Mechanical unloading is accompanied by reverse metabolic remodelling in the failing heart: Identification of a novel citraconate-mediated pathway.

Aims: Although functional recovery of the failing heart with left ventricular assist device (LVAD) unloading can occur, the underpinning mechanism is unclear. We aimed to characterize the effect of myocardial biochemical effect of LVAD support in vivo and in vitro.

Methods and results: We performed targeted metabolomics and lipidomics on transcardiac (arterial and coronary sinus) blood samples collected from healthy volunteers (n = 13), patients with end-stage heart failure with reduced ejection fraction (HFrEF, n = 20), and LVAD-supported HFrEF patients (n = 18). Complementary biochemical studies in myocardial tissue samples from healthy donor, HFrEF and LVAD patients, and cardiomyoblasts were performed. Myocardial uptake of intermediates in purine, nucleotide, and tricarboxylic acid (TCA) cycle pathways was depressed in HFrEF patients, with recovery in LVAD patients. Glucose uptake was suppressed in HFrEF but restored in LVAD. Metabolite changes suggestive of impaired fatty acid oxidation were present in HFrEF but not in LVAD. We found that the metabolite citraconate was significantly released by HFrEF hearts compared to controls and this was corroborated, in separate patients, by increased levels of citraconate in HFrEF myocardium but not in LVAD. Whilst citraconate increased succinate deydrogenase (SDH) activity in cardiomyoblasts, its isomer itaconate suppressed SDH activity. SDH activity was maintained in HFrEF myocardium but was diminished in LVAD myocardium.

Conclusions: We report, for the first time, the in-vivo biochemical effects of LVAD unloading in the human heart. Our data identify citraconate as a potentially important regulator of the TCA cycle in the failing heart.

The Historical Evolution of Academic Surgery at Royal Prince Alfred Hospital.

Surgical teaching and research at Royal Prince Alfred Hospital has evolved substantially since the hospital was opened in 1882. Economic constraints, World Wars, developments in technology, changes to healthcare policy and society’s expectations have all presented opportunities and obstacles, and ultimately shaped the current practice of academic surgery at the Hospital. This article aims to trace the historical evolution of academic surgery at Royal Prince Alfred Hospital (RPAH) and discuss the internal and external factors which drove these changes.

Head-to-head comparison of V-A ECMO, Impella and ECPELLA in normal ovine hearts.

Temporary mechanical circulatory support (MCS), including veno-arterial extracorporeal membrane oxygenation (ECMO) and micro-axial pumps (Impella), is increasingly used in clinical practice for refractory circulatory failure. Complex physiological responses to each technique or their combination (ECPELLA) remain debated and are often specific to cardiovascular pathology. A paucity of data on physiological responses to MCS in normal subjects makes comprehensive understanding of such responses in variable disease states difficult, as well as during weaning MCS in recovering hearts. This translational investigation compared three MCS techniques with variable pump flows in healthy sheep (n = 7) to establish baseline for future studies in cardiomyopathic models. All MCS techniques increased arterial elastance, but reduced LV myocardial work, coronary arterial flow and LV myocardial oxygen consumption. ECPELLA was more effective in increasing total systemic blood flow and MAP. The overall similarity between the MCS techniques suggests that the more invasive and complex combination of devices (ECPELLA) can only be justified for management of the severe failing heart as the means for decompressing LV. A study investigating the comparative impacts of different regimes and MCS techniques in a cardiomyopathic model is warranted.

Longitudinal outcomes following international multicentre experience with robotic aortic valve replacement

Objectives: In an effort to maintain the technical aspects of traditional prosthetic surgical aortic valve replacement (AVR) while reducing invasiveness and facilitate options for concomitant operations, transaxillary lateral mini-thoracotomy endoscopic robotic-assisted aortic valve replacement (RAVR) has been introduced. The present data highlight the contemporary international collaborative experience.

Methods: All consecutive patients undergoing standardized RAVR across 10 international sites (1/2020-7/2024) were evaluated using a central database with 1 year follow-up.

Results: A total of 300 patients were analysed with a median predicted risk of 1.6% with aortic stenosis in 85.7%, nearly half with bicuspid valves. Biological prostheses were implanted in 220 (73.3%) with a median valve size 23 mm, 10% receiving aortic root enlargement, with 17% of all patients undergoing concomitant procedures. Median cross-clamp 120 min with no conversions to sternotomy. Median length of stay was 5 days, 4.3% with prolonged ventilation, 1.7% renal failure, 1.0% stroke and 8.3% required re-thoracotomy for evacuation of haemothorax. There were two 30-day operative mortalities (0.7%). The new permanent pacemaker rate for the full cohort was 2.6%. Of 163 patients with complete 1-year clinical and echocardiographic follow-up, mean aortic valve gradient was 10 mmHg and all but 2 patients (1.2%) had trace to no prosthetic or paravalvular insufficiency.

Conclusions: RAVR is safe and effective, providing the reproducible benefits of surgical AVR while affording a less invasive approach that permits the opportunity for concomitant procedures. For low and intermediate risk patients with aortic valve disease, RAVR is a potential reproducible alternative for patients and heart teams.

Keywords: Robotic valve surgery; Robotic-assisted aortic valve replacement.

Heart Has Intrinsic Ketogenic Capacity that Mediates NAD+ Therapy in HFpEF

Background: Heart failure with preserved ejection fraction (HFpEF) has overtaken heart failure with reduced ejection fraction as the leading type of heart failure globally and is marked by high morbidity and mortality rates, yet with only a single approved pharmacotherapy: SGLT2i (sodium-glucose co-transporter 2 inhibitor). A prevailing theory for the mechanism underlying SGLT2i is nutrient deprivation signaling, of which ketogenesis is a hallmark. However, it is unclear whether the canonical ketogenic enzyme, HMGCS2 (3-hydroxy-3-methylglutaryl-coenzyme A synthase 2), plays any cardiac role in HFpEF pathogenesis or therapeutic response.

Methods: We used human myocardium, human HFpEF and heart failure with reduced ejection fraction transcardiac blood sampling, an established murine model of HFpEF, ex vivo Langendorff perfusion, stable isotope tracing in isolated cardiomyocytes, targeted metabolomics, proteomics, lipidomics, and a novel cardiomyocyte-specific conditional HMGCS2-deficient model that we generated.

Results: We demonstrate, for the first time, the intrinsic capacity of the human heart to produce ketones via HMGCS2. We found that increased acetylation of HMGCS2 led to a decrease in the enzyme’s specific activity. However, this was overcome by an increase in the steady-state levels of protein. Oxidized form of nicotinamide adenine dinucleotide repletion restored HMGCS2 function via deacetylation, increased fatty acid oxidation, and rescued cardiac function in HFpEF. Critically, using a conditional, cardiomyocyte-specific HMGCS2 knockdown murine model, we revealed that the oxidized form of nicotinamide adenine dinucleotide is unable to rescue HFpEF in the absence of cardiomyocyte HMGCS2.

Conclusions: The canonical ketogenic enzyme, HMGCS2, mediates the therapeutic effects of the oxidized form of nicotinamide adenine dinucleotide repletion in HFpEF by restoring normal lipid metabolism and mitochondrial function.

Longitudinal outcomes following international multicenter experience with robotic aortic valve replacement

Objectives: In an effort to maintain the technical aspects of traditional prosthetic surgical aortic valve replacement (AVR) while reducing invasiveness and facilitate options for concomitant operations, transaxillary lateral mini-thoracotomy endoscopic robotic-assisted aortic valve replacment (RAVR) has been introduced. The present data highlights the contemporary international collaborative experience.

Methods: All consecutive patients undergoing standardized RAVR across 10 international sites (1/2020-7/2024) were evaluated using a central database with 1 year follow-up.

Results: A total of 300 patients were analyzed with a median predicted risk of 1.6% with aortic stenosis in 85.7%, nearly half with bicuspid valves. Biological prostheses were implanted in 220 (73.3%) with a median valve size 23 mm, 10% receiving aortic root enlargement, with 17% of all patients undergoing concomitant procedures. Median cross-clamp 120 min with no conversions to sternotomy. Median length of stay was 5 days, 4.3% with prolonged ventilation, 1.7% renal failure, 1.0% stroke, 8.3% required re-thoracotomy for evacuation of haemothorax. There were two 30-day operative mortalities (0.7%). The new permanent pacemaker rate for the full cohort was 2.6%. Of 163 patients with complete 1-year clinical and echocardiographic follow-up, mean aortic valve gradient was 10 mmHg and all but two patients (1.2%) had trace to no prosthetic or paravalvular insufficiency.

Conclusions: RAVR is safe and effective, providing the reproducible benefits of surgical AVR while affording a less invasive approach that permits the opportunity for concomitant procedures. For low and intermediate risk patients with aortic valve disease, RAVR is a potential reproducible alternative for patients and heart teams.

Keywords: RAVR; Robotic Aortic Valve Replacement; Robotic Valve Surgery.

Transcriptional, proteomic and metabolic drivers of cardiac regeneration

Following injury, many organs are capable of rapid regeneration of necrotic tissue to regain normal function. In contrast, the damaged heart typically replaces tissue with a collagen-rich scar, due to the limited regenerative capacity of its functional contractile cardiomyocytes (CMs). However, this regenerative capacity varies dramatically during development and between species. Furthermore, studies have shown that cardiac regeneration can be enhanced to return contractile function to the damaged heart following myocardial infarction (MI). In this review, we outline the proliferative capacity of CMs in utero, postnatally and in adulthood. We also describe the regenerative capacity of the heart following MI injury. Finally, we focus on the various therapeutic strategies that aim to augment cardiac regeneration in preclinical animal models. These include altering transcripts, microRNAs, extracellular matrix proteins and inducing metabolic rewiring. Together, these therapies aim to return function to the damaged heart and potentially improve the lives of the millions of heart failure patients currently suffering worldwide.

Keywords: Cardiovascular Diseases; Heart Failure; Heart Failure, Systolic; Myocardial Infarction.

Mitral valve replacement versus repair for severe mitral regurgitation in patients with reduced left ventricular ejection fraction

Objective: This study compares early and long-term outcomes following mitral valve (MV) repair and replacement in patients with mitral regurgitation (MR) and reduced left ventricular ejection fraction (LVEF).

Methods: Patients with primary or secondary MR and LVEF <50% who underwent MV replacement or repair (with/without atrial septal defect closure and/or atrial fibrillation ablation) between 2005 and 2017 at our center were retrospectively analyzed using unadjusted and propensity score matching techniques (42 pairs).

Results: A total of 356 patients with either primary (n = 162 [45.5%]) or secondary MR (n = 194 [54.5%]) and LVEF <50% underwent MV repair (n = 293 [82.3%]) or replacement (n = 63 [17.7%]) during the study period. In-hospital mortality was 0.3% (repair) and 1.6% (replacement) in the unmatched cohort (P = .32); there were no in-hospital deaths after matching. Estimated survival was 72.8% (repair) versus 50.1% (replacement) at 8 years in the unmatched (P < .001), and 64.3% (repair) versus 50.7% (replacement) in the matched groups (P = .028). Eight-year cumulative incidence of reoperation was 7.0% and 11.6% in unmatched (P = .28), and 9.9% and 12.7% in matched (P = .69) repair and replacement groups, respectively. Markedly reduced LVEF (<40%) was among the independent predictors of long-term mortality (hazard ratio, 1.7; 95% CI, 1.2-2.4; P = .002). In secondary MR, MV repair showed an 8-year survival benefit over replacement (65.1% vs 44.6%; P = .002), with no difference in reoperation rate (11.6% [repair] vs 17.0% [replacement]; P = .11).

Conclusions: MV repair performed in primary or secondary MR and reduced LVEF provides superior long-term results compared with replacement. Severe LV dysfunction is a significant predictor of reduced survival following MV surgery.

Keywords: heart failure; mitral regurgitation; mitral valve repair; mitral valve replacement.

Cutibacterium acnes infective endocarditis-an emerging pathogen

Objectives: The study aimed to review a multicentre experience of patients undergoing surgical intervention for infective endocarditis caused by Cutibacterium acnes and to analyse the diagnostic challenges and operative results.

Methods: We retrospectively reviewed 8812 patients undergoing cardiac surgery for endocarditis at 12 cardiac surgical departments across Germany. The overall population was divided based on the type of endocarditis (i.e. native and prosthetic valve endocarditis). Primary outcomes were in-hospital mortality, 1- and 5-year survival.

Results: Cutibacterium acnes caused endocarditis in 269 patients (3.1%). Median age was 65 years (54-72 years) and 237 (88.1%) were male. We observed significantly higher rates of native valve endocarditis in patients aged 21-40, whereas prosthetic valve endocarditis was more frequent in all other age groups (P < 0.001). The median EuroSCORE II of the cohort was 10.7 (5.0-29.6), with it being significantly higher in the prosthetic valve endocarditis group (P < 0.001). Blood culture-negative infective endocarditis was initially reported in 54.3% of the patients. The in-hospital mortality was comparable between the groups (P = 0.340). Survival at 1 and 5 years was significantly higher in the native valve endocarditis group (P < 0.001).

Conclusions: Cutibacterium acnes causes native valve endocarditis, especially in younger patients. The incidence of endocarditis caused by C.acnes is alarming and is at par with well-known endocarditis pathogens such as the HACEK group. The pathogen has a low virulence and presents with a rather indolent course. The diagnosis of C.acnes endocarditis is challenging and requires a multimodal specialized approach. Surgical treatment is associated with acceptable outcomes.

Keywords: Cutibacterium acnes; Infective endocarditis; Valvular heart disease.

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