Poly(U) polymerase activity in Caenorhabditis elegans regulates abundance and tailing of sRNA and mRNA.

Terminal nucleotidyl transferases add nucleotides to the 3' end of RNA to modify their stability and function. In Caenorhabditis elegans, the terminal uridyltransferases/poly(U) polymerases PUP-1 (aka CID-1, CDE-1), PUP-2, and PUP-3 affect germline identity, survival, and development. Here, we identify small RNA (sRNA) and mRNA targets of these PUPs and of a fourth predicted poly(U) polymerase, F43E2.1/PUP-4. Using genetic and RNA sequencing approaches, we identify RNA targets of each PUP and the U-tail frequency and length of those targets. At the whole organism level, PUP-1 is responsible for most sRNA U-tailing, and other PUPs contribute to modifying discrete subsets of sRNAs. Moreover, expression of PUP-2, PUP-3, and especially PUP-4 limit uridylation on some sRNAs. The relationship between uridylation status and sRNA abundance suggests that U-tailing can have a negative or positive effect on abundance depending on context. sRNAs modified by PUP activity primarily target mRNAs that are ubiquitously expressed or most highly expressed in the germline. mRNA data obtained with a Nanopore-based method reveal that addition of U-tails to non-adenylated mRNA is substantially reduced in the absence of PUP-3. Overall, this work identifies PUP RNA targets, defines the effect of uridylation loss on RNA abundance, and reveals the complexity of PUP regulation in C. elegans development.

Exploring Changes in Myocyte Structure, Contractility, and Energetics From Mechanical Unloading in Patients With Heart Failure Undergoing Ventricular Assist Device Implantation: A Systematic Review and Meta-Analysis.

AIMS: Recent reports of myocardial recovery after mechanical unloading with left ventricular assist devices (LVADs) have challenged the prevailing notion that end-stage heart failure (HF) is irreversible. To improve our understanding of this phenomenon, we comprehensively analysed the structural, functional, and energetic changes in failing human cardiomyocytes after LVAD implantation. METHODS: Based on a prospectively registered protocol (PROSPERO-CRD42022380214), 30 eligible studies were identified from 940 records with a pooled population of 648 patients predominantly with non-ischaemic cardiomyopathy. RESULTS: LVAD led to a substantial regression in myocyte size similar to that of donor hearts (standardised mean difference, -1.29; p<0.001). The meta-regression analysis revealed that HF duration was a significant modifier on the changes in myocyte size. There were some suggestions of fibrosis reversal (-5.17%; p=0.009); however, this was insignificant after sensitivity analysis. Developed force did not improve in cardiac trabeculae (n=5 studies); however, non-physiological isometric contractions were tested. At the myocyte level (n=4 studies), contractile kinetics improved where the time-to-peak force reduced by 41.7%-50.7% and time to 50% relaxation fell by 47.4%-62.1% (p<0.05). Qualitatively, LVAD enhanced substrate utilisation and mitochondrial function (n=6 studies). Most studies were at a high risk of bias. CONCLUSION: The regression of maladaptive hypertrophy, partial fibrosis reversal, and normalisation in metabolic pathways after LVAD may be a testament to the heart's remarkable plasticity, even in the advanced stages of HF. However, inconsistencies exist in force-generating capabilities. Using more physiological force-length work-loop assays, addressing the high risks of bias and clinical heterogeneity are crucial to better understand the phenomenon of reverse remodelling.

Quantitative Aggregation of Microbiome Sequencing Data Provides Insights into the Associations between the Skin Microbiome and Psoriasis.

Although prior studies have reported distinct skin microbiome profiles associated with psoriasis, differences in methods and analyses limit generalizable conclusions. Individual studies have actually reported conflicting findings; for example, Propionibacterium and Staphylococcus have been significantly associated with both psoriatic lesions and healthy skin. Qualitative reviews have attempted to summarize this body of work, but there is great variability across the studies' findings and methods. To better unify these data, we created a meta-analysis of all publicly available datasets by utilizing a uniform bioinformatics pipeline and reference database to investigate associations of the skin microbiome in psoriasis. A total of 977 skin swab samples (341 lesional, 295 nonlesional, and 341 healthy) from 6 studies were analyzed. The aggregated analysis revealed a higher relative abundance of microorganisms, including Staphylococcus aureus and Corynebacterium simulans, among others, from patients with psoriasis than those from healthy swab samples; in addition, Cutibacterium acnes, Lawsonella unclassified, and S warneri were significantly higher in healthy samples. Furthermore, comparison of functional pathways predicted from 16S gene markers showed that L-ornithine biosynthesis and L-histidine biosynthesis were lower in psoriatic lesions than in healthy controls. Taken together, this meta-analysis allows for a more generalizable association between the skin microbiome and psoriasis.

A comparison of the outcomes of pulmonary versus extrapulmonary extensive-stage small cell carcinoma.

BACKGROUND: Extrapulmonary small cell carcinomas (EPSCCs) are rare cancers, comprising 0.1-0.4% of all cancers. The scarcity of EPSCC studies has led current treatment strategies to be extrapolated from small cell lung cancer (SCLC), justified by analogous histological and clinical features. AIMS: We conducted a retrospective cohort study comparing the outcomes of extensive-stage (ES) SCLC and EPSCC. METHODS: Patients diagnosed with ES SCLC or EPSCC between 2010 and 2020 from four hospitals in Sydney were identified. Patients who received active treatment and best supportive care were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and overall response rates (ORRs). RESULTS: Three hundred and eighty-four patients were included (43 EPSCC vs. 340 SCLC). EPSCC were of genitourinary (n = 15), unknown primary (n = 13) and gastrointestinal (n = 12) origin. Treatment modalities for EPSCC compared to SCLC included palliative chemotherapy (56% vs 73%), palliative radiotherapy (47% vs 59%) and consolidation chest radiotherapy (10% of SCLC). Overall, median OS was 6.4 versus 7 months for EPSCC versus SCLC respectively, but highest in prostate EPSCC (25.6 months). Of those who received chemotherapy (22 EPSCC vs 233 SCLC), median OS was 10.4 versus 8.4 months (HR OS 0.81, 95% confidence interval (CI): 0.5-1.31, P = 0.38); PFS was 5.4 versus 5.5 months (HR PFS 0.93, 95% CI: 0.58-1.46, P = 0.74) and ORR were 73% versus 68%. CONCLUSIONS: EPSCC and SCLC appeared to have comparable OS and treatment outcomes. However, the wide range of OS in EPSCC highlights the need for an improved understanding of its genomics to explore alternative therapeutics.

Rising arterial stiffness with accumulating comorbidities associates with heart failure with preserved ejection fraction.

AIMS: Comorbidities play a significant role towards the pathophysiology of heart failure with preserved ejection fraction (HFpEF), characterized by abnormal macrovascular function and altered ventricular-vascular coupling. However, our understanding of the role of comorbidities and arterial stiffness in HFpEF remains incomplete. We hypothesized that HFpEF is preceded by a cumulative rise in arterial stiffness as cardiovascular comorbidities accumulate, beyond that associated with ageing. METHODS AND RESULTS: Arterial stiffness was assessed using pulse wave velocity (PWV) in five groups: Group A, healthy volunteers (n = 21); Group B, patients with hypertension (n = 21); Group C, hypertension and diabetes mellitus (n = 20); Group D, HFpEF (n = 21); and Group E, HF with reduced ejection fraction (HFrEF) (n = 11). All patients were aged 70 and above. Mean PWV increased from Groups A to D (PWV 10.2, 12.2, 13.0, and 13.7 m/s, respectively) as vascular comorbidities accumulated independent of age, renal function, haemoglobin, obesity (body mass index), smoking status, and hypercholesterolaemia. HFpEF exhibited the highest PWV and HFrEF displayed near-normal levels (13.7 vs. 10 m/s, P = 0.003). PWV was inversely related to peak oxygen consumption (r = -0.304, P = 0.03) and positively correlated with left ventricular filling pressures (E/e') on echocardiography (r = -0.307, P = 0.014). CONCLUSIONS: This study adds further support to the concept of HFpEF as a disease of the vasculature, underlined by an increasing arterial stiffness that is driven by vascular ageing and accumulating vascular comorbidities, for example, hypertension and diabetes. Reflecting a pulsatile arterial afterload associated with diastolic dysfunction and exercise capacity, PWV may provide a clinically relevant tool to identify at-risk intermediate phenotypes (e.g. pre-HFpEF) before overt HFpEF occurs.

Giant Klebsiella pneumoniae pyogenic liver abscess in the left liver lobe presenting with dyspepsia and vaginal discharge.

Pyogenic liver abscess (PLA) commonly occurs in the right liver lobe, causing the typical symptoms of fever and right upper quadrant pain. Less than one-third of cases occur in the left lobe. We describe an unusual presentation of a giant left-sided PLA that was compressing the stomach and surrounding venous vasculature, causing the respective symptoms of gastro-oesophageal reflux and vaginal discharge from secondary pelvic congestion syndrome. CT revealed a solitary 14 cm×10 cm×10 cm multiloculated lesion, replacing most of the left liver lobe. It was successfully treated with intravenous antibiotics and percutaneous drainage, resulting in complete resolution at 1-year follow-up. This case explores the predisposing risk factor of diabetes in PLA and its association with Klebsiella pneumoniae, which was the offending pathogen in our patient. We also discuss the phenomenon of secondary pelvic venous congestion syndrome and compare similar cases of left-sided PLA, highlighting the different modes of presentation and treatment options.

The Role of the Vasculature in Heart Failure.

The contribution of the vasculature in the development and progression of heart failure (HF) syndromes is poorly understood and often neglected. Incorporating both arterial and venous systems, the vasculature plays a significant role in the regulation of blood flow throughout the body in meeting its metabolic requirements. A deterioration or imbalance between the cardiac and vascular interaction can precipitate acute decompensated HF in both preserved and reduced ejection fraction phenotypes. This is characterised by the increasingly recognised concept of ventricular-arterial coupling: a well-balanced relationship between ventricular and vascular stiffness, which has major implications in HF. Often, the cause of decompensation is unknown, with international guidelines mainly centred on arrhythmia, infection, acute coronary syndrome and its mechanical complications as common causes of decompensation; the vascular component is often underrecognised. A better understanding of the vascular contribution in cardiovascular failure can improve risk stratification, earlier diagnosis and facilitate earlier optimal treatment. This review focuses on the role of the vasculature by integrating the concepts of ventricular-arterial coupling, arterial stiffness and venous return in a failing heart.

Profiling the Biomechanical Responses to Workload on the Human Myocyte to Explore the Concept of Myocardial Fatigue and Reversibility: Rationale and Design of the POWER Heart Failure Study.

It remains unclear why some patients develop heart failure without evidence of structural damage. One theory relates to impaired myocardial energetics and ventricular-arterial decoupling as the heart works against adverse mechanical load. In this original study, we propose the novel concept of myocardial fatigue to capture this phenomenon and aim to investigate this using human cardiomyocytes subjected to a modern work-loop contractility model that closely mimics in vivo cardiac cycles. This proof-of-concept study (NCT04899635) will use human myocardial tissue samples from patients undergoing cardiac surgery to develop a reproducible protocol to isolate robust calcium-tolerant cardiomyocytes. Thereafter, work-loop contractility experiments will be performed over a range of preload, afterload and cycle frequency as a function of time to elicit any reversible reduction in contractile performance (i.e. fatigue). This will provide novel insight into mechanisms behind heart failure and myocardial recovery and serve as a valuable research platform in translational cardiovascular research.

Myocardial Fatigue at a Glance.

Expanding on the modern lexicon of heart failure (HF), the novel mechano-energetic concept of myocardial fatigue describes a transiently energy-depleted myocardium with impaired contractility and relaxation in the face of adverse haemodynamic load. It encompasses established concepts of ventricular-arterial decoupling, deranged cardiac energetics and impaired myocardial efficiency, offering an alternative explanation for functional causes of HF.

Real-world evaluation of glucose-lowering therapies and the use of weight-adjusted variable rate intravenous insulin infusion in the management of hyperglycaemia in patients with acute coronary syndrome (REGULATE-ACS).

INTRODUCTION: Admission hyperglycaemia in acute coronary syndromes (ACS) is a strong independent predictor of adverse clinical outcomes post-ACS. We examined the safety, efficacy, and feasibility of a modified, weight-adjusted variable rate intravenous insulin infusion (VRIII) and evaluated current practice of prescribing novel cardio-protective glucose-lowering therapies in patients presenting with acute hyperglycaemia across the ACS spectrum. METHODS: REGULATE-ACS was an observational single-centre study of consecutive patients admitted with acute hyperglycaemia post-ACS between 2020 and 2021. Following updated local guidance on a modified VRIII, we evaluated its safety and efficacy in glycaemic control, cardio-metabolic complications including hypoglycaemia (blood glucose <3 mmol/L) and 30-day mortality. We also determined the prescription of glucose-lowering therapies pre-discharge. RESULTS: Out of 107 patients, mean age was 64.9 ± 12.2 years, 82% had known diabetes, and 15% newly diagnosed diabetes. 86.9% (n = 93) had an admission glucose ≥11 mmol/L. In patients treated with VRIII (n = 63/93, 67.7%), glucose improved from 17.5 to 9.0 mmol/L (IQR 7.1-12.1), which was 3 mmol/L lower (p = 0.03) than in patients not treated with VRIII (n = 30/93, 32.3%) where median glucose reduced from 12.6 to 12 mmol/L (IQR 8.6-13.9). No significant hypoglycaemia, arrhythmia or worsening pulmonary oedema associated with VRIII was found. Novel glucose-lowering therapies were initiated in 20/71 (28.2%) and 3/15 (20.0%) of patients with prior and newly diagnosed diabetes, respectively. CONCLUSION: This real-world analysis provides further support of efficacy, safety, and feasibility of a modified, weight-adjusted VRIII in managing acute hyperglycaemia in ACS. Despite established cardio-protective benefits of novel glucose-lowering therapies, <1/3 of eligible patients received such agents pre-discharge, demanding further research and awareness.

Developing a contemporary community clinic for patients with heart failure with preserved ejection fraction within the current National Health Service model.

INTRODUCTION: The diagnostic and therapeutic arsenal for heart failure with preserved ejection (HFpEF) has expanded. With novel therapies (eg, sodium-glucose co-transporter 2 inhibitors) and firmer recommendations to optimise non-cardiac comorbidities, it is unclear if outpatient HFpEF models can adequately deliver this. We; therefore, evaluated the efficacy of an existing dedicated HFpEF clinic to find innovative ways to design a more comprehensive model tailored to the modern era of HFpEF. METHODS: A single-centre retrospective analysis of 202 HFpEF outpatients was performed over 12 months before the COVID-19 pandemic. Baseline characteristics, clinic activities (eg, medication changes, lifestyle modifications, management of comorbidities) and follow-up arrangements were compared between a HFpEF and general cardiology clinic to assess their impact on mortality and morbidity at 6 and 12 months. RESULTS: Between the two clinic groups, the sample population was evenly matched with a typical HFpEF profile (mean age 79±9.6 years, 55% female and a high prevalence of cardiometabolic comorbidities). While follow-up practices were similar, the HFpEF clinic delivered significantly more interventions on lifestyle changes, blood pressure and heart rate control (p<0.0001) compared with the general clinic. Despite this, no significant differences in all-cause hospitalisation and mortality were observed. This may be attributed to the fact that clinic activities were primarily cardiology-focused. Importantly, non-cardiovascular admissions accounted for >60% of hospitalisation, including causes of recurrent admissions. CONCLUSION: This study suggests that existing general and emerging dedicated HFpEF clinics may not be adequate in addressing the multifaceted aspects of HFpEF as clinic activities concentrated primarily on cardiological measures. Although the small cohort and short follow-up period are important limitations, this study reminds clinicians that HFpEF patients are more at risk of non-cardiac than HF-related events. We have therefore proposed a pragmatic framework that can comprehensively deliver the modern guideline-directed recommendations and management of non-cardiac comorbidities through a multidisciplinary approach.

Vitamin D Levels in Alopecia Areata and Other Alopecias: A Retrospective Case- Control Study at a Single Institution.

Recent research has associated alopecia areata (AA), an autoimmune disorder, with deficiency of Vitamin D, which regulates immune processes. This retrospective study compared Vitamin D levels in AA patients to those of other alopecia diagnoses and nonalopecia controls. When compared to controls, patients with AA or other alopecia diagnoses did not demonstrate lower Vitamin D levels. However, when compared to other alopecia diagnoses, AA patients had a statistically significantly higher proportion of patients with Vitamin D deficiency and a lower mean Vitamin D level. Our findings suggest a greater association between lower Vitamin D levels and AA compared to other alopecia diagnoses. Further prospective studies investigating Vitamin D levels and supplementation in AA patients are needed to further elucidate this association and its potential relevance.

Protein drift-diffusion dynamics and phase separation in curved cell membranes and dendritic spines: Hybrid discrete-continuum methods.

We develop methods for investigating protein drift-diffusion dynamics in heterogeneous cell membranes and the roles played by geometry, diffusion, chemical kinetics, and phase separation. Our hybrid stochastic numerical methods combine discrete particle descriptions with continuum-level models for tracking the individual protein drift-diffusion dynamics when coupled to continuum fields. We show how our approaches can be used to investigate phenomena motivated by protein kinetics within dendritic spines. The spine geometry is hypothesized to play an important biological role regulating synaptic strength, protein kinetics, and self-assembly of clusters. We perform simulation studies for model spine geometries varying the neck size to investigate how phase-separation and protein organization is influenced by different shapes. We also show how our methods can be used to study the roles of geometry in reaction-diffusion systems including Turing instabilities. Our methods provide general approaches for investigating protein kinetics and drift-diffusion dynamics within curved membrane structures.

Characteristics of Patients with Hair Loss after Isotretinoin Treatment: A Retrospective Review Study.

Background: Oral isotretinoin has been used to treat acne for decades. Although the side effects of isotretinoin are mostly predictable, one less common side effect of isotretinoin use is hair loss, typically telogen effluvium. Objective: This study is a retrospective report on the development of alopecia in patients on isotretinoin therapy. Methods: To characterize these patients, they were further compared to other patients in the same time period who were prescribed isotretinoin and did not experience hair loss. Results: Of 6330 patients with hair loss, 48 had been prescribed isotretinoin at some time between 2013 and 2018. Of these 48 patients, hair loss occurred concurrently or within two years after taking isotretinoin in 19 patients. When compared to controls, patients who experienced hair loss from isotretinoin were older, had greater cumulative isotretinoin doses, and had longer durations of treatment. Conclusion: Although the exact mechanism of how retinoids affect hair loss is still unclear, our findings suggest dosage or duration of usage may be associated. This information may be useful in counseling patients who may be concerned about hair loss when considering isotretinoin treatment.

Rigid forceps and excimer laser use for complex inferior cava filter retrieval: a preliminary quantitative analysis of available evidence.

PURPOSE: The present study aims to evaluate the safety and efficacy of advanced inferior vena cava filter (IVCF) retrieval using laser assistance compared with forceps via systematic review and quantitative aggregation of available data. METHODS: Pubmed and Embase were queried from establishment to September 2021. Original studies with a sample size ≥ 5 that reported at least one primary outcome of patients who underwent laser- or forceps-assisted IVCF retrieval were included. Primary outcomes included technical success and complication rates. Baseline characteristics were extracted: age, sex, presence of filter thrombus, strut penetration, previous retrieval attempt, filter dwell time, fluoroscopy time, and filter type. Complications were categorized by type and severity. Categorical data was pooled and evaluated with chi-square or Fisher exact tests. RESULTS: From the 16 included studies, a total of 673 and 368 patients underwent laser- and forceps-assisted IVCF retrieval, respectively. Successful retrieval was achieved in 98.1 and 93.7% patients from the laser and forceps groups, respectively (p < 0.001). Major complication rates (1.6 vs 2.1%, p = 0.629) and risk of injury to cava or adjacent organs (1.0 vs 1.4%, p = 0.534) were similar between the two groups. A higher proportion of filters from the laser arm were closed-cell design (75.4 vs 68.1%, p = 0.020). CONCLUSION: Based on limited available evidence, forceps- and laser-assisted complex IVCF retrievals were equally safe. The use of laser sheath is associated with a higher retrieval rate than forceps alone, though the baseline characteristics of two cohorts were not controlled. Future large-scale case-controlled comparative studies with longer clinical follow-up are warranted.

Late maternal diagnosis of DiGeorge syndrome with congenital hypoparathyroidism following antenatal detection of the same 22q11.2 microdeletion syndrome in the fetus.

Genetic causes of hypocalcaemia can be overlooked in patients who present without apparent syndromic features. One relatively common but under-recognised genetic disorder is DiGeorge syndrome, which is often diagnosed in childhood but rarely in adulthood. Its enigmatic diagnosis can be attributed to its broad heterogeneous clinical presentation, such as the absence of cardiac abnormalities with only subtly abnormal facies. The presence of hypoparathyroidism-related hypocalcaemia may be the first early sign. We describe a young female adult with childhood-onset hypocalcaemia who was diagnosed with DiGeorge syndrome during her pregnancy when the fetus was found to have the same condition on antenatal screening and autopsy. This case reminds clinicians to consider the genetic causes of hypoparathyroidism-induced hypocalcaemia early on in childhood, while acknowledging the possibility of a late diagnosis in adulthood. We also highlight the risks of severe hypocalcaemia in pregnancy and outline a systematic approach to the evaluation of chronic hypocalcaemia.

Kolkata-Coventry comparative registry study of acute heart failure: an insight into the impact of public, private and universal health systems on patient outcomes in low-middle income cities (KOLCOV HF Study).

INTRODUCTION: Survival gaps in acute heart failure (AHF) continue to expand globally. Multinational heart failure (HF) registries have highlighted variations between countries. Whether discrepancies in HF practice and outcomes occur across different health systems (ie, private, public or universal healthcare) within a city or between countries remain unclear. Insight into organisational care is also scarce. With increasing public scrutiny of health inequalities, a study to address these limitations is timely. METHOD: KOLCOV-HF study prospectively compared patients with AHF in public (Nil Ratan Sircar Hospital (NRS)) versus private (Apollo Gleneagles Hospital (AGH)) hospitals of Kolkata, India, and one with universal health coverage in a socioeconomically comparable city of Coventry, England (University Hospitals Coventry & Warwickshire (UHCW)). Data variables were adapted from UK's National HF Audit programme, collected over 24 months. Predictors of in-hospital mortality and length of hospitalisation were assessed for each centre. RESULTS: Among 1652 patients, in-hospital mortality was highest in government-funded NRS (11.9%) while 3 miles north, AGH had significantly lower mortality (7.5%, p=0.034), similar to UHCW (8%). This could be attributed to distinct HF phenotypes and differences in clinical and organisational care. As expected, low blood pressure was associated with a significantly greater risk of death in patients served by public hospitals UHCW and NRS. CONCLUSION: Marked differences in HF characteristics, management and outcomes exist intra-regionally, and between low-middle versus high-income countries across private, public and universal healthcare systems. Physicians and policymakers should take caution when applying country-level data locally when developing strategies to address local evidence-practice gaps in HF.

Delayed onset of neurogenic pulmonary oedema following an evolving ischaemic stroke.

Any insult to the central nervous system can lead to the rare occurrence of neurogenic pulmonary oedema (NPO). It is usually associated with significant neurological injury (eg, subarachnoid haemorrhage or traumatic brain injury) with a relatively rapid onset. As an exception to this observation, we report a middle-aged woman who developed NPO 72 hours after the onset of a subtle but evolving right middle cerebral artery infarction confirmed on CT. Aggressive use of diuretics and vasodilators, as is normally the case for cardiogenic pulmonary oedema, can compromise cerebral blood flow and the ischaemic penumbra. This case illustrates how the diagnostic and therapeutic challenges were successfully addressed with the aid of bedside ultrasonography and close haemodynamic monitoring to reverse the respiratory failure while protecting the brain.

Myocardial Fatigue: a Mechano-energetic Concept in Heart Failure.

PURPOSE OF REVIEW: This review combines existing mechano-energetic principles to provide a refreshing perspective in heart failure (HF) and examine if the phenomenon of myocardial fatigue can be rigorously tested in vitro with current technological advances as a bridge between pre-clinical science and clinical practice. RECENT FINDINGS: As a testament to the changing paradigm of HF pathophysiology, there has been a shift of focus from structural to functional causes, as reflected in its modern universal definition and redefined classification. Bolstered by recent landmark trials of sodium-glucose cotransport-2 inhibitors across the HF spectrum, there is a rekindled interest to revisit the basic physiological tenets of energetic efficiency, metabolic flexibility, and mechanical load on myocardial performance. Indeed, these principles are well established in the study of skeletal muscle fatigue. Since both striated muscles share similar sarcomeric building blocks, is it possible that myocardial fatigue can occur in the face of sustained adverse supra-physiological load as a functional cause of HF? Myocardial fatigue is a mechano-energetic concept that offers a novel functional mechanism in HF. It is supported by current studies on exercise-induced cardiac fatigue and reverse translational science such as from recent landmark trials on sodium glucose co-transporter 2 inhibitors in HF. We propose a novel framework of myocardial fatigue, injury, and damage that aligns with the contemporary notion of HF as a continuous spectrum, helps determine the chance and trajectory of myocardial recovery, and aims to unify the plethora of cellular and molecular mechanisms in HF.