"Efficacy and Safety of OnabotulinumtoxinA for the Treatment of Platysma Prominence: A Randomized Phase 2 Dose-Ranging Study".

BACKGROUND: With aging, repetitive contraction of the platysma leads to an increase in platysma prominence (PP) characterized by the accentuation of vertical neck bands and blunting of the jawline's contour. METHODS: This multicenter, double-blind, phase 2 study evaluated onabotulinumtoxinA (onabotA) treatment in adults with Moderate to Severe PP. Participants were randomized to receive 1 treatment of onabotA low dose (LD), onabotA high dose (HD), or placebo, and were followed for 4 months. Efficacy endpoints were the achievement of a ≥ 1-grade improvement on both the left and right sides at Day 14 at maximum contraction as assessed by the investigator (primary) or by participants (secondary) using validated scales. Safety was evaluated throughout. RESULTS: Participants in the modified intent-to-treat population (N = 164) had a mean age of 50 years; 95.1% were female and 93.9% were White. The primary endpoint was met for both onabotA groups, with investigator-assessed ≥ 1-grade improvement in 77.8% (LD) and 88.2% (HD) vs 12.0% (placebo) of participants on Day 14 (P < 0.0001 vs placebo). Based on participant self-assessment, 75.9% (LD) and 88.2% (HD) vs 18.0% (placebo) achieved ≥ 1-grade improvement on Day 14 (P < 0.0001 vs placebo). Most treatment-related adverse events (AEs) were procedure-related, transient, and mild in severity. The most frequent onabotA-related AE was neck muscle weakness, reported in the HD group. CONCLUSIONS: OnabotA was effective in improving the appearance of PP based on both investigators' and participants' ratings. Treatment was well tolerated.

Directional atherectomy for retained valves in a femoropopliteal saphenous vein bypass graft.

We describe the case of a 62-year-old man presenting 2 months after a reversed great saphenous vein femoropopliteal bypass performed for critical limb ischemia. He was found to have early, high-grade bypass graft stenosis on duplex ultrasound. Subsequent angiography demonstrated flow limitations secondary to two areas of retained venous valves in the proximal and mid-portions of the vein graft. The culprit valve lesions were successfully lysed endovascularly with a HawkOne (Medtronic) directional atherectomy device. This case demonstrates a safe, novel use of a directional atherectomy device for treatment of remnant valves causing hemodynamically significant flow problems in peripheral vein grafts.

Interleukin 17A Contributes to Blood-Brain Barrier Disruption of Hypothalamic Paraventricular Nucleus in Rats With Myocardial Infarction.

BACKGROUND: Elevated inflammatory cytokines in the periphery have been identified as active contributors to neuroinflammation and sympathetic overactivity in heart failure (HF). Yet, the exact mechanisms by which these cytokines breach the blood-brain barrier (BBB) to exert their effects on the brain remain elusive. Interleukin 17A has been linked to BBB disruption in various neurologic disorders, and its levels were significantly augmented in circulation and the brain in HF. The present study aimed to determine whether the BBB integrity was compromised within the hypothalamic paraventricular nucleus (PVN), and if so, whether interleukin 17A contributes to BBB disruption in myocardial infarction-induced HF. METHODS AND RESULTS: Male Sprague-Dawley rats underwent coronary artery ligation to induce HF or sham surgery. Some HF rats received bilateral PVN microinjections of an interleukin 17 receptor A small interfering RNA or a scrambled small interfering RNA adeno-associated virus. Four weeks after coronary artery ligation, the permeability of the BBB was evaluated by intracarotid injection of fluorescent dyes (fluorescein isothiocyanate-dextran 10 kDa+rhodamine-dextran 70 kDa). Compared with sham-operated rats, HF rats exhibited an elevated extravasation of fluorescein isothiocyanate-dextran 10 kDa within the PVN but not in the brain cortex. The plasma interleukin 17A levels were positively correlated with fluorescein isothiocyanate 10 kDa extravasation in the PVN. The expression of caveolin-1, a transcytosis marker, was augmented, whereas the expression of tight junction proteins was diminished in HF rats. Interleukin 17 receptor A was identified within the endothelium of PVN microvessels. Treatment with interleukin 17 receptor A small interfering RNA led to a significant attenuation of fluorescein isothiocyanate 10 kDa extravasation in the PVN and reversed expression of caveolin-1 and tight junction-associated proteins in the PVN. CONCLUSIONS: Collectively, these data indicate that BBB permeability within the PVN is enhanced in HF and is likely attributable to increased interleukin 17A/interleukin 17 receptor A signaling in the BBB endothelium, by promoting caveolar transcytosis and degradation of tight junction complexes.

Pre-clinical evaluation of biomarkers for the early detection of nephrotoxicity following alpha-particle radioligand therapy.

PURPOSE: Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as an additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLT nephrotoxicity. METHODS: A bifunctional cyclic peptide, melanocortin 1 ligand (MC1L), labeled with [203Pb]Pb-MC1L, was used for [212Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [212Pb]Pb-MC1L in a dose-escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. RESULTS: Biodistribution analysis identified [212Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [212Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [212Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. CONCLUSION: Urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

Heresy - Is there a role for ultrasound in management of the non-palpable testicle?

INTRODUCTION: AUA Guidelines do not support the routine use of ultrasound (US) in evaluation of boys with an undescended testicle (UDT) prior to urology referral. Multiple studies have demonstrated that real time US is inferior to a physical examination by a pediatric urologist in detecting an UDT. However, improved US technology, which now permits detection of the non-palpable testis located just proximal to the internal ring, may aid in guiding the surgical approach to the non-palpable testis. We evaluated US findings of boys deemed to have a non-palpable UDT and compared them to surgical findings. OBJECTIVE: To assess the role of pre-operative ultrasonography in guiding surgical management in boys deemed to have a non-palpable testis by a pediatric urologist. STUDY DESIGN: US of boys with a non-palpable UDT, as reported by a pediatric urologist on physical exam, during a 3-year period, were reviewed. All US were performed jointly by a technician and pediatric radiologist. Patient demographics, laterality, and intra-operative findings were assessed. RESULTS: Thirty-one boys with a non-palpable testicle on physical exam underwent scrotal/inguinal/pelvis US at a median age of 7.5 months (IQR 2.5-12.3 months). Two patients had bilateral non-palpable testicles, 21 had a non-palpable left sided testicle and 8 had a non-palpable right sided testicle. Of the 33 non-palpable testes, 5 (15.2%) were identified in the inguinal canal. Sixteen (48.5%) were visualized in the lower pelvis just proximal to the internal ring and graded as intra-abdominal. Four (12.1%) nubbins or very atrophic testes were identified in the inguinal region or scrotum and 5 (15.2%) testes were not identified on US. Three (9.1%) testes were observed to be mobile between the lower pelvis just proximal to the internal ring and the inguinal canal. Of the 8 patients with testes that were identified in the inguinal canal, or mobile between the lower pelvis and inguinal canal, 7 avoided a diagnostic laparoscopy and underwent an inguinal orchiopexy. Of the 16 testicles located in the lower pelvis proximal to the internal ring, only 2 underwent laparoscopy/laparoscopic orchiopexy. DISCUSSION: In cases of a non-palpable testicle following a physical examination by a urologist, an ultrasound can impact the operative plan, and allow for patients to avoid laparoscopy. In our cohort, 87.5% of non-palpable testes avoided laparoscopic surgery after ultrasound identification of a viable testis. CONCLUSIONS: US in the evaluation of cryptorchidism can guide surgical management in select cases in which a testis is non-palpable following careful examination by a urologist.

Pre-clinical Evaluation of Biomarkers for Early Detection of Nephrotoxicity Following Alpha-particle Radioligand Therapy.

Purpose: Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLTs nephrotoxicity. Methods: A bifunctional cyclic peptide, melanocortin ligand-1(MC1L), labeled with [ 203 Pb]Pb-MC1L, was used for [ 212 Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [ 212 Pb]Pb-MC1L in a dose escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. Results: Biodistribution analysis identified [ 212 Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [ 212 Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary Neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [ 212 Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. Conclusion: urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

Coronary artery endothelial function and aging in people with HIV and HIV-negative individuals.

Coronary artery disease (CAD) is a common comorbidity in people with human immunodeficiency virus (HIV) (PWH) and impaired coronary endothelial function (CEF) plays a central role in the pathogenesis of CAD. Age-related impaired CEF among PWH, however, is not well characterized. We investigated the association between CEF and age in males and females with and without HIV using 3-T magnetic resonance imaging (MRI). We measured the changes in coronary cross-sectional area (CSA) and coronary blood flow during isometric handgrip exercise (IHE), an established endothelial-dependent stressor with smaller increases in CSA and coronary blood flow indicative of impaired CEF. We included 106 PWH and 82 individuals without HIV. Differences in demographic and clinical characteristics between PWH and individuals without HIV were explored using Pearson's χ2 test for categorical variables and Welch's t test for continuous variables. Linear regression models were used to examine the association between CEF and age. CEF was significantly lower in PWH as compared with individuals without HIV. Coronary endothelial dysfunction was also present at younger ages in PWH than in the individuals without HIV and there were significant differences in CEF between the PWH and individuals without HIV across age groups. Among the individuals without HIV, the percent changes in CSA were inversely related to age in unadjusted and adjusted models. There was no significant association between CEF and age in PWH. To the best of our knowledge, this is the first study to examine the relationship between age and CEF in PWH, and our results suggest that factors other than age significantly impair CEF in PWH across the life span.NEW & NOTEWORTHY This is the first study to examine the relationship between age and coronary endothelial function (CEF) in people with human immunodeficiency virus (HIV) (PWH). CEF was assessed using magnetic resonance imaging (MRI) in people with and without HIV. Although age and CEF were significantly inversely related in individuals without HIV, there was no association between age and CEF in PWH.

Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection.

Malignant testicular germ cells tumors (TGCTs) are the most common solid cancers in young men. Current TGCT diagnostics include conventional serum protein markers, but these lack the sensitivity and specificity to serve as accurate markers across all TGCT subtypes. MicroRNAs (miRNAs) are small non-coding regulatory RNAs and informative biomarkers for several diseases. In humans, miRNAs of the miR-371-373 cluster are detectable in the serum of patients with malignant TGCTs and outperform existing serum protein markers for both initial diagnosis and subsequent disease monitoring. We previously developed a genetically engineered mouse model featuring malignant mixed TGCTs consisting of pluripotent embryonal carcinoma (EC) and differentiated teratoma that, like the corresponding human malignancies, originate in utero and are highly chemosensitive. Here, we report that miRNAs in the mouse miR-290-295 cluster, homologs of the human miR-371-373 cluster, were detectable in serum from mice with malignant TGCTs but not from tumor-free control mice or mice with benign teratomas. miR-291-293 were expressed and secreted specifically by pluripotent EC cells, and expression was lost following differentiation induced by the drug thioridazine. Notably, miR-291-293 levels were significantly higher in the serum of pregnant dams carrying tumor-bearing fetuses compared to that of control dams. These findings reveal that expression of the miR-290-295 and miR-371-373 clusters in mice and humans, respectively, is a conserved feature of malignant TGCTs, further validating the mouse model as representative of the human disease. These data also highlight the potential of serum miR-371-373 assays to improve patient outcomes through early TGCT detection, possibly even prenatally.

Fibroepithelial stromal polyp of bladder-a mimicker of sarcoma or angiomyxoma at uncommon location.

The fibroepithelial stromal polyp is a benign polypoid proliferation of the stroma with overlying epithelium. Because the lesion contains atypical stromal cells, sometimes it can be overdiagnosed as sarcoma or with myxoid stroma, it can be misdiagnosed as angiomyxoma. The reported locations are mainly in the lower female genital tract, urethra, and rarely extragenital sites, such as the breast, and are exceptionally rare in the bladder. We encountered a 65-year-old man who presented with two small velvety, erythematous patches on the posterior bladder wall. The final diagnosis is a fibroepithelial stromal polyp of the bladder. Familiarity with this lesion will prevent overinterpretation of this benign lesion as a malignancy.

Validating the Reliability and Clinical Relevance of an Infraorbital Hollow Photonumeric Scale.

Background: Infraorbital hollowing is a facial aesthetic issue for which a broad age range of patients seek treatment. Expanding treatment options for this region warrants the development of validated tools to objectively assess infraorbital hollow (IOH) severity before and after treatment. Objectives: To validate a 4-point rating scale to assess depression of IOH, depression relative to the mid-pupillary line, and visibility of the lateral orbital rim. Methods: The IOH scale described herein was developed and subjected to live validation with a total of 73 patients representing the full range of IOH severities. Scale validation was performed by board-certified plastic surgeons and dermatologists (3 raters) over 2 rounds, 2 weeks apart. Intrarater and interrater reliabilities were used to demonstrate test-retest reliability as quantitated with percentage of agreement, weighted kappa statistic with 95% confidence interval (CI), and intraclass correlation coefficient with 95% CI. The clinical relevance of a 1-grade difference was evaluated by comparing rater assessments of 77 photo pairs with their previously determined designation as "clinically different" or "not clinically different." Results: The IOH scale demonstrated substantial to near-perfect intrarater and interrater reliabilities when utilized by trained raters to assess a diverse group of live patients. Furthermore, clinically relevant differences between grades were established, and detection of a 1-point difference could be achieved by trained evaluators using the IOH scale. Conclusions: This highly reliable, clinically relevant, and validated IOH scale provides a user-friendly, standardized grading system to objectively evaluate and track changes in infraorbital hollowing in clinical practice and research.

Chromophobe Renal Cell Carcinoma with Sarcomatoid Differentiation.

Chromophobe renal cell carcinoma (chRCC) is one of the less common types of kidney cancer and generally portends a more favorable prognosis. RCC with sarcomatoid differentiation has a more aggressive clinical course with poor outcomes. Four cases of chRCC with varying degrees of sarcomatoid differentiation were retrospectively reviewed at our institution, and clinicopathologic data as well as clinical courses were reported. Patients with higher degrees of sarcomatoid differentiation and larger tumors at presentation generally had and worse overall survival. chRCC with sarcomatoid differentiation portends a poor prognosis with limited data on systemic treatment options for metastatic disease.

Preclinical optimization of a diode laser-based clamp-free partial nephrectomy in a large animal model.

Kidney cancer is a common urologic malignancy with either laparoscopic (LPN) or robotic partial nephrectomy as therapeutic options of choice for localized tumors. However, renal resection and suturing are challenging steps of the procedure that can lead to complications such as prolonged warm ischemia, bleeding, and urinary fistulas. LPN with a diode laser is an efficient technique due to its cutting and/or coagulation attributes. Surprisingly, key laser features such as wavelength and power remain undefined. Using a large porcine model, we evaluated the laser range of wavelength and power in a clamp-free LPN and compared it to the established gold-standard LPN technique (i.e., cold-cutting and suturing). By analyzing surgery duration, bleeding, presence of urine leak, tissue damage related to the resected renal fragment and the remaining organ, hemoglobin levels, and renal function, we show that an optimized experimental diode laser clamp-free LPN (wavelength, 980 nm; power, 15 W) had shorter surgery time with less bleeding, and better postoperative renal function recovery when compared to the well-established technique. Together, our data indicate that partial nephrectomy with a diode laser clamp-free LPN technique is an improved alternative to the gold-standard technique. Therefore, translational clinical trials towards human patient applications are readily feasible.

Plasma Lipid Analysis of Simultaneous Application of Radiofrequency Synchronized With HIFEM for Fat Reduction in Same-Day Multiple Sessions.

BACKGROUND: High-intensity focused electromagnetic field (HIFEM) and synchronized radiofrequency (RF) technologies have been shown to be safe and effective on multiple body parts. OBJECTIVE: To determine the plasma lipid levels and liver function tests of consecutive HIFEM + RF procedures delivered on the same day. METHODS: Eight women and 2 men (24-59 years, BMI 22.4-30.6 kg/m 2 ) underwent 4 30-minute consecutive HIFEM + RF procedures. The treated area differed according to gender (females: abdomen and lateral and inner thighs; males: abdomen and front and back thighs). Liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyltransferase [GGT], alkaline phosphatase [ALP]) and lipid profile (cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], triglycerides [TG]) was monitored from blood samples drawn before the treatment, 1 hour, 24 to 48 hours, and 1 month after treatment. The subject's satisfaction, comfort, abdominal circumference, and digital photographs were also monitored. RESULTS: All 10 patients completed planned treatments and follow-up blood draws. No significant fluctuation or notable deviation in the measured blood parameters was observed. The average values during the study were in a range of AST 15.7 to 16.7IU/L, ALT 11.9 to 13.4IU/L, GGT 11.6 to 13.8IU/L, and ALP 71.4 to 77.2IU/L, TG 1.0 mmol/L, HDL 1.7 mmol/L, LDL 3.0 mmol/L, and cholesterol 5.0 to 5.1 mmol/L corresponded to the normal ranges. Subjects reported high comfort during the treatment and satisfaction with their results. No adverse event occurred. CONCLUSION: Plasma levels remained stable and normal or lipids and LFTs for multiple same-day treatments of RF plus HIFEM.

Safety and Efficacy of a Novel, Variable-Sequenced, Long-Pulsed, 532-nm and 1,064-nm Laser With Cryogen Spray Cooling for Pigmented and Vascular Lesions.

BACKGROUND: Patients frequently seek treatment for vascular and pigmented lesions. More recently, a novel, variable-sequenced, long-pulsed, 532-nm and 1,064-nm laser with cryogen spray cooling was developed to offer greater flexibility in treatments. OBJECTIVE: A prospective clinical trial evaluated the safety and efficacy of a novel, variable-sequenced, long-pulsed, 532-nm and 1,064-nm laser with cryogen spray cooling (DermaV, Lutronic, South Korea). MATERIALS AND METHODS: Subjects with vascular and/or pigmented lesions were enrolled and underwent laser treatments. RESULTS: Twenty-three subjects were enrolled with vascular lesions (39.1%), pigmented lesions (17.4%), and both (43.5%). Mean age was 53.1 years, and 91.3% were women. Fitzpatrick skin types II-IV were included. All subjects were treated with 532 nm, and 4 were also treated with 1,064 nm. According to 4 blinded physician reviewers, correct before and after photographs were selected in 94.7%, 92.1%, 84.2%, and 76.3% of cases. Overall, 86.8% were responders, meaning that at least 3 of 4 reviewers agreed. For Global Aesthetic Improvement Scale, improvement occurred in 81.6%, 81.6%, 81.6%, and 76.3% of cases. No serious adverse events occurred. Overall, 87.0% of subjects reported being very satisfied or satisfied. CONCLUSION: A novel, variable-sequenced, long-pulsed, 532-nm and 1,064-nm laser with cryogen spray cooling can safely and effectively improve vascular and pigmented lesions.

Concurrent Xanthogranulomatous Pyelonephritis and Upper Urinary Tract Transitional Cell Carcinoma.

A 37-year-old male with a history of chronic nephrolithiasis presented to the ED with gross hematuria, clot retention, and right flank pain. The patient had radiological findings of perinephric stranding, marked hydronephrosis, and marked thinning of the right renal parenchyma on computed tomography (CT), all suggestive of xanthogranulomatous pyelonephritis (XGP). The specimen following radical nephrectomy revealed urothelial carcinoma (UC) in a background of XGP but with no evidence of spread to regional lymph nodes. Follow-up imaging revealed hypodense lesions in the liver which demonstrated UC on biopsy. This is the first reported case of a young patient presenting with such an advanced stage of UC in the setting of XGP. It illustrates the link between inflammatory processes of the kidney and malignancy of the upper urinary tract.

The Relationship Between Impaired Coronary Endothelial Function and Systemic Markers of Inflammation in People Living With HIV.

BACKGROUND: People with HIV (PWH) are at an increased risk of cardiovascular disease, partially believed to be related to chronically elevated systemic inflammation. Abnormal systemic endothelial function (SEF) and coronary endothelial function (CEF) develop early in atherogenesis and predict adverse events. It is unknown whether abnormal CEF is related to systemic inflammation in PWH. METHODS: In this substudy of a prior randomized controlled trial in PWH without prior clinical coronary artery disease suppressed on antiretroviral therapy with CEF as a primary end point (N = 82), we investigated the associations between baseline serum markers of inflammation and adhesion and baseline CEF, assessed by noninvasive MRI measures of percentage changes in coronary blood flow and cross-sectional area during isometric handgrip exercise, and SEF using brachial ultrasound for flow-mediated dilation. We also evaluated whether baseline marker levels were associated with CEF after 8 weeks in the placebo group (N = 40). RESULTS: CEF measures were abnormal at baseline, based on trial entry criteria. A higher value of CEF was directly associated with levels of interleukin 10, whereas CEF at baseline was inversely associated with E-selectin. Worse CEF at 8 weeks was directly associated with baseline tumor necrosis factor alpha, intercellular adhesion molecule 1, C-reactive protein, interferon gamma and sICAM-3. SEF at baseline or 8 weeks was not associated with any baseline markers. CONCLUSION: Coronary but not systemic endothelial dysfunction was significantly associated with select markers of inflammation and adhesion in PWH. Furthermore, CEF but not SEF at 8 weeks was associated with baseline levels of inflammation. Our findings suggest that abnormal CEF and systemic markers of inflammation are linked in PWH.

dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.

Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ∼1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB-CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.