ABSTRACT
Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans1. Atrial-tissue fibrosis is a central pathophysiological feature of atrial fibrillation that also hampers its treatment; the underlying molecular mechanisms are poorly understood and warrant investigation given the inadequacy of present therapies2. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism3, is also produced by atrial cardiomyocytes in substantial quantities and acts as a paracrine signal that affects neighbouring collagen-producing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of calcitonin receptor signalling in mice causes atrial fibrosis and increases susceptibility to atrial fibrillation. In mice in which liver kinase B1 is knocked down specifically in the atria, atrial-specific knockdown of calcitonin promotes atrial fibrosis and increases and prolongs spontaneous episodes of atrial fibrillation, whereas atrial-specific overexpression of calcitonin prevents both atrial fibrosis and fibrillation. Human patients with persistent atrial fibrillation show sixfold lower levels of myocardial calcitonin compared to control individuals with normal heart rhythm, with loss of calcitonin receptors in the fibroblast membrane. Although transcriptome analysis of human atrial fibroblasts reveals little change after exposure to calcitonin, proteomic analysis shows extensive alterations in extracellular matrix proteins and pathways related to fibrogenesis, infection and immune responses, and transcriptional regulation. Strategies to restore disrupted myocardial calcitonin signalling thus may offer therapeutic avenues for patients with atrial fibrillation.
Subject(s)
Arrhythmias, Cardiac/metabolism , Calcitonin/metabolism , Fibrinogen/biosynthesis , Heart Atria/metabolism , Myocardium/metabolism , Paracrine Communication , Animals , Arrhythmias, Cardiac/pathology , Arrhythmias, Cardiac/physiopathology , Atrial Fibrillation , Collagen Type I/metabolism , Female , Fibroblasts/metabolism , Fibrosis/metabolism , Fibrosis/pathology , Heart Atria/cytology , Heart Atria/pathology , Heart Atria/physiopathology , Humans , Male , Mice , Myocardium/cytology , Myocardium/pathology , Myocytes, Cardiac/metabolism , Receptors, Calcitonin/metabolismABSTRACT
Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia of the cardiac muscle, which results in myocardial infarction (MI). Junctophilin-2 (JPH2) is a membrane protein that ensures efficient calcium handling and proper excitation-contraction coupling. Studies have identified loss of JPH2 due to calpain-mediated proteolysis as a key pathogenic event in ischemia-induced heart failure (HF). Our findings show that calpain-2-mediated JPH2 cleavage yields increased levels of a C-terminal cleaved peptide (JPH2-CTP) in patients with ischemic cardiomyopathy and mice with experimental MI. We created a novel knock-in mouse model by removing residues 479-SPAGTPPQ-486 to prevent calpain-2-mediated cleavage at this site. Functional and molecular assessment of cardiac function post-MI in cleavage site deletion (CSD) mice showed preserved cardiac contractility and reduced dilation, reduced JPH2-CTP levels, attenuated adverse remodeling, improved T-tubular structure, and normalized SR Ca2+-handling. Adenovirus mediated calpain-2 knockdown in mice exhibited similar findings. Pulldown of CTP followed by proteomic analysis revealed valosin-containing protein (VCP) and BAG family molecular chaperone regulator 3 (BAG3) as novel binding partners of JPH2. Together, our findings suggest that blocking calpain-2-mediated JPH2 cleavage may be a promising new strategy for delaying the development of HF following MI.
Subject(s)
Calpain , Heart Failure , Membrane Proteins , Myocardial Infarction , Animals , Calpain/metabolism , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Heart Failure/metabolism , Heart Failure/etiology , Humans , Mice , Membrane Proteins/metabolism , Membrane Proteins/genetics , Disease Progression , Male , Disease Models, Animal , Proteolysis , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Muscle ProteinsABSTRACT
BACKGROUND: Left ventricular assist devices (LVAD) represent an important therapeutic option for patients progressing to end-stage heart failure. Women have been historically underrepresented in LVAD studies, and have been reported to have worse outcomes despite technological optimisation. We aimed to systematically explore the evidence on sex disparities in the use and outcomes of LVAD implantation. METHODS: A systematic database search with meta-analysis was conducted of comparative original articles of men versus women undergoing LVAD implantation, in EMBASE, MEDLINE, Cochrane database and Google Scholar, from inception to July 2022. Primary outcomes were stroke (haemorrhagic and ischaemic) and early/overall mortality. Secondary outcomes were LVAD thrombosis, right VAD implantation, major bleeding, kidney dysfunction, and device/driveline infection. RESULTS: Our search yielded 137 relevant studies, including 22 meeting the inclusion criteria with a total of 53 227 patients (24.2% women). Overall mortality was higher in women (odds ratio [OR] 1.35, 95% confidence interval [CI] 1.05-1.62, p = 0.02), as was overall stroke (OR 1.32, 95%CI 1.06-1.66, p = 0.01), including ischemic (OR 1.80, 95%CI 1.22-2.64, p = 0.003) and haemorrhagic (OR 1.72, 95%CI 1.09-2.70, p = 0.02). Women had more frequent right VAD implantation (OR 2.11, 95%CI 1.24-3.57, p = 0.006) and major bleeding (OR 1.40, 95%CI 1.06-1.85, p = 0.02). Kidney dysfunction, LVAD thrombosis, and device/driveline infections were comparable between sexes. CONCLUSIONS: Our analysis suggests that women face a greater risk of adverse events and mortality post-LVAD implantation. Although the mechanisms remain unclear, the difference in outcomes is thought to be multifactorial. Further research, that includes comprehensive pre-operative characteristics and post-operative outcomes, is encouraged.
Subject(s)
Heart Failure , Heart-Assist Devices , Stroke , Thoracic Surgical Procedures , Male , Humans , Female , Heart-Assist Devices/adverse effects , Heart Failure/surgery , Heart Failure/complications , Stroke/etiology , Hemorrhage/etiology , Retrospective Studies , Treatment OutcomeABSTRACT
OBJECTIVES: Development in device technology and the scarcity of donor's hearts have increased the number of patients with advanced heart failure receiving durable left ventricular assist devices (LVADs) as a bridge to transplantation and destination therapy, with improved prognosis compared with guideline-directed medical therapy. We sought to examine the impact of modern durable LVADs on the quality of life (QoL) of the recipients. METHODS: We carried out a systematic review of articles on QoL following the implantation of third-generation LVADs published between January 2010 and February 2021. Included studies were critically analyzed and evidence synthesis was carried out into a meta-analysis. RESULTS: The systematic search yielded 269 articles, 11 of which met the search predefined criteria. Three of them reported results of randomized trials and eight were retrospective and registry studies. Statistically significant QoL improvement from baseline was observed in all published reports. When using the EuroQol 5L questionnaire (scale 0-100) as a QoL tool 6 months post-LVAD implantation, a meta-analysis of four included studies demonstrated a mean difference increase of 28.9 points (95% confidence interval: 26.71-31.14). CONCLUSIONS: Third-generation LVADs confer a significant improvement in QoL and their use can be supported not only for prognosis but also for symptom control. Although methodological limitations should be considered, the available QoL outcomes can be a useful tool in patient selection and the decision-making process.
Subject(s)
Heart Failure , Heart-Assist Devices , Heart Failure/surgery , Humans , Quality of Life , Registries , Retrospective StudiesABSTRACT
AIMS: Operability of type A acute aortic dissections (TAAAD) is currently based on non-standardized decision-making process, and it lacks a disease-specific risk evaluation model that can predict mortality. We investigated patient, intraoperative data, surgeon, and centre-related variables for patients who underwent TAAAD in the UK. METHODS AND RESULTS: We identified 4203 patients undergoing TAAAD surgery in the UK (2009-18), who were enrolled into the UK National Adult Cardiac Surgical Audit dataset. The primary outcome was operative mortality. A multivariable logistic regression analysis was performed with fast backward elimination of variables and the bootstrap-based optimism-correction was adopted to assess model performance. Variation related to hospital or surgeon effects were quantified by a generalized mixed linear model and risk-adjusted funnel plots by displaying the individual standardized mortality ratio against expected deaths. Final variables retained in the model were: age [odds ratio (OR) 1.02, 95% confidence interval (CI) 1.02-1.03; P < 0.001]; malperfusion (OR 1.79, 95% CI 1.51-2.12; P < 0.001); left ventricular ejection fraction (moderate: OR 1.40, 95% CI 1.14-1.71; P = 0.001; poor: OR 2.83, 95% CI 1.90-4.21; P < 0.001); previous cardiac surgery (OR 2.29, 95% CI 1.71-3.07; P < 0.001); preoperative mechanical ventilation (OR 2.76, 95% CI 2.00-3.80; P < 0.001); preoperative resuscitation (OR 3.36, 95% CI 1.14-9.87; P = 0.028); and concomitant coronary artery bypass grafting (OR 2.29, 95% CI 1.86-2.83; P < 0.001). We found a significant inverse relationship between surgeons but not centre annual volume with outcomes. CONCLUSIONS: Patient characteristics, intraoperative factors, cardiac centre, and high-volume surgeons are strong determinants of outcomes following TAAAD surgery. These findings may help refining clinical decision-making, supporting patient counselling and be used by policy makers for quality assurance and service provision improvement.
Subject(s)
Aortic Dissection , Cardiac Surgical Procedures , Adult , Aortic Dissection/surgery , Hospital Mortality , Humans , Postoperative Complications , Retrospective Studies , Risk Factors , Stroke Volume , Treatment Outcome , United Kingdom/epidemiology , Ventricular Function, LeftABSTRACT
AIMS: Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans. METHODS AND RESULTS: Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2.-) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2.- production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM. CONCLUSIONS: We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin.
Subject(s)
Canagliflozin , Sodium-Glucose Transporter 2 Inhibitors , Canagliflozin/metabolism , Canagliflozin/pharmacology , Humans , Myocardium , Myocytes, Cardiac/metabolism , Oxidation-Reduction , Sodium-Glucose Transporter 2 Inhibitors/pharmacologyABSTRACT
BACKGROUND: Why some but not all patients with severe aortic stenosis (SevAS) develop otherwise unexplained reduced systolic function is unclear. We investigate the hypothesis that reduced creatine kinase (CK) capacity and flux is associated with this transition. METHODS: We recruited 102 participants to 5 groups: moderate aortic stenosis (ModAS) (n=13), SevAS, left ventricular (LV) ejection fraction ≥55% (SevAS-preserved ejection fraction, n=37), SevAS, LV ejection fraction <55% (SevAS-reduced ejection fraction, n=15), healthy volunteers with nonhypertrophied hearts with normal systolic function (normal healthy volunteer, n=30), and patients with nonhypertrophied, non-pressure-loaded hearts with normal systolic function undergoing cardiac surgery and donating LV biopsy (non-pressure-loaded heart biopsy, n=7). All underwent cardiac magnetic resonance imaging and 31P magnetic resonance spectroscopy for myocardial energetics. LV biopsies (AS and non-pressure-loaded heart biopsy) were analyzed for CK total activity, CK isoforms, citrate synthase activity, and total creatine. Mitochondria-sarcomere diffusion distances were calculated by using serial block-face scanning electron microscopy. RESULTS: In the absence of failure, CK flux was lower in the presence of AS (by 32%, P=0.04), driven primarily by reduction in phosphocreatine/ATP (by 17%, P<0.001), with CK kf unchanged (P=0.46). Although lowest in the SevAS-reduced ejection fraction group, CK flux was not different from the SevAS-preserved ejection fraction group (P>0.99). Accompanying the fall in CK flux, total CK and citrate synthase activities and the absolute activities of mitochondrial-type CK and CK-MM isoforms were also lower (P<0.02, all analyses). Median mitochondria-sarcomere diffusion distances correlated well with CK total activity (r=0.86, P=0.003). CONCLUSIONS: Total CK capacity is reduced in SevAS, with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo magnetic resonance spectroscopy measures of resting CK flux suggest that ATP delivery is reduced earlier, at the moderate AS stage, where LV function remains preserved. These findings show that significant energetic impairment is already established in moderate AS and suggest that a fall in CK flux is not by itself a necessary cause of transition to systolic failure. However, because ATP demands increase with AS severity, this could increase susceptibility to systolic failure. As such, targeting CK capacity and flux may be a therapeutic strategy to prevent and treat systolic failure in AS.
Subject(s)
Aortic Valve Stenosis/blood , Creatine Kinase/blood , Energy Metabolism/physiology , Stroke Volume/physiology , Ventricular Dysfunction, Left/blood , Ventricular Function, Left/physiology , Adenosine Triphosphate/blood , Adult , Aged , Aged, 80 and over , Aortic Valve Stenosis/diagnosis , Aortic Valve Stenosis/physiopathology , Biomarkers/blood , Female , Humans , Magnetic Resonance Spectroscopy/methods , Male , Middle Aged , Prospective Studies , Ventricular Dysfunction, Left/diagnosis , Ventricular Dysfunction, Left/physiopathologyABSTRACT
Left ventricular (LV) rupture after radiofrequency catheter ablation (RFCA) is a rare but life-threatening complication. We describe a case of LV rupture secondary to RFCA successfully treated with a transaortic, intraventricular patch exclusion surgical repair, assisted by transoesophageal echocardiography and epicardial ultrasound assessment. Patch exclusion technique can offer a physiological repair with better preservation of myocardial mechanical characteristics and possibly less damage to healthy myocardium and surrounding structures.
Subject(s)
Catheter Ablation , Catheter Ablation/adverse effects , Echocardiography, Transesophageal , Heart Ventricles/diagnostic imaging , Heart Ventricles/surgery , Humans , Treatment OutcomeABSTRACT
OBJECTIVES: To identify clinical and procedural practice predictors of avoidable complications during transcatheter aortic valve replacement (TAVR). BACKGROUND: TAVR is evolving as a viable strategy for treatment of aortic stenosis (AS). Vascular complications, major bleeding, or pericardial tamponade may be influenced by procedural practice. METHODS: The Oxford TAVR (OxTAVI) prospective registry was retrospectively analyzed to identify predictors of avoidable procedural complications in a contemporary cohort of transfemoral TAVR between January 2015 and September 2018. The primary endpoint was defined as a hierarchic composite of in-hospital mortality, pericardial effusion/cardiac tamponade, major bleeding, and vascular access complications. Individual components of the primary endpoint have been analyzed separately. RESULTS: Five-hundred-twenty-nine patients underwent transfemoral TAVR using contemporary techniques during the study period and were enrolled in the OxTAVI registry. Female sex and high frailty were associated with a higher risk of death, major bleeding, vascular complication or pericardial tamponade. The use of ultrasound (US) guidance for vascular access management was independently associated with a reduced composite primary endpoint (OR = 0.35, CI:0.14-0.86, p = .02) after adjustment for clinical confounders, largely driven by a threefold reduction in vascular access complication (OR = 0.29, CI:0.15-0.55, p < .001). Performing rapid pacing via the left ventricle guidewire (LV-GW) was associated with a significant decrease in the risk of cardiac tamponade/pericardial effusion (OR = 0.19, CI:0.05-0.66, p = .009). CONCLUSION: US-guided vascular access management and rapid pacing via the LV-GW are important determinants of reduced procedural complications during TAVR.
Subject(s)
Aortic Valve Stenosis/surgery , Cardiac Pacing, Artificial , Postoperative Complications/prevention & control , Transcatheter Aortic Valve Replacement , Ultrasonography, Interventional , Ventricular Function, Left , Aged , Aged, 80 and over , Aortic Valve Stenosis/diagnostic imaging , Aortic Valve Stenosis/mortality , Aortic Valve Stenosis/physiopathology , Cardiac Pacing, Artificial/adverse effects , Cardiac Pacing, Artificial/mortality , Female , Frail Elderly , Frailty/mortality , Hospital Mortality , Humans , Male , Postoperative Complications/mortality , Registries , Retrospective Studies , Risk Assessment , Risk Factors , Severity of Illness Index , Sex Factors , Time Factors , Transcatheter Aortic Valve Replacement/adverse effects , Transcatheter Aortic Valve Replacement/mortality , Treatment Outcome , Ultrasonography, Interventional/adverse effects , Ultrasonography, Interventional/mortalityABSTRACT
We report a case of culture-negative aortic valve endocarditis secondary to Tropheryma whipplei infection. Our patient underwent aortic valve replacement after 4 weeks of antibiotic therapy with persistently negative blood culture results. Despite a technically uneventful operation, the patient showed continued sepsis and was unresponsive to a broad-spectrum of antibiotic therapy with subsequent multiorgan failure. He died on the 5th postoperative day, and diagnosis was established at postmortem examination. In this case report, we discuss the diagnosis and treatment of a rare type of endocarditis caused by T. whipplei.
Subject(s)
Aortic Valve/surgery , Endocarditis, Bacterial/microbiology , Endocarditis, Bacterial/surgery , Tropheryma , Whipple Disease , Anti-Bacterial Agents/administration & dosage , Endocarditis, Bacterial/complications , Endocarditis, Bacterial/drug therapy , Fatal Outcome , Heart Valve Prosthesis Implantation , Humans , Male , Middle Aged , Multiple Organ Failure/etiology , Rare DiseasesABSTRACT
INTRODUCTION: Arterial graft physiology influences the long-term outcome of coronary artery bypass grafting (CABG). We studied factors that can affect the overall resistance to flow using internal mammary artery grafting to the left anterior descending artery. METHODS: This was a prospective, nonrandomized observational study of 100 consecutive patients who underwent elective on-pump isolated or combined valve surgery and CABG. Coronary stenoses were assessed using conventional and quantitative coronary angiography assessment. The flow and pulsatility index (PI) of the grafts were assessed by transit-time flowmetry during cardioplegic arrest and at the end of the operation. Fractional polynomials were used to explore linearity, followed by multivariable regression analysis. RESULTS: Univariate analysis demonstrated higher flows at the end of the operation in patients who had higher flows with the cross-clamp on (P < .001), in males (P = .004), in patients with a low PI at the end of the operation (P = .04), and in patients with a larger size of the recipient artery (P = .005). Multivariable regression analysis showed that the graft flow at the end of the operation was significantly associated with the mean flow with the cross-clamp on (P < .001), sex (P = .003), and PI at the end of the operation (P = .003). Concomitant valve surgery did not influence flows. Male patients had 18 mL/min higher flow. CONCLUSIONS: The graft flow at the end of the operation can be determined by the flow with the cross-clamp on, the PI with the cross-clamp off and coronary artery. We reported differences in the graft flows between sexes, and for first the time, we introduced the concepts of "adequate flow" and "resistance-to-forward-flow" for patent coronary grafts.
Subject(s)
Coronary Artery Bypass/methods , Mammary Arteries/transplantation , Vascular Patency , Aged , Blood Flow Velocity , Female , Humans , Male , Mammary Arteries/physiology , Multivariate Analysis , Sex CharacteristicsABSTRACT
Changes in the kinetics of the creatine kinase (CK) shuttle are sensitive markers of cardiac energetics but are typically measured at rest and in the prone position. This study aims to measure CK kinetics during pharmacological stress at 3 T, with measurement in the supine position. A shorter "stressed saturation transfer" (StreST) extension to the triple repetition time saturation transfer (TRiST) method is proposed. We assess scanning in a supine position and validate the MR measurement against biopsy assay of CK activity. We report normal ranges of stress CK forward rate (kfCK ) for healthy volunteers and obese patients. TRiST measures kfCK in 40 min at 3 T. StreST extends the previously developed TRiST to also make a further kfCK measurement during <20 min of dobutamine stress. We test our TRiST implementation in skeletal muscle and myocardium in both prone and supine positions. We evaluate StreST in the myocardium of six healthy volunteers and 34 obese subjects. We validated MR-measured kfCK against biopsy assays of CK activity. TRiST kfCK values matched literature values in skeletal muscle (kfCK = 0.25 ± 0.03 s-1 vs 0.27 ± 0.03 s-1 ) and myocardium when measured in the prone position (0.32 ± 0.15 s-1 ), but a significant difference was found for TRiST kfCK measured supine (0.24 ± 0.12 s-1 ). This difference was because of different respiratory- and cardiac-motion-induced B0 changes in the two positions. Using supine TRiST, cardiac kfCK values for normal-weight subjects were 0.15 ± 0.09 s-1 at rest and 0.17 ± 0.15 s-1 during stress. For obese subjects, kfCK was 0.16 ± 0.07 s-1 at rest and 0.17 ± 0.10 s-1 during stress. Rest myocardial kfCK and CK activity from LV biopsies of the same subjects correlated (R = 0.43, p = 0.03). We present an independent implementation of TRiST on the Siemens platform using a commercially available coil. Our extended StreST protocol enables cardiac kfCK to be measured during dobutamine-induced stress in the supine position.
Subject(s)
Creatine Kinase/metabolism , Heart/physiopathology , Magnetic Resonance Spectroscopy , Rest , Stress, Physiological , Adult , Biopsy , Case-Control Studies , Female , Humans , Kinetics , Male , Middle Aged , Myocardium/metabolism , Obesity/enzymology , Obesity/physiopathology , Posture , Reproducibility of Results , RespirationABSTRACT
RATIONALE: Adiponectin has anti-inflammatory effects in experimental models, but its role in the regulation of myocardial redox state in humans is unknown. Although adiponectin is released from epicardial adipose tissue (EpAT), it is unclear whether it exerts any paracrine effects on the human myocardium. OBJECTIVE: To explore the cross talk between EpAT-derived adiponectin and myocardial redox state in the human heart. METHODS AND RESULTS: EpAT and atrial myocardium were obtained from 306 patients undergoing coronary artery bypass grafting. Functional genetic polymorphisms that increase ADIPOQ expression (encoding adiponectin) led to reduced myocardial nicotinamide adenine dinucleotide phosphate oxidase-derived O2 (-), whereas circulating adiponectin and ADIPOQ expression in EpAT were associated with elevated myocardial O2 (-). In human atrial tissue, we demonstrated that adiponectin suppresses myocardial nicotinamide adenine dinucleotide phosphate oxidase activity, by preventing AMP kinase-mediated translocation of Rac1 and p47(phox) from the cytosol to the membranes. Induction of O2 (-) production in H9C2 cardiac myocytes led to the release of a transferable factor able to induce peroxisome proliferator-activated receptor-γ-mediated upregulation of ADIPOQ expression in cocultured EpAT. Using a NOX2 transgenic mouse and a pig model of rapid atrial pacing, we found that oxidation products (such as 4-hydroxynonenal) released from the heart trigger peroxisome proliferator-activated receptor-γ-mediated upregulation of ADIPOQ in EpAT. CONCLUSIONS: We demonstrate for the first time in humans that adiponectin directly decreases myocardial nicotinamide adenine dinucleotide phosphate oxidase activity via endocrine or paracrine effects. Adiponectin expression in EpAT is controlled by paracrine effects of oxidation products released from the heart. These effects constitute a novel defense mechanism of the heart against myocardial oxidative stress.
Subject(s)
Adiponectin/biosynthesis , Adipose Tissue/metabolism , Myocardium/metabolism , PPAR gamma/biosynthesis , Pericardium/metabolism , Adipose Tissue/cytology , Animals , Cell Line , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myocardium/cytology , Organ Culture Techniques , Oxidation-Reduction , Pericardium/cytology , Rats , SwineABSTRACT
AIMS: Experimental evidence suggests that telomere length (TL) is shortened by oxidative DNA damage, reflecting biological aging. We explore the value of blood (BTL) and vascular TL (VTL) as biomarkers of systemic/vascular oxidative stress in humans and test the clinical predictive value of BTL in acute myocardial infarction (AMI). METHODS AND RESULTS: In a prospective cohort of 290 patients surviving recent AMI, BTL measured on admission was a strong predictor of all-cause [hazard ratio (HR) [95% confidence interval (CI)]: 3.21 [1.46-7.06], P = 0.004] and cardiovascular mortality (HR [95% CI]: 3.96 [1.65-9.53], P = 0.002) 1 year after AMI (for comparisons of short vs. long BTL, as defined by a T/S ratio cut-off of 0.916, calculated using receiver operating characteristic analysis; P adjusted for age and other predictors). To explore the biological meaning of these findings, BTL was quantified in 727 consecutive patients undergoing coronary artery bypass grafting (CABG), and superoxide (O2.-) was measured in peripheral blood mononuclear cells (PBMNC). VTL/vascular O2.- were quantified in saphenous vein (SV) and mammary artery (IMA) segments. Patients were genotyped for functional genetic polymorphisms in P22ph°x (activating NADPH-oxidases) and vascular smooth muscle cells (VSMC) selected by genotype were cultured from vascular tissue. Short BTL was associated with high O2.- in PBMNC (P = 0.04) but not in vessels, whereas VTL was related to O2.- in IMA (ρ = -0.49, P = 0.004) and SV (ρ = -0.52, P = 0.01). Angiotensin II (AngII) incubation of VSMC (30 days), as a means of stimulating NADPH-oxidases, increased O2.- and reduced TL in carriers of the high-responsiveness P22ph°x alleles (P = 0.007). CONCLUSION: BTL predicts cardiovascular outcomes post-AMI, independently of age, whereas VTL is a tissue-specific (rather than a global) biomarker of vascular oxidative stress. The lack of a strong association between BTL and VTL reveals the importance of systemic vs. vascular factors in determining clinical outcomes after AMI.
Subject(s)
Myocardial Infarction/mortality , Oxidative Stress/physiology , Telomere/physiology , Aged , Biomarkers/metabolism , Cardiovascular Diseases/mortality , Female , Humans , Leukocytes, Mononuclear/metabolism , Male , Mammary Arteries/metabolism , Middle Aged , Muscle, Smooth, Vascular/metabolism , Myocardial Infarction/genetics , NADPH Oxidases/metabolism , Oxidative Stress/genetics , Polymorphism, Genetic/genetics , Prognosis , Prospective Studies , Saphenous Vein/metabolism , Superoxides/metabolismABSTRACT
BACKGROUND: Perfusion cardiovascular magnetic resonance (CMR) performed with inadequate adenosine stress leads to false-negative results and suboptimal clinical management. The recently proposed marker of adequate stress, the "splenic switch-off" sign, detects splenic blood flow attenuation during stress perfusion (spleen appears dark), but can only be assessed after gadolinium first-pass, when it is too late to optimize the stress response. Reduction in splenic blood volume during adenosine stress is expected to shorten native splenic T1, which may predict splenic switch-off without the need for gadolinium. METHODS: Two-hundred and twelve subjects underwent adenosine stress CMR: 1.5 T (n = 104; 75 patients, 29 healthy controls); 3 T (n = 108; 86 patients, 22 healthy controls). Native T1spleen was assessed using heart-rate-independent ShMOLLI prototype sequence at rest and during adenosine stress (140 µg/kg/min, 4 min, IV) in 3 short-axis slices (basal, mid-ventricular, apical). This was compared with changes in peak splenic perfusion signal intensity (ΔSIspleen) and the "splenic switch-off" sign on conventional stress/rest gadolinium perfusion imaging. T1spleen values were obtained blinded to perfusion ΔSIspleen, both were derived using regions of interest carefully placed to avoid artefacts and partial-volume effects. RESULTS: Normal resting splenic T1 values were 1102 ± 66 ms (1.5 T) and 1352 ± 114 ms (3 T), slightly higher than in patients (1083 ± 59 ms, p = 0.04; 1295 ± 105 ms, p = 0.01, respectively). T1spleen decreased significantly during adenosine stress (mean ΔT1spleen ~ -40 ms), independent of field strength, age, gender, and cardiovascular diseases. While ΔT1spleen correlated strongly with ΔSIspleen (rho = 0.70, p < 0.0001); neither indices showed significant correlations with conventional hemodynamic markers (rate pressure product) during stress. By ROC analysis, a ΔT1spleen threshold of ≥ -30 ms during stress predicted the "splenic switch-off" sign (AUC 0.90, p < 0.0001) with sensitivity (90%), specificity (88%), accuracy (90%), PPV (98%), NPV (42%). CONCLUSIONS: Adenosine stress and rest splenic T1-mapping is a novel method for assessing stress responses, independent of conventional hemodynamic parameters. It enables prediction of the visual "splenic switch-off" sign without the need for gadolinium, and correlates well to changes in splenic signal intensity during stress/rest perfusion imaging. ΔT1spleen holds promise to facilitate optimization of stress responses before gadolinium first-pass perfusion CMR.
Subject(s)
Adenosine/administration & dosage , Heart Diseases/diagnostic imaging , Magnetic Resonance Imaging , Myocardial Perfusion Imaging/methods , Spleen/blood supply , Spleen/diagnostic imaging , Vasodilator Agents/administration & dosage , Adult , Aged , Area Under Curve , Case-Control Studies , Contrast Media/administration & dosage , Coronary Circulation , False Negative Reactions , Female , Gadolinium/administration & dosage , Heart Diseases/physiopathology , Heart Rate , Hemodynamics , Humans , Male , Middle Aged , Predictive Value of Tests , ROC Curve , Reproducibility of Results , Splanchnic CirculationABSTRACT
BACKGROUND: The management of atrial fibrillation remains a challenge. This condition remodels atrial electrical properties, which promote resistance to treatment. Although remodelling has long been a therapeutic target in atrial fibrillation, its causes remain incompletely understood. We aimed to evaluate the role of miR-31-dependent reduction in dystrophin and neuronal nitric oxide synthase (nNOS, also known as NOS1) on atrial electrical properties and atrial fibrillation inducibility. METHODS: We recruited 258 patients (209 patients in sinus rhythm and 49 with permanent atrial fibrillation) from the John Radcliffe Hospital, Oxford, UK; written informed consent was obtained from each participant. We also used a goat model of pacing-induced atrial fibrillation (24 with atrial fibrillation vs 20 controls in normal sinus rythm) and nNos-knock-out mice (n=28 compared with 27 wild-type littermates). Gene expression of miR-31, dystrophin, and nNOS was assessed by quantitative RT-PCR; protein content was measured by immunoblotting; NOS activity was evaluated with high-performance liquid chromatography; action potential duration (APD) and rate dependent adaptation were assessed by single-cell patch-clamping, and atrial fibrillation inducibility was evaluated by transoesophageal atrial burst stimulation. FINDINGS: We found that atrial-specific upregulation of miR-31 in human atrial fibrillation caused dystrophin (DYS) translational repression and accelerated mRNA degradation of nNOS leading to a profound reduction in atrial DYS and nNOS protein content and in nitric oxide availability. In human atrial myocytes obtained from patients in sinus rhythm, nNOS inhibition was sufficient to recapitulate hallmark features of remodelling induced by atrial fibrillation, such as shortening of APD and loss of APD rate-dependency, but had no effect in patients with atrial fibrillation. In mice, nNos gene deletion or inhibition shortened atrial APD and increased atrial fibrillation inducibility in vivo. Inhibition of miR-31 in human atrial fibrillation recovered DYS and nNOS, and normalised APD and APD rate-dependency. Prevention of miR-31 binding to nNOS 3'UTR recovered both nNOS protein and gene expression but had no effect on the DYS protein or mRNA level (consistent with the mRNA degradation of nNOS by miR-31). Prevention of miR-31 binding to DYS 3'UTR increased DYS protein but not mRNA is consistent with translation repression of DYS by miR-31; recovery of DYS protein increased nNOS protein but not mRNA in keeping with a stabilising effect of DYS on nNOS protein. In goats, a reduction in dystrophin and nNOS protein content was associated with upregulation of miR-31 in the atria but not in the ventricles. INTERPRETATION: The findings suggest that atrial-specific upregulation of miR-31 in human atrial fibrillation is a key mechanism causing atrial loss of dystrophin and nNOS; this loss leads to the electrical phenotype induced by atrial fibrillation. FUNDING: British Heart Foundation (BHF) Programme grant (for BC and XL), BHF Centre of Excellence in Oxford (SR), Leducq Foundation (in part for BC and SR), the European Union's seventh Framework Programme Grant Agree.
ABSTRACT
OBJECTIVES: The premise of this retrospective study was to evaluate the intraoperative use of closed-incision negative pressure therapy (ciNPT) to help reduce the incidence of postoperative sternal wound infections in multimorbid patients with an elevated risk of developing a sternal wound infection post cardiac surgery versus a cohort that received standard-of-care dressings. METHODS: Data for all adult patients were collected from each cardiothoracic surgery unit across 3 hospitals in the United Kingdom. High-risk patients had 2 or more recognized risk factors. Fisher's exact test (two-tailed) and unpaired t-test were used to help analyse categorical and continuous data. Propensity matching was performed to compare the 2 groups. RESULTS: A total of 5,288 patients who had cardiac surgery were included. Propensity matching led to 766 matched cases. There were significantly fewer sternal wound infections in the ciNPT group [43 (5.6%) vs 119 (15.5%) cases; P = 0.0001], as well as fewer deep sternal wound infections [14 (1.8%) vs 31 (4.0%) cases; P = 0.0149] and superficial sternal wound infections [29 (3.8%) vs 88 (11.4%) cases; P = 0.0001]. A higher mean length of stay in the ciNPT group was statistically significant (11.23 ± 13 vs 9.66 ± 10 days; P = 0.0083) as was a significantly higher mean logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) (11.143 ± 13 vs 8.094 ± 11; P = 0.0001). A statistically significant higher readmission to the intensive care unit due to sternal wound infection was noted for the controls [16 (2.08%) vs 3 (0.39%) readmissions; P = 0.0042]. CONCLUSIONS: The ciNPT appears to be an effective intervention to help reduce the incidence of sternal wound infection in high-risk individuals undergoing cardiac surgery.
ABSTRACT
OBJECTIVE: bicuspid aortic valve (BAV) stands as the most prevalent congenital heart condition intricately linked to aortic pathologies encompassing aortic regurgitation (AR), aortic stenosis, aortic root dilation, and aortic dissection. The aetiology of BAV is notably intricate, involving a spectrum of genes and polymorphisms. Moreover, BAV lays the groundwork for an array of structural heart and aortic disorders, presenting varying degrees of severity. Establishing a tailored clinical approach amid this diverse range of BAV-related conditions is of utmost significance. In this comprehensive review, we delve into the epidemiology, aetiology, associated ailments, and clinical management of BAV, encompassing imaging to aortic surgery. Our exploration is guided by the perspectives of the aortic team, spanning six distinct guidelines. METHODS: We conducted an exhaustive search across databases like PubMed, Ovid, Scopus, and Embase to extract relevant studies. Our review incorporates 84 references and integrates insights from six different guidelines to create a comprehensive clinical management section. RESULTS: BAV presents complexities in its aetiology, with specific polymorphisms and gene disorders observed in groups with elevated BAV prevalence, contributing to increased susceptibility to other cardiovascular conditions. The altered hemodynamics inherent to BAV instigate adverse remodelling of the aorta and heart, thus fostering the development of epigenetically linked aortic and heart diseases. Employing TTE screening for first-degree relatives of BAV patients might be beneficial for disease tracking and enhancing clinical outcomes. While SAVR is the primary recommendation for indicated AVR in BAV, TAVR might be an option for certain patients endorsed by adept aortic teams. In addition, proficient teams can perform aortic valve repair for AR cases. Aortic surgery necessitates personalized evaluation, accounting for genetic makeup and risk factors. While the standard aortic replacement threshold stands at 55 mm, it may be tailored to 50 mm or even 45 mm based on patient-specific considerations. CONCLUSION: This review reiterates the significance of considering the multifactorial nature of BAV as well as the need for further research to be carried out in the field.
ABSTRACT
BACKGROUND: Visceral obesity is directly linked to increased cardiovascular risk, including heart failure. OBJECTIVES: This study explored the ability of human epicardial adipose tissue (EAT)-derived microRNAs (miRNAs) to regulate the myocardial redox state and clinical outcomes. METHODS: This study screened for miRNAs expressed and released from human EAT and tested for correlations with the redox state in the adjacent myocardium in paired EAT/atrial biopsy specimens from patients undergoing cardiac surgery. Three miRNAs were then tested for causality in an in vitro model of cardiomyocytes. At a clinical level, causality/directionality were tested using genome-wide association screening, and the underlying mechanisms were explored using human biopsy specimens, as well as overexpression of the candidate miRNAs and their targets in vitro and in vivo using a transgenic mouse model. The final prognostic value of the discovered targets was tested in patients undergoing cardiac surgery, followed up for a median of 8 years. RESULTS: EAT miR-92a-3p was related to lower oxidative stress in human myocardium, a finding confirmed by using genetic regulators of miR-92a-3p in the human heart and EAT. miR-92a-3p reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase-derived superoxide (O2.-) by targeting myocardial expression of WNT5A, which regulated Rac1-dependent activation of NADPH oxidases. Finally, high miR-92a-3p levels in EAT were independently related with lower risk of adverse cardiovascular events. CONCLUSIONS: EAT-derived miRNAs exert paracrine effects on the human heart. Indeed miR-92a-3p suppresses the wingless-type MMTV integration site family, member 5a/Rac1/NADPH oxidase axis and improves the myocardial redox state. EAT-derived miR-92a-3p is related to improved clinical outcomes and is a rational therapeutic target for the prevention and treatment of obesity-related heart disease.