ABSTRACT
AIMS: With an ageing population, the presence of asymptomatic valvular heart disease (VHD) in the community remains unknown. The aim of this study is to determine the prevalence and associated factors of asymptomatic VHD in individuals ≥60 years old and to evaluate the feasibility of echocardiographic screening for VHD in this population. METHODS AND RESULTS: This was a prospective cohort study conducted between 2007 and 2016 in the UK. Asymptomatic patients with no prior indication for echocardiography were invited to participate and evaluated with a health questionnaire, clinical examination, and transthoracic echocardiography. A total of 10,000 individuals were invited through their general practices. A total of 5429 volunteered to participate, of whom 4237 were eligible for inclusion. VHD was diagnosed in more than a quarter of patients (28.2%). The most common types of VHD were regurgitation of the tricuspid (13.8%), mitral (12.8%), and aortic (8.3%) valves (trivial regurgitation was not included). The rate of prevalence of clinically significant VHD was 2.4% (2.2% moderate and 0.2% severe), with mitral and aortic regurgitation being the most common. The only parameter associated with significant VHD was age (odds ratio 1.07 per 1 year increment, 95% confidence interval 1.05-1.09, P < 0.001). The number needed to scan to diagnose one clinically significant case of VHD is 42 for individuals ≥60 and 15 for those ≥75 years old. CONCLUSION: Asymptomatic VHD is present in a significant proportion of otherwise healthy individuals without known VHD over 60 years old. Age is strongly associated with an increased incidence of significant VHD.
Subject(s)
Asymptomatic Diseases , Echocardiography , Heart Valve Diseases , Humans , Female , Male , Aged , Prospective Studies , Prevalence , Heart Valve Diseases/diagnostic imaging , Heart Valve Diseases/epidemiology , Middle Aged , Asymptomatic Diseases/epidemiology , United Kingdom/epidemiology , Cohort Studies , Aged, 80 and over , Risk Assessment , Age FactorsABSTRACT
Increased proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs) is recognised as a universal hallmark of pulmonary arterial hypertension (PAH), in part related to the association with reduced pyruvate dehydrogenase (PDH) activity, resulting in decreased oxidative phosphorylation of glucose and increased aerobic glycolysis (Warburg effect). Perhexiline is a well-recognised carnitine palmitoyltransferase-1 (CPT1) inhibitor used in cardiac diseases, which reciprocally increases PDH activity, but is associated with variable pharmacokinetics related to polymorphic variation of the cytochrome P450-2D6 (CYP2D6) enzyme, resulting in the risk of neuro and hepatotoxicity in 'slow metabolisers' unless blood levels are monitored and dose adjusted. We have previously reported that a novel perhexiline fluorinated derivative (FPER-1) has the same therapeutic profile as perhexiline but is not metabolised by CYP2D6, resulting in more predictable pharmacokinetics than the parent drug. We sought to investigate the effects of perhexiline and FPER-1 on PDH flux in PASMCs from patients with PAH. We first confirmed that PAH PASMCs exhibited increased cell proliferation, enhanced phosphorylation of AKTSer473, ERK 1/2Thr202/Tyr204 and PDH-E1αSer293, indicating a Warburg effect when compared to healthy PASMCs. Pre-treatment with perhexiline or FPER-1 significantly attenuated PAH PASMC proliferation in a concentration-dependent manner and suppressed the activation of the AKTSer473 but had no effect on the ERK pathway. Perhexiline and FPER-1 markedly activated PDH (seen as dephosphorylation of PDH-E1αSer293), reduced glycolysis, and upregulated mitochondrial respiration in these PAH PASMCs as detected by Seahorse analysis. However, both perhexiline and FPER-1 did not induce apoptosis as measured by caspase 3/7 activity. We show for the first time that both perhexiline and FPER-1 may represent therapeutic agents for reducing cell proliferation in human PAH PASMCs, by reversing Warburg physiology.
ABSTRACT
Acute myocardial infarction (AMI) remains a leading cause of death worldwide. Increased formation of reactive oxygen species (ROS) during the early reperfusion phase is thought to trigger lipid peroxidation and disrupt redox homeostasis, leading to myocardial injury. Whilst the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) is chiefly recognised for its central role in ethanol metabolism, substantial experimental evidence suggests an additional cardioprotective role for ALDH2 independent of alcohol intake, which mitigates myocardial injury by detoxifying breakdown products of lipid peroxidation including the reactive aldehydes, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Epidemiological evidence suggests that an ALDH2 mutant variant with reduced activity that is highly prevalent in the East Asian population increases AMI risk. Additional studies have uncovered a strong association between coronary heart disease and this ALDH2 mutant variant. It appears this enzyme polymorphism (in particular, in ALDH2*2/2 carriers) has the potential to have wide-ranging effects on thiol reactivity, redox tone and therefore numerous redox-related signaling processes, resilience of the heart to cope with lifestyle-related and environmental stressors, and the ability of the whole body to achieve redox balance. In this review, we summarize the journey of ALDH2 from a mitochondrial reductase linked to alcohol metabolism, via pre-clinical studies aimed at stimulating ALDH2 activity to reduce myocardial injury to clinical evidence for its protective role in the heart.
Subject(s)
Aldehyde Dehydrogenase, Mitochondrial , Ethanol , Myocardial Infarction , Oxidation-Reduction , Polymorphism, Genetic , Humans , Aldehyde Dehydrogenase, Mitochondrial/genetics , Aldehyde Dehydrogenase, Mitochondrial/metabolism , Myocardial Infarction/genetics , Myocardial Infarction/metabolism , Animals , Ethanol/metabolism , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase/metabolism , Reactive Oxygen Species/metabolismABSTRACT
Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of ß-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of ß-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.
Subject(s)
Aortic Valve Stenosis , Cardiomyopathy, Hypertrophic , Humans , Peroxisome Proliferator-Activated Receptors , Cardiomyopathy, Hypertrophic/genetics , Hypertrophy, Left Ventricular/genetics , Aortic Valve Stenosis/genetics , Fatty Acids/metabolismABSTRACT
BACKGROUND: Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved. OBJECTIVES: This study aims to investigate sex-specific differences in DCM presentation, natural history, and prognostic factors. METHODS: The authors conducted a prospective observational cohort study of DCM patients assessing baseline characteristics, cardiac magnetic resonance imaging, biomarkers, and genotype. The composite outcome was cardiovascular mortality or major heart failure (HF) events. RESULTS: Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline, female patients had higher left ventricular ejection fraction, smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%), and lower high-sensitivity cardiac troponin I than males (all P < 0.05) with no difference in time from diagnosis, age at enrollment, N-terminal pro-B-type natriuretic peptide levels, pathogenic DCM genetic variants, myocardial fibrosis extent, or medications used for HF. Despite a more favorable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted HR: 3.14; 95% CI: 1.55-6.35; P = 0.001). Between 2 and 5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, left ventricular ejection fraction, left atrial volume, N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin I, left bundle branch block, and NYHA functional class were not sex-specific prognostic factors. CONCLUSIONS: The authors identified a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences.
Subject(s)
Cardiomyopathies , Cardiomyopathy, Dilated , Heart Failure , Humans , Male , Female , Cardiomyopathy, Dilated/pathology , Natriuretic Peptide, Brain , Stroke Volume , Ventricular Function, Left , Prospective Studies , Sex Characteristics , Troponin I , Prognosis , FibrosisABSTRACT
Earlier studies revealed the presence of cysteine persulfide (CysSSH) and related polysulfide species in various mammalian tissues. CysSSH has both antioxidant and oxidant properties, modulates redox-dependent signal transduction and has been shown to mitigate oxidative stress. However, its functional relevance in the setting of myocardial ischaemia-reperfusion injury (IRI) remains unknown. The present study was undertaken to (1) study the dynamics of production and consumption of persulfides under normoxic and hypoxic conditions in the heart, and (2) determine whether exogenous administration of the CysSSH donor, cysteine trisulfide (Cys-SSS-Cys) at the onset of reperfusion rescues functional impairment and myocardial damage by interfering with lipid peroxidation. Utilising a well-established ex vivo Langendorff murine model, we here demonstrate that endogenous tissue concentrations of CysSSH are upregulated when oxygen supply is compromised (global myocardial ischaemia) and rapidly restored to baseline levels upon reperfusion, suggestive of active regulation. In a separate set of experiments, exogenous administration of Cys-SSS-Cys for 10 min at the onset of reperfusion was found to decrease malondialdehyde (MDA) concentrations, formation of 4-hydroxynonenal (4-HNE) protein adducts and rescue the heart from injury. Cys-SSS-Cys also restored post-ischaemic cardiac function, improving both coronary flow and left ventricular developed pressure (LVDP). Taken together, these results support the notion that endogenous CysSSH plays an important role as a "redox preconditioning" agent to combat the oxidative insult in myocardial IRI.
Subject(s)
Ischemic Preconditioning, Myocardial , Ischemic Preconditioning , Myocardial Reperfusion Injury , Mice , Animals , Myocardial Reperfusion Injury/prevention & control , Myocardial Reperfusion Injury/metabolism , Lipid Peroxidation , Cysteine/metabolism , Myocardium/metabolism , Mammals/metabolismABSTRACT
AIMS: Experimental studies demonstrate protective effects of doxycycline on myocardial ischaemia-reperfusion injury. The trial investigated whether doxycycline administered prior to reperfusion in patients presenting with ST-elevation myocardial infarction (STEMI) reduces infarct size (IS) and ameliorates adverse left ventricular (LV) remodelling. METHODS AND RESULTS: In this randomized, double-blind, placebo-controlled trial, patients presenting with STEMI undergoing primary percutaneous coronary intervention (PPCI) were randomized to either intravenous doxycycline or placebo prior to reperfusion followed by 7 days of oral doxycycline or placebo. The primary outcome was final IS adjusted for area-at-risk (fIS/AAR) measured on two cardiac magnetic resonance scans â¼6 months apart. Of 103 participants, 50 were randomized to doxycycline and 53 to placebo and were matched for age (59 ± 12 vs. 60 ± 10 years), male sex (92% vs. 79%), diabetes mellitus (26% vs. 11%) and left anterior descending artery occlusion (50% vs. 49%), all P > 0.05. Patients treated with doxycycline had a trend for larger fIS/AAR [0.79 (0.5-0.9) vs. 0.61 (0.47-0.76), P = 0.06], larger fIS at 6 months [18.8% (12-26) vs. 13.6% (11-21), P = 0.08], but similar acute IS [21.7% (17-34) vs. 19.4% (14-27), P = 0.19] and AAR [26% (20-36) vs. 24.7% (16-31), P = 0.22] compared with placebo. Doxycycline did not ameliorate adverse LV remodelling [%Δend-diastolic volume index, 1.1% (-3.8-8.4) vs. -1.34% (-6.1-5.8), P = 0.42] and was independently associated with larger fIS (regression coefficient = 0.175, P = 0.03). CONCLUSION: Doxycycline prior to PPCI neither reduced IS acutely or at six months nor attenuated adverse LV remodelling. These data raise safety concerns regarding doxycycline use in STEMI for infarct modulation and healing.
Subject(s)
Myocardial Reperfusion Injury , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Humans , Male , ST Elevation Myocardial Infarction/diagnosis , ST Elevation Myocardial Infarction/drug therapy , ST Elevation Myocardial Infarction/etiology , Doxycycline/therapeutic use , Percutaneous Coronary Intervention/adverse effects , Magnetic Resonance Imaging , Treatment OutcomeABSTRACT
BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine.
Subject(s)
Cardiomyopathies , Cardiomyopathy, Dilated , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/genetics , Creatinine , Female , Fibrosis , Humans , Male , Middle Aged , Proteomics , Stroke VolumeABSTRACT
Autism spectrum disorder (ASD) is a neurodevelopmental impairment characterized by deficits in social interaction skills, impaired communication, and repetitive and restricted behaviors that are thought to be due to altered neurotransmission processes. The amino acid glutamate is an essential excitatory neurotransmitter in the human brain that regulates cognitive functions such as learning and memory, which are usually impaired in ASD. Over the last several years, increasing evidence from genetics, neuroimaging, protein expression, and animal model studies supporting the notion of altered glutamate metabolism has heightened the interest in evaluating glutamatergic dysfunction in ASD. Numerous pharmacological, behavioral, and imaging studies have demonstrated the imbalance in excitatory and inhibitory neurotransmitters, thus revealing the involvement of the glutamatergic system in ASD pathology. Here, we review the effects of genetic alterations on glutamate and its receptors in ASD and the role of non-invasive imaging modalities in detecting these changes. We also highlight the potential therapeutic targets associated with impaired glutamatergic pathways.
Subject(s)
Autism Spectrum Disorder , Animals , Autism Spectrum Disorder/metabolism , Brain/metabolism , Disease Models, Animal , Glutamic Acid/metabolism , Synaptic TransmissionABSTRACT
BACKGROUND AND AIM OF THE WORK: Qatar Biobank (QBB) is actively acquiring data on the range of short- and long-term health impacts associated with COVID-19. This is performed through the COVID-19 biorepository National project. In this report, we describe the most common indications for the referral to Qatar's healthcare system of COVID-19 biorepository participants in comparison with the Qatar Biobank (QBB) general population study. Methods Patients with a laboratory diagnosis of COVID-19, who were Qatar residents that could communicate in Arabic, English, Hindi and Urdu were eligible to participate in the COVID-19 biorepository project. Biological samples of Consented participants were collected on a weekly basis until recovery, and then monthly for a year. Participants were also offered a bone density scan three months after recovery and non-contrast MRI brain and whole-body scan six months after recovery. Number of participants requiring referral for medical follow up after recovery for any abnormal clinically significant findings were recorded and statistically compared to general population referred participants Results: The majority of referrals for the general population study was for osteopenia versus diabetes for the COVID-19 biorepository project Conclusion Descriptive analysis of the referral data of the COVID-19 participants and QBB general population (not previously affected by the virus) shows a clear difference between the two populations' reasons for referrals. Diabetes for COVID 19 recovered participants versus osteopenia for general population Keywords: COVID19, Reason for Referrals, Diabetes, Qatar biobank.
Subject(s)
COVID-19 , Biological Specimen Banks , Delivery of Health Care , Humans , Qatar/epidemiology , Referral and ConsultationABSTRACT
In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal muscle PCr recovery using phosphorus magnetic resonance spectroscopy (31P-MRS) before and after ingestion of a ketone ester drink. We recruited 28 healthy individuals: 12 aged 23-70 years for cardiac 31P-MRS, and 16 aged 60-75 years for skeletal muscle 31P-MRS. Baseline and post-intervention resting cardiac and dynamic skeletal muscle 31P-MRS scans were performed in one visit, where 25 g of the ketone monoester, deltaG®, was administered after the baseline scan. Administration was timed so that post-intervention 31P-MRS would take place 30 min after deltaG® ingestion. The deltaG® ketone drink was well-tolerated by all participants. In participants who provided blood samples, post-intervention blood glucose, lactate and non-esterified fatty acid concentrations decreased significantly (-28.8%, p ⪠0.001; -28.2%, p = 0.02; and -49.1%, p ⪠0.001, respectively), while levels of the ketone body D-beta-hydroxybutyrate significantly increased from mean (standard deviation) 0.7 (0.3) to 4.0 (1.1) mmol/L after 30 min (p ⪠0.001). There were no significant changes in cardiac PCr/ATP or skeletal muscle metabolic parameters between baseline and post-intervention. Acute ketone supplementation caused mild ketosis in blood, with drops in glucose, lactate, and free fatty acids; however, such changes were not associated with changes in 31P-MRS measures in the heart or in skeletal muscle. Future work may focus on the effect of longer-term ketone supplementation on tissue energetics in groups with compromised mitochondrial function.
ABSTRACT
OBJECTIVE: The effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM. METHODS: Prospective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; >14 units/week for women, >21 units/week for men) at cohort enrolment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited. RESULTS: DCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared with patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group: n=92, 94% vs n=306, 61%, p=<0.001). After adjustment for biological sex, moderate excess alcohol was not associated with adverse cardiac structure. There was no difference in midwall myocardial fibrosis between groups. Prior moderate excess alcohol consumption did not affect prognosis (HR 1.29, 95% CI 0.73 to 2.26, p=0.38) during median follow-up of 3.9 years. CONCLUSION: DCM patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation, but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with DCM.
Subject(s)
Cardiomyopathy, Alcoholic , Cardiomyopathy, Dilated , Alcohol Drinking/adverse effects , Cardiomyopathy, Alcoholic/complications , Cardiomyopathy, Dilated/complications , Female , Humans , Male , Prognosis , Prospective Studies , Ventricular Function, Left , Ventricular RemodelingABSTRACT
The immune system is a well-known vital regulator of tumor growth, and one of the main hallmarks of cancer is evading the immune system. Immune system deregulation can lead to immune surveillance evasion, sustained cancer growth, proliferation, and metastasis. Tumor-mediated disruption of the immune system is accomplished by different mechanisms that involve extensive crosstalk with the immediate microenvironment, which includes endothelial cells, immune cells, and stromal cells, to create a favorable tumor niche that facilitates the development of cancer. The essential role of non-coding RNAs such as microRNAs (miRNAs) in the mechanism of cancer cell immune evasion has been highlighted in recent studies. miRNAs are small non-coding RNAs that regulate a wide range of post-transcriptional gene expression in a cell. Recent studies have focused on the function that miRNAs play in controlling the expression of target proteins linked to immune modulation. Studies show that miRNAs modulate the immune response in cancers by regulating the expression of different immune-modulatory molecules associated with immune effector cells, such as macrophages, dendritic cells, B-cells, and natural killer cells, as well as those present in tumor cells and the tumor microenvironment. This review explores the relationship between miRNAs, their altered patterns of expression in tumors, immune modulation, and the functional control of a wide range of immune cells, thereby offering detailed insights on the crosstalk of tumor-immune cells and their use as prognostic markers or therapeutic agents.
Subject(s)
MicroRNAs , Neoplasms , Endothelial Cells/metabolism , Humans , Macrophages/pathology , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasms/pathology , Tumor Microenvironment/geneticsABSTRACT
BACKGROUND: Publicly funded trials do not usually offer financial incentives to volunteers. An intensive level of medical care could act as an additional motivator for participation. Our aim was to establish whether patients may draw any clinical benefit from volunteering in a clinical trial. METHODS: We analysed the recruitment process of a phase II randomised controlled trial, the Inorganic Nitrate in Angina Study. RESULTS: Two-hundred and thirteen patients with a history of stable angina and who had been under at least annual primary care review were screened for participation by history taking, examination, 12-lead electrocardiography, treadmill test and echocardiography. Thirty-five (16.4%) patients were found to have significant unstable or new clinical pathology, requiring urgent clinical attention. We identified 17 (7.9%) patients with unstable angina. Furthermore, we found new undiagnosed pathologies: amyloidosis in two (0.9%), hypertrophic cardiomyopathy in two (0.9%), left ventricular systolic dysfunction (ejection fraction <45%) in three (1.4%), left ventricular thrombus in one (0.4%), significant valvular disease in five (2.4%) and arrhythmias in six (2.8%). CONCLUSION: Compared with routine care, patients screened for a clinical trial may come under an increased level of scrutiny that may affect their clinical management. This may act as additional motivator to attract patients to future studies.
Subject(s)
Electrocardiography , Ventricular Dysfunction, Left , Echocardiography , Exercise Test , Humans , Stroke VolumeABSTRACT
Attention-deficit hyperactivity disorder (ADHD) is a neurological and neurodevelopmental childhood-onset disorder characterized by a persistent pattern of inattentiveness, impulsiveness, restlessness, and hyperactivity. These symptoms may continue in 55-66% of cases from childhood into adulthood. Even though the precise etiology of ADHD is not fully understood, it is considered as a multifactorial and heterogeneous disorder with several contributing factors such as heritability, auxiliary to neurodevelopmental issues, severe brain injuries, neuroinflammation, consanguineous marriages, premature birth, and exposure to environmental toxins. Neuroimaging and neurodevelopmental assessments may help to explore the possible role of genetic variations on ADHD neuropsychobiology. Multiple genetic studies have observed a strong genetic association with various aspects of neuropsychobiological functions, including neural abnormalities and delayed neurodevelopment in ADHD. The advancement in neuroimaging and molecular genomics offers the opportunity to analyze the impact of genetic variations alongside its dysregulated pathways on structural and functional derived brain imaging phenotypes in various neurological and psychiatric disorders, including ADHD. Recently, neuroimaging genomic studies observed a significant association of brain imaging phenotypes with genetic susceptibility in ADHD. Integrating the neuroimaging-derived phenotypes with genomics deciphers various neurobiological pathways that can be leveraged for the development of novel clinical biomarkers, new treatment modalities as well as therapeutic interventions for ADHD patients. In this review, we discuss the neurobiology of ADHD with particular emphasis on structural and functional changes in the ADHD brain and their interactions with complex genomic variations utilizing imaging genetics methodologies. We also highlight the genetic variants supposedly allied with the development of ADHD and how these, in turn, may affect the brain circuit function and related behaviors. In addition to reviewing imaging genetic studies, we also examine the need for complementary approaches at various levels of biological complexity and emphasize the importance of combining and integrating results to explore biological pathways involved in ADHD disorder. These approaches include animal models, computational biology, bioinformatics analyses, and multimodal imaging genetics studies.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Adult , Animals , Attention Deficit Disorder with Hyperactivity/diagnostic imaging , Attention Deficit Disorder with Hyperactivity/genetics , Brain/diagnostic imaging , Child , Genetic Predisposition to Disease , Genetic Variation , Humans , NeuroimagingABSTRACT
INTRODUCTION: Heart failure (HF) in hypertrophic cardiomyopathy (HCM) is associated with high morbidity and mortality. Predictors of HF, in particular the role of myocardial fibrosis and microvascular ischemia remain unclear. We assessed the predictive value of cardiovascular magnetic resonance (CMR) for development of HF in HCM in an observational cohort study. METHODS: Serial patients with HCM underwent CMR, including adenosine first-pass perfusion, left atrial (LA) and left ventricular (LV) volumes indexed to body surface area (i) and late gadolinium enhancement (%LGE- as a % of total myocardial mass). We used a composite endpoint of HF death, cardiac transplantation, and progression to NYHA class III/IV. RESULTS: A total of 543 patients with HCM underwent CMR, of whom 94 met the composite endpoint at baseline. The remaining 449 patients were followed for a median of 5.6 years. Thirty nine patients (8.7%) reached the composite endpoint of HF death (n = 7), cardiac transplantation (n = 2) and progression to NYHA class III/IV (n = 20). The annual incidence of HF was 2.0 per 100 person-years, 95% CI (1.6-2.6). Age, previous non-sustained ventricular tachycardia, LV end-systolic volume indexed to body surface area (LVESVI), LA volume index ; LV ejection fraction, %LGE and presence of mitral regurgitation were significant univariable predictors of HF, with LVESVI (Hazard ratio (HR) 1.44, 95% confidence interval (95% CI) 1.16-1.78, p = 0.001), %LGE per 10% (HR 1.44, 95%CI 1.14-1.82, p = 0.002) age (HR 1.37, 95% CI 1.06-1.77, p = 0.02) and mitral regurgitation (HR 2.6, p = 0.02) remaining independently predictive on multivariable analysis. The presence or extent of inducible perfusion defect assessed using a visual score did not predict outcome (p = 0.16, p = 0.27 respectively). DISCUSSION: The annual incidence of HF in a contemporary ambulatory HCM population undergoing CMR is low. Myocardial fibrosis and LVESVI are strongly predictive of future HF, however CMR visual assessment of myocardial perfusion was not.
Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Coronary Circulation , Heart Failure/etiology , Magnetic Resonance Imaging , Microcirculation , Myocardial Perfusion Imaging , Myocardium/pathology , Adult , Aged , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/pathology , Cardiomyopathy, Hypertrophic/physiopathology , Disease Progression , Female , Fibrosis , Heart Failure/physiopathology , Humans , Male , Middle Aged , Predictive Value of Tests , Prognosis , Registries , Retrospective Studies , Risk Assessment , Risk Factors , Stroke Volume , Time Factors , Ventricular Function, LeftABSTRACT
Cardiovascular disease remains the leading cause of death worldwide despite major advances in technology and treatment, with coronary heart disease (CHD) being a key contributor. Following an acute myocardial infarction (AMI), it is imperative that blood flow is rapidly restored to the ischaemic myocardium. However, this restoration is associated with an increased risk of additional complications and further cardiomyocyte death, termed myocardial ischaemia reperfusion injury (IRI). Endogenously produced nitric oxide (NO) plays an important role in protecting the myocardium from IRI. It is well established that NO mediates many of its downstream functions through the 'canonical' NO-sGC-cGMP pathway, which is vital for cardiovascular homeostasis; however, this pathway can become impaired in the face of inadequate delivery of necessary substrates, in particular L-arginine, oxygen and reducing equivalents. Recently, it has been shown that during conditions of ischaemia an alternative pathway for NO generation exists, which has become known as the 'nitrate-nitrite-NO pathway'. This pathway has been reported to improve endothelial dysfunction, protect against myocardial IRI and attenuate infarct size in various experimental models. Furthermore, emerging evidence suggests that nitrite itself provides multi-faceted protection, in an NO-independent fashion, against a myriad of pathophysiologies attributed to IRI. In this review, we explore the existing pre-clinical and clinical evidence for the role of nitrate and nitrite in cardioprotection and discuss the lessons learnt from the clinical trials for nitrite as a perconditioning agent. We also discuss the potential future for nitrite as a pre-conditioning intervention in man.
Subject(s)
Cardiotonic Agents , Myocardial Reperfusion Injury , Nitrites , Cardiotonic Agents/pharmacology , Clinical Trials as Topic , Humans , Myocardial Reperfusion Injury/prevention & control , Nitrites/pharmacologyABSTRACT
BACKGROUND: Nicotinamide adenine dinucleotide (NAD+), a critical coenzyme present in every living cell, is involved in a myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD+ is often studied in the context of aging, cancer, and neurodegenerative and metabolic disorders. SCOPE OF REVIEW: Cellular NAD+ depletion is associated with compromised adaptive cellular stress responses, impaired neuronal plasticity, impaired DNA repair, and cellular senescence. Increasing evidence has shown the efficacy of boosting NAD+ levels using NAD+ precursors in various diseases. This review provides a comprehensive understanding into the role of NAD+ in aging and other pathologies and discusses potential therapeutic targets. MAJOR CONCLUSIONS: An alteration in the NAD+/NADH ratio or the NAD+ pool size can lead to derailment of the biological system and contribute to various neurodegenerative disorders, aging, and tumorigenesis. Due to the varied distribution of NAD+/NADH in different locations within cells, the direct role of impaired NAD+-dependent processes in humans remains unestablished. In this regard, longitudinal studies are needed to quantify NAD+ and its related metabolites. Future research should focus on measuring the fluxes through pathways associated with NAD+ synthesis and degradation.
Subject(s)
Metabolic Networks and Pathways , NAD/metabolism , Signal Transduction , Aging/metabolism , Animals , Energy Metabolism , Humans , Metabolic Diseases/metabolism , Mitochondria/metabolism , Neoplasms/metabolism , Neurodegenerative Diseases/metabolism , SirtuinsABSTRACT
Circular RNAs (circRNAs) are an evolutionarily conserved novel class of non-coding endogenous RNAs (ncRNAs) found in the eukaryotic transcriptome, originally believed to be aberrant RNA splicing by-products with decreased functionality. However, recent advances in high-throughput genomic technology have allowed circRNAs to be characterized in detail and revealed their role in controlling various biological and molecular processes, the most essential being gene regulation. Because of the structural stability, high expression, availability of microRNA (miRNA) binding sites and tissue-specific expression, circRNAs have become hot topic of research in RNA biology. Compared to the linear RNA, circRNAs are produced differentially by backsplicing exons or lariat introns from a pre-messenger RNA (mRNA) forming a covalently closed loop structure missing 3' poly-(A) tail or 5' cap, rendering them immune to exonuclease-mediated degradation. Emerging research has identified multifaceted roles of circRNAs as miRNA and RNA binding protein (RBP) sponges and transcription, translation, and splicing event regulators. CircRNAs have been involved in many human illnesses, including cancer and neurodegenerative disorders such as Alzheimer's and Parkinson's disease, due to their aberrant expression in different pathological conditions. The functional versatility exhibited by circRNAs enables them to serve as potential diagnostic or predictive biomarkers for various diseases. This review discusses the properties, characterization, profiling, and the diverse molecular mechanisms of circRNAs and their use as potential therapeutic targets in different human malignancies.