What Role do Mitochondria Have in Diastolic Dysfunction? Implications for Diabetic Cardiomyopathy and Heart Failure With Preserved Ejection Function

McCandless, Martin G.; Altara, Raffaele; Booz, George W.; Kurdi, Mazen

doi:10.1097/fjc.0000000000001228

Cited by 7 publications

(7 citation statements)

References 87 publications

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“…This was accompanied by an increase in oxidative stress and inflammatory mediators. Although it is widely accepted that dysregulation in mitochondrial homeostasis has a significant impact on cardiac contractility, 13 the root cause of this phenomenon in AD remains unclear.…”

Section: Alzheimer's Disease and Cardiovascular Healthmentioning

confidence: 99%

Proteinopathy: Shared Feature Between the Heart and Brain in Alzheimer's Disease

Amin,

Booz,

Zouein

2024

Journal of Cardiovascular Pharmacology

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I put my heart and my soul into my work, and have lost my mind in the process." Vincent Van Gogh ALZHEIMER'S DISEASE BURDEN AND CLINICAL PATHOGENESISA lzheimer's disease (AD) comprises around 70% of all dementia cases and is the leading cause of death among neurological diseases. Over the last 30 years, the burden of AD has substantially increased across the globe. Between 2010 and 2020, worldwide fatalities from AD and dementia showed a 44% rise, surpassing the 21% increase in deaths related to heart disease. The United States burden of AD and related dementias is projected to double by 2050, during which around 13 million individuals are expected to suffer from AD. 1 Although aging is a primary risk factor, it is also possible to experience an early onset of AD. 2 The progression of the disease starts from preclinical stages and advances toward mild cognitive impairment, eventually leading to AD dementia. Detecting the disease in its early stages remains a challenge as clinical symptoms tend to appear years later. This gradual and debilitating pattern of AD causes a significant financial and human burden. One of the main focuses of extensive research on AD is the accumulation of amyloidb (Ab) plaques and neurofibrillary tau tangles in the brain, which is considered to be a hallmark in the development of the disease. Recently, the FDA granted accelerated approval to the Ab-directed monoclonal antibody lecanemab that prevents its deposition to treat AD. 3 ALZHEIMER'S DISEASE AND CARDIOVASCULAR HEALTHNumerous epidemiological studies have explored the link between cardiovascular diseases and AD. Evidence suggests that older individuals with cardiovascular disease are at a high risk of developing AD. 4,5 This interrelationship is reinforced by the fact that both conditions share similar risk factors and genetic profiles such as hypertension, hypercholesteremia, obesity, and APOE polymorphisms. Additionally, alterations in vascular and perfusion mechanisms may contribute to the development of AD because individuals with AD often exhibit a decrease in cerebral blood flow. 6 Chronic hypoperfusion causes oxidative stress and neuronal death. 7 Over time, energy depletion may trigger development of Ab plaques and neurofibrillary tangles. However, this remains a putative mechanism in the absence of clinical proof.Approaching the brain-heart interaction from a different perspective, AD may be linked to cardiac pathologies (Fig. 1). Cohort studies have revealed an association between AD and diastolic dysfunction. [8][9][10] Additionally, the degree of cognitive impairment seems to be related to the severity of diastolic dysfunction. It is natural for cardiac and cognitive From the

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Section: Alzheimer's Disease and Cardiovascular Healthmentioning

confidence: 99%

Proteinopathy: Shared Feature Between the Heart and Brain in Alzheimer's Disease

Amin,

Booz,

Zouein

2024

Journal of Cardiovascular Pharmacology

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“…Furthermore, the AMPK pathway stimulates mitochondrial biogenesis through peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α)-dependent transcriptional control and promotes mitophagy [ 61 ]. Mitochondrial dysfunction plays a central role in developing diabetic cardiomyopathy [ 66 ]. High glucose and fatty acid fluxes overload the mitochondrial electron transfer chains, leading to increased mitochondrial proton leak, increased emission of reactive oxygen species (ROS), mitochondrial oxidative damage, attenuated oxidative phosphorylation, and decreased ATP production, which is required for myocardial relaxation [ 67 ].…”

Section: Molecular Mechanism Of Diabetic Cardiomyopathymentioning

confidence: 99%

“…The central importance of ROS is demonstrated by the fact that this can be prevented when ROS generation is eliminated [ 66 ]. In addition, excessive glucose flux also leads to the overproduction of glycolysis intermediates, which triggers multiple pathogenic signaling pathways, including the methylglyoxal (MG)/advanced glycation end-products (AGEs) pathway, the hexosamine pathway, protein kinase C signaling, and the aldose reductase/sorbitol polyol pathway [ 66 ]. Cardiac-specific overexpression of the protein kinase C β2 isoform resulted in cardiac hypertrophy and fibrosis.…”

Section: Molecular Mechanism Of Diabetic Cardiomyopathymentioning

confidence: 99%

Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice

et al. 2023

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Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium–glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin–angiotensin–aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.

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“…The strong diabetic component may skew the model towards that of diabetic cardiomyopathy, which is defined as “the existence of abnormal myocardial structure and performance in the absence of other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease, in individuals with diabetes mellitus.” 119 As noted elsewhere, there are significant differences between HFpEF and diabetic cardiomyopathy, and between the db/db mouse and the ZSF1 rat, particularly with regard to mitochondrial function and metabolism. 120 …”

Section: Conventional Preclinical Modelsmentioning

confidence: 99%

Genomic, Proteomic, and Metabolic Comparisons of Small Animal Models of Heart Failure With Preserved Ejection Fraction: A Tale of Mice, Rats, and Cats

Smith

Altara

Amin

et al. 2022

JAHA

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Heart failure with preserved ejection fraction (HFpEF) remains a medical anomaly that baffles researchers and physicians alike. The overall phenotypical changes of diastolic function and left ventricular hypertrophy observed in HFpEF are definable; however, the metabolic and molecular alterations that ultimately produce these changes are not well established. Comorbidities such as obesity, hypertension, and diabetes, as well as general aging, play crucial roles in its development and progression. Various animal models have recently been developed to better understand the pathophysiological and metabolic developments in HFpEF and to illuminate novel avenues for pharmacotherapy. These models include multi‐hit rodents and feline aortic constriction animals. Recently, genomic, proteomic, and metabolomic approaches have been used to define altered signaling pathways in the heart associated with HFpEF, including those involved in inflammation, cGMP‐related, Ca 2+ handling, mitochondrial respiration, and the unfolded protein response in endoplasmic reticulum stress. This article aims to present an overview of what has been learnt by these studies, focusing mainly on the findings in common while highlighting unresolved issues. The knowledge gained from these research models will not simply be of benefit for treating HFpEF but will undoubtedly provide new insights into the mechanisms by which the heart deals with external stresses and how the processes involved can fail.

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What Role do Mitochondria Have in Diastolic Dysfunction? Implications for Diabetic Cardiomyopathy and Heart Failure With Preserved Ejection Function

Cited by 7 publications

References 87 publications

Proteinopathy: Shared Feature Between the Heart and Brain in Alzheimer's Disease

Proteinopathy: Shared Feature Between the Heart and Brain in Alzheimer's Disease

Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice

Genomic, Proteomic, and Metabolic Comparisons of Small Animal Models of Heart Failure With Preserved Ejection Fraction: A Tale of Mice, Rats, and Cats

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