • malonyl-CoA decarboxylase, which normally converts malonyl-CoA back to acetyl-CoA,
  • elevates malonyl-CoA levels, inhibiting mitochondrial FFA uptake and thus protects the failing heart.

Nutritional Support for the Mitochondria

Human Studies                                       Animal or In Vitro Studies

Alpha lipoic acid                                                    Resveratrol
Co-Enzyme Q10                                                      EgCG
Acetyl-L-Carnitine                                                Curcumin

Lipoic Acid & Acetyl-L-Carnitine

Alpha lipoic acid is known to be a mitochondrial antioxidant that preserves or improves mitochondrial function.

  •  lipoic acid can prevent arterial calcification, and
  • arterial calcification may be related to mitochondrial dysfunction
  • methods are under study to increase lipoic acid synthase production, the enzyme responsible for making lipoic acid in the body.

Co-Enzyme Q10

It is well known that statin drugs taken for high cholesterol severely reduce CoQ10 levels, and causes other negative cardiovascular side effects.
A  study on CAD patients has shown that over 8 weeks of supplementing with 300mg of CoQ10 reversed

  • mitochondrial dysfunction (as measured by a reduced lactate:pyruvate ratio) and
  • improved endothelial function (as measured by increased flow-mediated dilation)

Other Mitochondrial Antioxidants

Other natural compounds that have been shown to have antioxidant effects in the mitochondria include

  • resveratrol, found in wine and grapes,
  • curcumin from turmeric and
  • EGCG, found abundantly in green tea extract.

But no studies have been conducted for these compounds in CVD.

Metabolic syndrome and serum carotenoids: findings of a cross-sectional study
in Queensland, Australia

Metabolic syndrome and serum carotenoids.

T Coyne, TI Ibiebele, PD Baade, CS McClintock and JE Shaw.
Viertel Center for Research in Cancer Control, Cancer Council Queensland, and School of Public Health,
Queensland University of Technology and University of Queensland, Brisbane, Australia
Several components of the metabolic syndrome are known to be oxidative stress-related conditions
  1. diabetes and
  2. cardiovascular disease,
Carotenoids are compounds derived primarily from plants and several have been shown to be potent antioxidant nutrients.
Both diabetes and cardiovascular disease are known to be oxidative stress-related conditions such that
  • antioxidant nutrients may play a protective role in these conditions.
Several cross–sectional surveys have found lower levels of serum carotenoids among those with impaired glucose metabolism or type 2 diabetes.
Carotenoids are compounds derived primarily from plants, several of which are known to be potent antioxidants.
Epidemiological evidence indicates that some serum carotenoids may play a protective role against the development of chronic diseases such as
  1. atherosclerosis,
  2. stroke,
  3. hypertension,
  4. certain cancers,
  5. inflammatory diseases and
  6. diabetic retinopathy.

The primary carotenoids found in human serum are

  1. α-carotene
  2. β-carotene
  3. β-cryptoxanthin
  4. lutein/zeaxanthin
  5. lycopene.
The aim of this study was to examine the associations between metabolic syndrome status and major serum carotenoids in adult Australians.
Data on the presence of the metabolic syndrome, based on International Diabetes Federation 2005 criteria, were collected from 1523 adults
aged 25 years and over in six randomly selected urban centers in Queensland, Australia, using a cross sectional study design.
The following were determined:
  1. Weight
  2. height
  3. BMI
  4. waist circumference
  5. blood pressure
  6. fasting and 2-34 hour blood glucose
  7. lipids
  8. five serum carotenoids.
Criteria used to assess the number of metabolic syndrome components present in a 171 participant using the
2005 International Diabetes Federation definition are as follows:
Components = 0 -none of the metabolic syndrome components (i.e. abdominal obesity, raised triglyceride,
reduced HDL-cholesterol, raised blood pressure, and impaired fasting plasma glucose) are present;
  1. Components = any 1 one of the five metabolic syndrome components is present ;
  2. Components = 2 – any two of the five components are present;
  3. Components = 3 any three of the components are present;
  4. Components = 4 – any four of the components are present;
  5. Components = 5 = all five metabolic syndrome components are present.
This study investigated the relationships between these five primary serum carotenoids and the metabolic syndrome
in a cross-sectional population-based study in Queensland, Australia.  Distributions of serum carotenoids were skewed
and therefore natural logarithmically transformed to better approximate the normal distribution for regression analyses.
Association between log transformed serum carotenoids as dependent variables and metabolic syndrome status were
assessed using multiple linear regression analysis. Results are reported as back transformed geometric means.
Analysis was performed for each serum carotenoid separately, and the sum of the five carotenoids,
adjusting for the following potential confounders:
  1. age
  2. sex
  3. education
  4. BMI
  5. smoking
  6. alcohol intake
  7. physical activity
  8. vitamin use.
Mean serum alpha-carotene, beta-carotene and the sum of the five carotenoid concentrations were significantly lower (p<0.05)
in persons with the metabolic syndrome (after adjusting for age,sex, education, BMI status, alcohol intake, smoking, physical activity
status and vitamin/mineral use) than persons without the syndrome. Alpha, beta and total carotenoids also decreased significantly
(p<0.05) with increased number of components of the metabolic syndrome, after adjusting for these confounders. These differences
were significant among former smokers and non-smokers, but not in current smokers. Low concentrations of serum
  • alpha-carotene,
  • beta carotene and
  • the sum of five carotenoids
appear to be associated with metabolic syndrome status.
The overall prevalence of the syndrome was 24% and was significantly higher among males than females. As would be expected, significant
differences in prevalence of the syndrome were seen with
  • body mass index
  • waist circumference
  • systolic and diastolic blood pressure
  • blood lipids.
Significant differences were also evident by
  • age group, smoking status, educational status and income.
Income was marginally inversely associated. The prevalence increased with age, and was lower in those with post graduate education.
No significant differences were seen by alcohol intake, physical activity levels,  vitamin usage, or fruit intake. There was actually an
  • inverse relationship between vegetable intake (not fruit) and serum carotenoids.
Those who consumed 4 serves or more of vegetable were less likely to have the metabolic syndrome
  • compared to those who consumed 1 serve or less of vegetables.
The mean concentrations of serum alpha-carotene, beta-carotene and the sum of the five carotenoids were significantly lower for participants
  • with the metabolic syndrome present compared with those without the syndrome, after adjusting for potential confounding variables.
Concentrations of alpha-carotene, beta-carotene and the sum of the five carotenoids decreased significantly as
  • the number of components of the metabolic syndrome increased after adjusting for potential confounding variables.
Similarly there was an inverse association between quartiles of
  • individual and total serum carotenoids and metabolic syndrome status and each of its components.
This study was designed to investigate the association between several serum carotenoids and the metabolic syndrome.
The data from the present population study suggest that several serum carotenoids are inversely related to the metabolic syndrome.
The study showed significantly lower concentrations present among those with the metabolic syndrome of
  1. α-carotene,
  2. β-carotene and
  3. the sum of the five carotenoids
 compared to those without.We also found decreasing concentrations of all the carotenoids tested as

  • the number of the metabolic syndrome components increased.
This was significant for
  1. α-carotene,
  2. β-carotene,
  3. β-cryptoxanthin
  4. total carotenoids.
    (not lycopenes)
These findings are consistent with data reported from the third National Health and Nutrition Examination Survey (NHANES III).
In the NHANES III study, significantly lower concentrations of all the carotenoids, except lycopene, were found among persons
with the metabolic syndrome compared with those without, after adjusting for confounding factors similar to those in our study.

Carnitine: A novel health factor-An overview. 

CD Dayanand, N Krishnamurthy, S Ashakiran, KN Shashidhar
Int J Pharm Biomed Res 2011; 2(2): 79-89.  ISSN No: 0976-0350
Carnitine comprises L-carnitine, acetyl –L-carnitine and Propionyl –L-carnitine. Carnitine is
  • obtained in greater amount from animal dietary sources than from plant sources.
The endogenous synthesis of carnitine takes place in animal tissues like
  • liver
  • kidney
  • brain
using precursor amino acids lysine and methionine by a pathway
  • dependent on iron, vitamin C, niacin, pyridoxine .
This is the basis of vegans generally depending on carnitine in larger proportion
  • through in vivo synthesis than omnivorous subjects.
The concentration of tri-methyl lysine residues and the tissue specificity of  butyro-betaine dehydrogenase
  • plays a significant role in regulating the carnitine biosynthesis.
Carnitine transport from the site of synthesis to target tissue occurs via blood.
The measurement of plasma carnitine concentration represents –
  • the balance between the rate of synthesis and rate of excretion
    • through specific transporter proteins.
The cellular functional role of carnitine depends on the uptake into cells through
  1. carnitine transport proteins and
  2. transport into mitochondrial matrix.
The function of carnitine is to traverse Long-chain Fatty Acids across inner mitochondrial membrane
  • for β-oxidation, thereby, generating ATP.
Carnitine deficiency results in muscle disorders.  The deficiency states are primary and secondar.
The primary is of systemic or myopathic, characterized by a defect of high affinity organic cation transporter protein (CTP)
  • present on the plasma membrane of liver and kidney and
  • also due to dysfunction of carnitine reabsorbtion through
    • similar transport proteins in renal tubules.
Secondary carnitine deficiency is associated with
  1. mitochondrial disorders and also
  2. defective β-oxidation such as CPT-II and acyl CoA dehydrogenase.
In recent times, carnitine has been extensively studied in various research activities to explore the therapeutic benefit.
Thus, carnitine justifies as a novel health factor.

Propionyl-L-carnitine Corrects Metabolic and Cardiovascular Alterations in
Diet-Induced Obese Mice and Improves Liver Respiratory Chain Activity

C Mingorance,  L Duluc, M Chalopin, G Simard, et al.
PLC improved the insulin-resistant state and reversed the increased total cholesterol
but not the increase in free fatty acid, triglyceride and HDL/LDL ratio induced by high-fat diet.
Vehicle-HF exhibited a reduced

  • cardiac output/body weight ratio,
  • endothelial dysfunction and
  • tissue decrease of NO production,

all of them being improved by PLC treatment.
The decrease of hepatic mitochondrial activity by high-fat diet was reversed by PLC.

Oral administration of PLC improves the insulin-resistant state developed by obese animals and
decreases the cardiovascular risk associated with the metabolically impaired mitochondrial function.

Omega-3 Fatty Acid and cardioprotection

The Benefits of Flaxseed    

By Elaine Magee, MPH, RD    WebMD Expert Column
Some call it one of the most powerful plant foods on the planet. There’s some evidence it may help reduce your risk of

  • heart disease, cancer, stroke, and diabetes.

That’s quite a tall order for a tiny seed that’s been around for centuries.

Flaxseed was cultivated in Babylon as early as 3000 BC. In the 8th century, King Charlemagne believed so strongly in the
health benefits of flaxseed that he passed laws requiring his subjects to consume it. Now, thirteen centuries later, some
experts say we have preliminary research to back up what Charlemagne suspected.

http://img.webmd.com/dtmcms/live/webmd/consumer_assets/site_images/article_
thumbnails/features/benefits_of_flaxseed_features/375x321_benefits_of_flaxseed_features.jpg

Not only has consumer demand for flaxseed grown, agricultural use has also increased.
Flaxseed is what’s used to feed all those chickens that are laying eggs with higher levels of omega-3 fatty acids.
Although flaxseed contains all sorts of healthy components, it owes its primary healthy reputation to three of them:

  1. Omega-3 essential fatty acids, have been shown to have heart-healthy effects.  1.8 grams of plant omega-3s/tablespoon ground.
  2. Lignans, which have both plant estrogen and antioxidant qualities.  75 to 800 times more lignans than other plant foods.
  3. Fiber. Flaxseed contains both the soluble and insoluble types.

Omega-3 Polyunsaturated Fatty Acids and Cardiovascular Diseases

CJ Lavie, RV Milani, MR Mehra, and HO Ventura.
J. Am. Coll. Cardiol. 2009;54;585-594.   http://dx.doi.org/10.1016/j.jacc.2009.02.084
Fish oil is obtained in the human diet by eating oily fish, such as
  • herring, mackerel, salmon, albacore tuna, and sardines, or
  • by consuming fish oil supplements or cod liver oil.
Fish do not naturally produce these oils, but obtain them through the ocean food chain from the marine microorganisms
  • that are the original source of the omega-3 polyunsaturated fatty acids (ω-3 PUFA) found in fish oils.
Numerous prospective and retrospective trials from many countries, including the U.S., have shown that moderate
  • fish oil consumption decreases the risk of major cardiovascular (CV) events, such as
  1. myocardial infarction (MI),
  2. sudden cardiac death (SCD),
  3. coronary heart disease (CHD),
  4. atrial fibrillation (AF), and most recently,
  5. death in patients with heart failure (HF).
Most of the evidence for benefits of the ω-3 PUFA has been obtained for
  • eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the long-chain fatty acids in this family.
There is support for a benefit from alpha-linolenic acid (ALA),
  • the plant-based precursor of EPA.
The American Heart Association (AHA) has currently endorsed the use of ω-3 PUFA in patients with documented CHD

  • at a dose of approximately 1 g/day of combined DHA and EPA, either in the form of fatty fish or fish oil supplements
The health benefits of these long chain fatty acids are numerous and remain an active area of research.
Omega-3 polyunsaturated fatty acid (ω-3 PUFA) therapy continues to show great promise in primary and,
  • particularly in secondary prevention of cardiovascular (CV) diseases.
This portion of discussion summarizes the current scientific data on the effects of the long chain ω-3 PUFA
  • in the primary and secondary prevention of various CV disorders.
The most compelling evidence for CV benefits of ω-3 PUFA comes from 4 controlled trials
  • of nearly 40,000 participants randomized to receive eicosapentaenoic acid (EPA)
  • with or without docosahexaenoic acid (DHA) in studies of patients
    • in primary prevention,
    • after myocardial infarction, and
    • with heart failure (HF).
The evidence from retrospective epidemiologic studies and from large randomized controlled trials
show the benefits of ω-3 PUFA, specifically EPA and DHA, in primary and secondary CV prevention
and provide insight into potential mechanisms of these observed benefits.

Background Epidemiologic Evidence

During the past 3 decades, numerous epidemiologic and observational studies have been published on the CV benefits of ω-3 PUFA.
As early as 1944, Sinclair described the rarity of CHD in Greenland Eskimos, who consumed a diet high in whale, seal, and fish.
More than 30 years ago, Bang and Dyberg reported that despite a diet low in fruit, vegetables, and complex carbohydrates but
high in saturated fat and cholesterol, serum cholesterol and triglycerides were lower in Greenland Inuit than in age-matched residents
of Denmark, and the risk of MI was markedly lower in the Greenland population compared with the Danes. These initial observations raised
speculation on the potential benefits of ω-3 PUFA (particularly EPA and DHA) as the protective “Eskimo factor”.
Potential EPA and DHA Effects   
  1. Antiarrhythmic effects
  2. Improvements in autonomic function
  3. Decreased platelet aggregation
  4. Vasodilation
  5. Decreased blood pressure
  6. Anti-inflammatory effects
  7. Improvements in endothelial function
  8. Plaque stabilization
  9. Reduced atherosclerosis
  10. Reduced free fatty acids and triglycerides
  11. Up-regulated adiponectin synthesis
  12. Reduced collagen deposition
The target EPA + DHA consumption should be at least 500 mg/day for individuals without underlying overt CV disease
  • and at least 800 to 1,000 mg/day for individuals with known coronary heart disease and HF.
Further studies are needed to determine optimal dosing and the relative ratio of DHA and EPA ω-3 PUFA that
  • provides maximal cardioprotection in those at risk of CV disease
  • as well in the treatment of atherosclerotic, arrhythmic, and primary myocardial disorders.
Lavie et al.  Omega-3 PUFA and CV Diseases  J Am Coll Cardiol 2009; 54(7): 585–94

Assessing Appropriateness of Lipid Management Among Patients With Diabetes Mellitus

Moving From Target to Treatment.   AJ Beard, TP Hofer, JR Downs, et al. and Diabetes Clinical Action Measures Workgroup
Performance measures that emphasize only a treat-to-target approach may motivate ove-rtreatment with high-dose statins,
  • potentially leading to adverse events and unnecessary costs.
We developed a clinical action performance measure for lipid management in patients with diabetes mellitus that is designed
  • to encourage appropriate treatment with moderate-dose statins while minimizing over-treatment.
We examined data from July 2010 to June 2011 for 964 818 active Veterans Affairs primary care patients ≥18 years of age with diabetes mellitus.
We defined 3 conditions as successfully meeting the clinical action measure for patients 50 to 75 years old:
  1.  having a low-density lipoprotein (LDL) <100 mg/dL,
  2. taking a moderate-dose statin regardless of LDL level or measurement, or
  3. receiving appropriate clinical action (starting, switching, or intensifying statin therapy) if LDL is ≥100 mg/dL.
We examined possible over-treatment for patients ≥18 years of age by examining the proportion of patients
  • without ischemic heart disease who were on a high-dose statin.
We then examined variability in measure attainment across 881 facilities using 2-level hierarchical multivariable logistic models.
Of 668 209 patients with diabetes mellitus who were 50 to 75 years of age, 84.6% passed the clinical action measure:
  1. 67.2% with LDL <100 mg/dL,
  2. 13.0% with LDL ≥100 mg/dL and either on a moderate-dose statin (7.5%) or with appropriate clinical action (5.5%), and
  3. 4.4% with no index LDL on at least a moderate-dose statin. Of the entire cohort ≥18 years of age, 13.7% were potentially over-treated.
Use of a performance measure that credits appropriate clinical action indicates that almost 85% of diabetic veterans 50 to 75 years of age
  • are receiving appropriate dyslipidemia management.

Exercise training and mitochondria in heart failure

The beneficial effects of exercise in the rehabilitation of patients with heart failure are well established,
with improvements observed in
  • exercise capacity,
  • quality of life,
  • hospitalization rates and
  • morbidity/mortality.
There is no evidence of training-induced
improvements in cardiac energy metabolism or
  • mitochondrial function, and
  • no modification of myocardial oxidative capacity,
  • oxidative enzymes, or
  • energy transfer enzymes
in exercising rats with experimental heart failure, but there is  evidence of
There are also improvements in
  • skeletal muscle oxidative capacity with
  • increased mitochondrial density
following endurance training in heart failure patients associated with alleviation of symptoms such as
  • exercise intolerance and
  • chronic fatigue.
The mechanism underlying improvements in mitochondrial function may perhaps be a result of
  • more effective peripheral oxygen delivery following training,
  • alleviating tissue hypoxia and oxidative stress.

Treating Type 2 diabetes, and lowering cardiovascular disease risk

Treating Diabetes and Obesity with an FGF21-Mimetic Antibody
Activating the βKlotho/FGFR1c Receptor Complex

IN Foltz, S Hu, C King, Xinle Wu, et al.  Amgen and Texas A&M HSC, Houston, TX.
Sci Transl Med  Nov 2012; 4(162), p. 162ra153
http://dx.doi.org/10.1126/scitranslmed.3004690

Fibroblast growth factor 21 (FGF21) is a distinctive member of the FGF family with potent beneficial effects on

  1. lipid
  2. body weight
  3. glucose metabolism

A monoclonal antibody, mimAb1, binds to βKlotho with high affinity and specifically

  • activates signaling from the βKlotho/FGFR1c (FGF receptor 1c) receptor complex.

Injection of mimAb1 into obese cynomolgus monkeys led to FGF21-like metabolic effects:

  1. decreases in body weight,
  2. plasma insulin,
  3. triglycerides, and
  4. glucose during tolerance testing.

Mice with adipose-selective FGFR1 knockout were refractory to FGF21-induced improvements

  • in glucose metabolism and body weight.

mimAb1 depends on βKlotho to activate FGFR1c, but

  • it is not expected to induce side effects caused by activating FGFR1c alone.

The results in obese monkeys (with mimAb1) and in FGFR1 knockout mice (with FGF21) demonstrated

  • the essential role of FGFR1c in FGF21 function and
  • suggest fat as a critical target tissue for the cytokine and antibody.

This antibody activates FGF21-like signaling through cell surface receptors, and  provided

  • preclinical validation for an innovative therapeutic approach to diabetes and obesity.

Influencing Factors on Cardiac Structure and Function Beyond Glycemic Control
in Patients With Type 2 Diabetes Mellitus (T2DM)

R Ichikawa, M Daimon, T Miyazaki, T Kawata, et al.     Cardiovasc Diabetol. 2013;12(38)

We studied 148 asymptomatic patients with T2DM without overt heart disease.
Early (E) and late (A) diastolic mitral flow velocity and early diastolic mitral annular velocity (e’)

  • were measured for assessing left ventricular (LV) diastolic function.

In addition

  • insulin resistance,
  • non-esterified fatty acid,
  • high-sensitive CRP,
  • estimated glomerular filtration rate,
  • waist/hip ratio,
  • abdominal visceral adipose tissue (VAT),
  • subcutaneous adipose tissue (SAT)

In T2DM (compared to controls),

  • E/A and e’ were significantly lower, and
  • E/e’, left atrial volume and LV mass were significantly greater

VAT  and age were independent determinants of

  • left atrial volume (β =0.203, p=0.011),
  • E/A (β =−0.208, p=0.002), e’ (β =−0.354, p<0.001) and
  • E/e’ (β=0.220, p=0.003).

Independent determinants of LV mass were

  • systolic blood pressure,
  • waist-hip ratio (β=0.173, p=0.024)
  • VAT/SAT ratio (β=0.162, p=0.049)

Excessive visceral fat accompanied by adipocyte dysfunction may play a greater role than

  • glycemic control in the development of diastolic dysfunction and LV hypertrophy in T2DM

Inhibition of oxidative stress and mtDNA damage

Novel pharmacological agents are needed that

  • optimize substrate metabolism and
  • maintain mitochondrial integrity,
  • improve oxidative capacity in heart and skeletal muscle, and
  • alleviate many of the clinical symptoms associated with heart failure.

The evidence for the attenuation or loss of effectiveness of neurohormonal antagonism as heart failure worsens

  • indicates future therapeutic targets must address the cellular and molecular mechanisms that contribute to heart failure.

Pharmacological Targets of oxidative stress and mitochondrial damage

Defective mitochondrial energetics and abnormal substrate metabolism are fundamental characteristics of CHF.

A significant benefit may be derived from developing therapies aimed at

  • preserving cardiac mitochondrial function and
  • optimizing substrate metabolism.
Oxidative stress is enhanced in myocardial remodelling and failure. The increased production of oxygen radicals in the failing heart
  • with preserved antioxidant enzyme activities suggests
  • mitochondrial electron transport as a source of oxygen radical generation
  • can be a therapeutic target against oxidant-induced damage in the failing myocardium.
Chronic increases in oxygen radical production in the mitochondria
  • leads to mitochondrial DNA (mtDNA) damage,
  • functional decline,
  • further oxygen radical generation, and
  • cellular injury.
MtDNA defects may thus play an important role in the
  • development and progression of myocardial remodelling and failure.
Reactive oxygen species induce
  1. myocyte hypertrophy,
  2. apoptosis, and
  3. interstitial fibrosis
  4. by activating matrix metallo-proteinases,
  5. promoting the development and
  6. progression of maladaptive myocardial remodelling and failure.
Oxidative stress has direct effects on cellular structure and function and
  • may activate integral signalling molecules in myocardial remodelling and failure (Figure).
ROS result in a phenotype characterized by
  • hypertrophy and apoptosis in isolated cardiac myocytes.
Therefore, oxidative stress and mtDNA damage are good therapeutic targets.
Overexpression of the genes for
  • peroxiredoxin-3 (Prx-3), a mitochondrial antioxidant, or
  • mitochondrial transcription factor A (TFAM),
    • could ameliorate the decline in mtDNA copy number in failing hearts.
Consistent with alterations in mtDNA, the
  • decrease in mitochondrial function was prevented,
  • proving that the activation of Prx-3 or TFAM gene expression
  • could ameliorate the pathophysiological processes seen
  1. in mitochondrial dysfunction and
  2. myocardial remodelling.
Inhibition of oxidative stress and mtDNA damage
  • could be novel and effective treatment strategies for heart failure.
Proposed mechanisms through which overexpression of the
  • mitochondrial transcription factor A (TFAM) gene prevents
  • mitochondrial DNA (mtDNA) damage,
  • oxidative stress, and
  • myocardial remodelling and failure.
In wild-type mice, mitochondrial transcription factor A
  • directly interacts with mitochondrial DNA to form nucleoids.
Stress such as ischaemia causes mitochondrial DNA damage, which
  1. increases the production of reactive oxygen species (ROS)
  2. leading to a catastrophic cycle of mitochondrial electron transport impairment,
  3. further reactive oxygen species generation, and mitochondrial dysfunction.
TFAM overexpression may protect mitochondrial DNA from damage by
  1. directly binding and stabilizing mitochondrial DNA and
  2. increasing the steady-state levels of mitochondrial DNA
ameliorating mitochondrial dysfunction and thus the development and progression of heart failure.

Conclusion

Heart failure is a multifactorial syndrome that is characterized by
  • abnormal energetics and substrate metabolism in heart and skeletal muscle.
Although existing therapies have been beneficial, there is a clear need for new approaches to treatment.
Pharmacological targeting of the cellular stresses underlying mitochondrial dysfunction, such as
  • elevated fatty acid levels,
  • tissue hypoxia and oxidative stress and
  • metabolic modulation of heart and skeletal muscle mitochondria,
    • appears to offer a promising therapeutic strategy for tackling heart failure.
Murray AJ, Anderson RE, Watson GC, et al. Uncoupling proteins in human heart. Lancet 2004; 364:1786.
Delarue J, Magnan C. Free fatty acids and insulin resistance. Curr Opin ClinNutr Metab Care 2007; 10:142
Lee L, Campbell R, Scheuermann-Freestone M, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trialof short-term use of a novel treatment. Circulation 2005; 112:3280
Tsutsui H, Kinugawa S, Matsushima S. Mitochondrial oxidative stress and dysfunction in myocardial remodelling. Cardiovasc Res. 2009;81(3):449-56. http://dxdoi.org/10.1093/cvr/cvn280.
C Maack, M Böhm. Targeting Mitochondrial Oxidative Stress in Heart Failure. J Am Coll Cardiol. 2011;58(1):83-86. http://dx.doi.org/10.1016/j.jacc.2011.01.032

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Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function    larryhbern
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Structure of the human mitochondrial genome.

Structure of the human mitochondrial genome. (Photo credit: Wikipedia)

English: Treatment Guidelines for Chronic Hear...

English: Treatment Guidelines for Chronic Heart Failure (Photo credit: Wikipedia)

English: Oxidative stress process Italiano: Pr...

English: Oxidative stress process Italiano: Processo dello stress ossidativo (Photo credit: Wikipedia)

Diagram taken from the paper "Dissection ...

Diagram taken from the paper “Dissection of mitochondrial superhaplogroup H using coding region SNPs” (Photo credit: Asparagirl)

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