Background Sodium–glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated consistent cardiovascular benefits across a broad range of high-risk populations. However, their role after transcatheter aortic valve implantation (TAVI) remains incompletely defined. Therefore, we conducted this study to comprehensively evaluate the association of SGLT2i therapy with mortality, heart failure, and renal outcomes after TAVI. Methods Randomized controlled trials and observational cohort studies comparing SGLT2i users with non-users or standard care were included. The prespecified outcomes were 1-year all-cause mortality, long-term all-cause mortality (follow-up ≥ 2 years), heart failure hospitalization, composite clinical endpoint, and acute kidney injury (AKI). Random-effects models pooled hazard ratios (HR) or odds ratios (OR) with 95% confidence intervals (CI). Results Eight studies comprising 14785 patients were included. Post-TAVI SGLT2i therapy was associated with a lower risk of 1-year all-cause mortality (HR 0.72; 95% CI 0.61 to 0.84; p < 0.001), ≥ 2-year all-cause mortality (HR 0.59; 95% CI 0.51 to 0.67; p < 0.001), heart failure hospitalization (HR 0.63; 95% CI 0.44 to 0.91; p = 0.013), composite clinical endpoint (HR 0.74; 95% CI 0.64 to 0.84; p < 0.001). In contrast, no significant overall reduction was observed for AKI (OR 0.68 95% CI 0.36 to 1.30; p = 0.247). The 1-year mortality and HF hospitalization estimates were sensitive to omission of individual studies. Conclusions In patients undergoing TAVI, SGLT2i therapy was associated with lower risks of short- and long-term mortality, heart failure hospitalization, and composite clinical events, whereas no statistically significant association with AKI was observed.

Duchenne muscular dystrophy (DMD) is a severe X-linked disorder with progressive myofiber degeneration and fibrosis from dystrophin deficiency. Current therapies are largely supportive with limited anti-fibrotic benefit, prompting new strategies. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) show emerging anti-fibrotic and anti-inflammatory effects. Open-access proteomic and transcriptomic data sets were integrated for in silico analyses, including differential gene expression, weighted gene co-expression network analysis, and pathway enrichment, to identify dysregulated pathways potentially reversible by SGLT2i. Immune cell composition was estimated using CIBERSORTx in human and murine data sets. Therapeutic effects were tested with empagliflozin (EMPA) in mdx mice (30 mg/kg per day for 4 weeks, starting at 12 weeks) and DMDmdx rats (10 mg/kg per day for 4 months, starting at 5 months), with vehicle controls. Validation used quantitative RT-PCR, grip-strength testing, and histologic fibrosis staining. Analyses highlighted dysregulated extracellular matrix organization, cytokine signaling, and immune responses. Forty overlapping genes were identified; hub genes included COL3A1, COL5A2, and TGFB1. EMPA reduced Tgfb1 expression in DMD rats and significantly decreased collagen deposition in skeletal muscle. Functional testing showed longer grip duration in EMPA-treated mice. Immune profiling revealed shifts in T cells and macrophages, indicating immunomodulation. Findings were consistent across species and data modalities analyzed. These results demonstrate that EMPA modulates fibrosis, inflammation, and muscle endurance in DMD models. These data support repurposing SGLT2i as a promising therapeutic strategy for DMD.

Duchenne muscular dystrophy (DMD) is a severe X-linked disorder with progressive myofiber degeneration and fibrosis from dystrophin deficiency. Current therapies are largely supportive with limited anti-fibrotic benefit, prompting new strategies. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) show emerging anti-fibrotic and anti-inflammatory effects. Open-access proteomic and transcriptomic data sets were integrated for in silico analyses, including differential gene expression, weighted gene co-expression network analysis, and pathway enrichment, to identify dysregulated pathways potentially reversible by SGLT2i. Immune cell composition was estimated using CIBERSORTx in human and murine data sets. Therapeutic effects were tested with empagliflozin (EMPA) in mdx mice (30 mg/kg per day for 4 weeks, starting at 12 weeks) and DMDmdx rats (10 mg/kg per day for 4 months, starting at 5 months), with vehicle controls. Validation used quantitative RT-PCR, grip-strength testing, and histologic fibrosis staining. Analyses highlighted dysregulated extracellular matrix organization, cytokine signaling, and immune responses. Forty overlapping genes were identified; hub genes included COL3A1, COL5A2, and TGFB1. EMPA reduced Tgfb1 expression in DMD rats and significantly decreased collagen deposition in skeletal muscle. Functional testing showed longer grip duration in EMPA-treated mice. Immune profiling revealed shifts in T cells and macrophages, indicating immunomodulation. Findings were consistent across species and data modalities analyzed. These results demonstrate that EMPA modulates fibrosis, inflammation, and muscle endurance in DMD models. These data support repurposing SGLT2i as a promising therapeutic strategy for DMD. (Am J Pathol 2026, 196: 745-765; https://doi.org/10.1016/j.ajpath.2025.11.002)

Duchenne muscular dystrophy (DMD) is a severe X-linked disorder with progressive myofiber degeneration and fibrosis from dystrophin deficiency. Current therapies are largely supportive with limited anti-fibrotic benefit, prompting new strategies. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) show emerging anti-fibrotic and anti-inflammatory effects. Open-access proteomic and transcriptomic data sets were integrated for in silico analyses, including differential gene expression, weighted gene co-expression network analysis, and pathway enrichment, to identify dysregulated pathways potentially reversible by SGLT2i. Immune cell composition was estimated using CIBERSORTx in human and murine data sets. Therapeutic effects were tested with empagliflozin (EMPA) in mdx mice (30 mg/kg per day for 4 weeks, starting at 12 weeks) and DMDmdx rats (10 mg/kg per day for 4 months, starting at 5 months), with vehicle controls. Validation used quantitative RT-PCR, grip-strength testing, and histologic fibrosis staining. Analyses highlighted dysregulated extracellular matrix organization, cytokine signaling, and immune responses. Forty overlapping genes were identified; hub genes included COL3A1, COL5A2, and TGFB1. EMPA reduced Tgfb1 expression in DMD rats and significantly decreased collagen deposition in skeletal muscle. Functional testing showed longer grip duration in EMPA-treated mice. Immune profiling revealed shifts in T cells and macrophages, indicating immunomodulation. Findings were consistent across species and data modalities analyzed. These results demonstrate that EMPA modulates fibrosis, inflammation, and muscle endurance in DMD models. These data support repurposing SGLT2i as a promising therapeutic strategy for DMD.

Objective: Heart failure in cancer patients remains underrepresented and challenging due to non-specific treatments and an incomplete understanding of cancer or cancer cachexia–induced cardiomyopathy. This study explores the roles of sarcomere impairment, altered Ca 2+ handling, and metabolic reprogramming in contributing to left ventricular (LV) dysfunction. Methods: Male BALB/c mice were subcutaneously inoculated with mouse colon-26 adenocarcinoma (C26) or IL-6–silenced C26 (C26 shIL-6) cells, while controls received PBS. Twenty days post-injection, cardiac function was evaluated via electrocardiography, transthoracic echocardiography, and ex vivo working heart assays. Isolated ventricular cardiomyocytes were analyzed for intracellular Ca 2+ transients and force–calcium relationships. Cardiac inflammation, metabolism, and fibrosis were quantified alongside proteomic analysis. Results: Despite similar tumor sizes, C26 mice exhibited cachexia with loss of subcutaneous fat and skeletal muscle and elevated serum IL-6. Both tumor-bearing groups trended toward impaired LV systolic and diastolic function, with a significant reduction in maximum calcium-activated tension (T_max; p < 0.05) in skinned cardiomyocyte preparations. Cachectic mice showed increased intracellular Ca 2+ transients, suggesting upregulated SERCA2 activity. While macrophage and T-cell infiltration and interstitial fibrosis were unchanged, neutrophil infiltration was enhanced in the cachectic group. Additionally, β-myosin heavy chain expression was upregulated, and metabolic profiling revealed a shift toward glucose utilization with reduced fatty acid oxidation, corroborated in h9c2 cells exposed to conditioned media from C26 and C26 shIL-6 cells. Unbiased proteomic analysis demonstrated significant downregulation of Bag3, Hspa4, Pln, Serca2, Pfkm, and Shdh exclusively in cachectic hearts. Discussion: In conclusion, cancer-induced cachexia in C26 mice leads to LV dysfunction, characterized by altered calcium handling in cardiomyocytes, metabolic reprogramming, and sarcomere impairment. These findings highlight key mechanisms contributing to cardiomyopathy in cachexia and provide potential targets for therapeutic intervention in cancer-related cardio metabolic dysfunction.

Diabetic cardiomyopathy (DCM) is a complex condition linked to diabetes, characterized by cardiac and vascular dysfunction, frequently concomitant with heart failure with preserved ejection fraction. The extracellular matrix glycoprotein Tenascin-C (TNC) has been found to be upregulated under diabetic conditions. However, the potential contributory role of TNC in the progression of DCM remains largely unclear. This study was designed to elucidate the role of TNC in the pathogenesis of DCM. Diabetes was induced in adult male wild-type (WT) and TNC knockout (TNC-KO) mice, through the administration of streptozotocin (50 mg/kg) for five consecutive days. At 18 weeks cardiac and aortic vascular function was evaluated using echocardiography and wire myography. Myocardium and plasma samples were collected for biochemical, histological, and molecular analyses. Cardiomyocytes and cardiac fibroblasts were used to investigate the impact of diabetes on TNC expression, inflammation, myocardial stiffness and function. Additionally, transcriptomic analysis of cardiac tissue by RNA-sequencing was conducted. Plasma TNC levels were assessed by enzyme-linked immunosorbent assay in cohorts of heart failure patients and type 2 diabetes mellitus. TNC-KO diabetic mice showed preserved left ventricular systolic and diastolic function, significantly reduced cardiac fibrosis and mitigated endothelial dysfunction compared to WT diabetic animals. Compared with cardiomyocytes of diabetic WT animals, cardiomyocytes of TNC-KO mice developed less stiffness (Fpassive). Additionally, exposing mouse cardiomyocytes and human cardiac fibroblasts to high glucose stress (30 mM) led to a significant increase in TNC expression. Conversely, recombinant human TNC promoted pro-inflammatory and oxidative stress markers in cardiomyocytes. The role of TNC in fibrosis and DCM was found to involve pathways related to p53 signaling and Serpin1k, Ccn1, Cpt1a, and Slc27a1, as identified by RNA sequencing analysis. Additionally, plasma TNC levels were significantly elevated in patients with heart failure, irrespective of diabetes status, compared to healthy individuals. Our findings indicate that in diabetes, TNC contributes to cardiac contractile dysfunction, myocardial fibrosis, oxidative stress, inflammation, and metabolic disturbances in diabetic mouse heart. These results implicate the potential of TNC inhibition as a novel therapeutic approach for treating DCM.

Duchenne muscular dystrophy (DMD), a severe muscle disease caused by mutations in the gene encoding for the intracellular protein dystrophin, is associated with impaired cardiac function and arrhythmias. A causative factor for complications in the dystrophic heart is abnormal calcium (Ca) handling in ventricular cardiomyocytes, and restoration of normal Ca homeostasis has emerged as therapeutic strategy. Here, we used a rodent model of DMD, the dystrophin-deficient DMDmdx rat, to test the following hypothesis: chronic administration of ivabradine (IVA), a drug clinically approved for the treatment of heart failure, improves Ca handling in dystrophic ventricular cardiomyocytes and thereby enhances contractile performance in the dystrophic heart. Intracellular Ca measurements revealed that 4-months administration of IVA to DMDmdx rats significantly improves Ca handling properties in dystrophic ventricular cardiomyocytes. In particular, IVA treatment increased electrically-evoked Ca transients and speeded their decay. This suggested enhanced sarcoplasmic reticulum Ca release and faster removal of Ca from the cytosol. Chronic IVA administration also enhanced the sarcoplasmic reticulum Ca load. Transthoracic echocardiography revealed a significant improvement of cardiac systolic function in IVA-treated DMDmdx rats. Thus, left ventricular ejection fraction and fractional shortening were enhanced, and end-systolic as well as end-diastolic diameters were diminished by the drug. Finally, chronic IVA administration neither significantly attenuated cardiac fibrosis and apoptosis, nor was vascular function improved by the drug. Collectively our findings suggest that long-term IVA administration enhances contractile function in the dystrophic heart by improvement of Ca handling in ventricular cardiomyocytes. Chronic IVA administration may be beneficial for DMD patients.

Background: There is currently no therapy targeting cancer-related cardiomyopathy and treatment of heart failure in the oncological setting is nonspecific. Moreover, cancer is often assocaited with cachexia and the pathophysiology of cancer-cachexia induced cardiac (dys)functions are not fully known. Methods: Colon-26 adenocarcinoma (C26; n=30) or shIL-6 (C26 shIL-6; n=30) cells were inoculated subcutaneously into the flank of syngeneic adult male BALB/cmice, meanwhile control mice were injected with PBS (n=25). Twenty days after the cells injection, cardiac function was assessed using transthoracic echocardiography, ex vivo isolated working heart methods. In addition, intracellular Ca 2+ transient and force-calcium relationships were assessed in isolated single ventricular cardiomyocytes (CMs). Cardiac inflammation, metabolism and fibrosis were also assessed. Results: Despite that tumor size was comparable between the cancer groups, C26 group showed a loss of subcutaneous fat and skeletal muscle confirming a cachectic phenotype in association with an elevation of serum IL-6 levels. Tumor-bearing mice groups show a tendecy towards to both LV systolic and diastolic dysfunction. Sarcomere dysfunction, including significantly reduced maximum calcium-activated tension (Tmax) and increased calcium sensitivity (decreased EC 50 ) was found in skinned cardiomyocyte preparation from both tumor-bearing mice in compared to controls (p<0.05, respectively). Intracellular Ca 2+ transient was exclusively increased in CM isolated from cachectic mice, suggesting the SERCA2 upregulation. Infiltration of macrophage or T-cells, nor interstital fibrosis were difference. β-myosin heavy chain expression is upregulated in a cell autonomous fashion in C26 mice. Comprehensive energetic and metabolims analysis showed shift to a profound glucose metabolsim and reduction in fatty acid oxidation in LV samples. This was futher proven in h9c2 cells were incubated with C26 or shIL6 cell culture medium. Discussion: Our results suggest that LV dysfunction in cancer mice is associated with sarcomere dysfunction while additional abnormal intracellular Ca 2+ handling is solely present in mice with cachectic phenotype. These functional alterations are independent from changes in myocardial fibrosis and inflammation but may rely on the cardiac metabolism alterations. These data provide new insights into how cancer and cancer-cachexia impacts the cardiac performance even prior to cancer therapy treatments.

Supplementary Methods and Figure Legends 1-2 from Colon Cancer Cell–Derived Tumor Necrosis Factor-α Mediates the Tumor Growth–Promoting Response in Macrophages by Up-regulating the Colony-Stimulating Factor-1 Pathway

Supplementary Figure 1 from Colon Cancer Cell–Derived Tumor Necrosis Factor-α Mediates the Tumor Growth–Promoting Response in Macrophages by Up-regulating the Colony-Stimulating Factor-1 Pathway

Telomerase reverse transcriptase (TERT) plays a key role in the maintenance of telomere DNA length. The rs10069690 single nucleotide variant, located in intron 4 of TERT, was found to be associated with telomere length and the risk of estrogen receptor-negative but not–positive breast cancer. This study aimed at analysis of the association of rs10069690 genotype and TERT expression with the risk, age at onset, prognosis, and clinically and molecularly relevant subtypes of breast cancer. Accordingly, rs10069690 was genotyped in a hospital-based case-control study of 403 female breast cancer patients and 246 female controls of a Central European (Austrian) study population, and the mRNA levels of TERT were quantified in 106 primary breast tumors using qRT-PCR. We found that in triple-negative breast cancer patients, the minor rs10069690 TT genotype tended to be associated with an increased breast cancer risk (OR, 1.87; 95% CI, 0.75–4.71; p = 0.155) and was significantly associated with 11.7 years younger age at breast cancer onset (p = 0.0002), whereas the CC genotype was associated with a poor brain metastasis-free survival (p = 0.009). Overall, our data show that the rs10069690 CC genotype and a high TERT expression tended to be associated with each other and with a poor prognosis. Our findings indicate a key role of rs10069690 in triple-negative breast cancer.

Chronic kidney disease is a global health problem affecting 10% to 12% of the population. Uremic cardiomyopathy is often characterized by left ventricular hypertrophy, fibrosis, and diastolic dysfunction. Dysregulation of neuregulin-1β signaling in the heart is a known contributor to heart failure. The systemically administered recombinant human neuregulin-1β for 10 days in our 5/6 nephrectomy-induced model of chronic kidney disease alleviated the progression of uremic cardiomyopathy and kidney dysfunction in type 4 cardiorenal syndrome. The currently presented positive preclinical data warrant clinical studies to confirm the beneficial effects of recombinant human neuregulin-1β in patients with chronic kidney disease.

Introduction: Ventilator-induced lung injury (VILI) may aggravate critical illness. Although angiotensin-converting enzyme (ACE) inhibition has beneficial effects in ventilator-induced lung injury, its clinical application is impeded by concomitant hypotension. We hypothesized that the aminopeptidase inhibitor ALT-00 may oppose the hypotension induced by an angiotensin-converting enzyme inhibitor, and that this combination would activate the alternative renin-angiotensin system (RAS) axis to counteract ventilator-induced lung injury. Methods: In separate experiments, C57BL/6 mice were mechanically ventilated with low (LVT, 6 mL/kg) and high tidal volumes (HVT, 30 mL/kg) for 4 h or remained unventilated (sham). High tidal volume-ventilated mice were treated with lisinopril (0.15 μg/kg/min) ± ALT-00 at 2.7, 10 or 100 μg/kg/min. Blood pressure was recorded at baseline and after 4 h. Lung histology was evaluated for ventilator-induced lung injury and the angiotensin (Ang) metabolite profile in plasma (equilibrium levels of Ang I, Ang II, Ang III, Ang IV, Ang 1-7, and Ang 1-5) was measured with liquid chromatography tandem mass spectrometry at the end of the experiment. Angiotensin concentration-based markers for renin, angiotensin-converting enzyme and alternative renin-angiotensin system activities were calculated. Results: High tidal volume-ventilated mice treated with lisinopril showed a significant drop in the mean arterial pressure at 4 h compared to baseline, which was prevented by adding ALT-00 at 10 and 100 μg/kg/min. Ang I, Ang II and Ang 1-7 plasma equilibrium levels were elevated in the high tidal volumes group versus the sham group. Lisinopril reduced Ang II and slightly increased Ang I and Ang 1-7 levels versus the untreated high tidal volumes group. Adding ALT-00 at 10 and 100 μg/kg/min increased Ang I and Ang 1-7 levels versus the high tidal volume group, and partly prevented the downregulation of Ang II levels caused by lisinopril. The histological lung injury score was higher in the high tidal volume group versus the sham and low tidal volume groups, and was attenuated by lisinopril ± ALT-00 at all dose levels. Conclusion: Combined angiotensin-converting enzyme plus aminopeptidase inhibition prevented systemic hypotension and maintained the protective effect of lisinopril. In this study, a combination of lisinopril and ALT-00 at 10 μg/kg/min appeared to be the optimal approach, which may represent a promising strategy to counteract ventilator-induced lung injury that merits further exploration.

Sympathetic nerve denervation after myocardial infarction (MI) predicts risk of sudden cardiac death. Therefore, therapeutic approaches limit infarct size, improving adverse remodeling and restores sympathetic innervation have a great clinical potential. Remote ischemic perconditioning (RIPerc) could markedly attenuate MI-reperfusion (MIR) injury. In this study, we aimed to assess its effects on cardiac sympathetic innervation and metabolism. Transient myocardial ischemia is induced by ligature of the left anterior descending coronary artery (LAD) in male Sprague–Dawley rats, and in vivo cardiac 2-[ 18 F]FDG and [ 11 C] m HED PET scans were performed at 14–15 days after ischemia. RIPerc was induced by three cycles of 5-min-long unilateral hind limb ischemia and intermittent 5 min of reperfusion during LAD occlusion period. The PET quantitative parameters were quantified in parametric polar maps. This standardized format facilitates the regional radioactive quantification in deficit regions to remote areas. The ex vivo radionuclide distribution was additionally identified using autoradiography. Myocardial neuron density (tyrosine hydroxylase positive staining) and chondroitin sulfate proteoglycans (CSPG, inhibiting neuron regeneration) expression were assessed by immunohistochemistry. There was no significant difference in the mean hypometabolism 2-[ 18 F]FDG uptake ratio (44.6 ± 4.8% vs. 45.4 ± 4.4%) between MIR rats and MIR + RIPerc rats ( P > 0.05). However, the mean [ 11 C] m HED nervous activity of denervated myocardium was significantly elevated in MIR + RIPerc rats compared to the MIR rats (35.9 ± 7.1% vs. 28.9 ± 2.3%, P < 0.05), coupled with reduced denervated myocardium area (19.5 ± 5.3% vs. 27.8 ± 6.6%, P < 0.05), which were associated with preserved left-ventricular systolic function, a less reduction in neuron density, and a significant reduction in CSPG and CD68 expression in the myocardium. RIPerc presented a positive effect on cardiac sympathetic-nerve innervation following ischemia, but showed no significant effect on myocardial metabolism.

OBJECTIVES: Ventilator-induced lung injury (VILI) is a major contributor to morbidity and mortality in critically ill patients. Mechanical damage to the lungs is potentially aggravated by the activation of the renin-angiotensin system (RAS). This article describes RAS activation profiles in VILI and discusses the effects of angiotensin (Ang) 1–7 supplementation or angiotensin-converting enzyme (ACE) inhibition with captopril as protective strategies. DESIGN: Animal study. SETTING: University research laboratory. SUBJECTS: C57BL/6 mice. INTERVENTIONS: Anesthetized mice ( n = 12–18 per group) were mechanically ventilated with low tidal volume (LV T , 6 mL/kg), high tidal volume (HV T , 15 mL/kg), or very high tidal volume (VHV T , 30 mL/kg) for 4 hours, or killed after 3 minutes (sham). Additional VHV T groups received infusions of 60 μg/kg/hr Ang 1–7 or a single dose of 100 mg/kg captopril. MEASUREMENTS AND MAIN RESULTS: VILI was characterized by increased bronchoalveolar lavage fluid levels of interleukin (IL)-6, keratinocyte-derived cytokine, and macrophage inflammatory protein-2 (MIP2). The Ang metabolites in plasma measured with liquid chromatography tandem mass spectrometry showed a strong activation of the classical (Ang I, Ang II) and alternative RAS (Ang 1–7, Ang 1–5), with highest concentrations found in the HV T group. Although the lung-tissue ACE messenger RNA expression was unchanged, its protein expression showed a dose-dependent increase under mechanical ventilation. The ACE2 messenger RNA expression decreased in all ventilated groups, whereas ACE2 protein levels remained unchanged. Both captopril and Ang 1–7 led to markedly increased Ang 1–7 plasma levels, decreased Ang II levels, and ACE activity (Ang II/Ang I ratio), and effectively prevented VILI. CONCLUSIONS: VILI is accompanied by a strong activation of the RAS. Based on circulating Ang metabolite levels and tissue expression of RAS enzymes, classical ACE-dependent and alternative RAS cascades were activated in the HV T group, whereas classical RAS activation prevailed with VHV T ventilation. Ang 1–7 or captopril protected from VILI primarily by modifying the systemic RAS profile.

Introduction: Cancer is independently associated with the alteration of cardiac function prior to cardiotoxic chemotherapy (CCT) exposure. Similar to cancer associated cachexia (CAC), the elevation and the deleterious role of IL-6 in plasma was associated with a reduced cardiac function in heart failure (HF) patients subpopulation. Cancer cells manipulate BCL-2-associated athanogene 3 (BAG3)-HSP70-regulated pathways in tumor cells, which is a key regulator of protein turnover and contractility in cardiomyocyte. Hypothesis: Here, we aimed to characterize the progression of cardiac dysfunction and the expression of BAG3 and HSP70 in tumor-bearing mice. Methods: Colon-26 adenocarcinoma cells (C26; n=22) with/without shIL-6 (C26 shIL-6; n=22) were injected subcutaneously adult male BALB/c mice. Control mice were injected with PBS (n=13). Echocardiographic examinations and invasive hemodynamic measurements ( in vivo and ex vivo using isolated working hearts system) were performed at 10 (early) and 20 (late) days post injection, respectively. The expression of BAG3 and Hsp70 were determined by Western blot. Results: The tumor size was comparable between the cancer groups. However, only C26 group showed a significant loss of subcutaneous fat and skeletal muscle (p<0.05, respectively), confirming cachectic condition. Echocardiography results show a tendency to decline of ejection fraction at the early phase (p~0.08 vs Control), and turned significance lower at late stage (p<0.05 vs Control) in tumor-bearing mice. In line with that, invasive hemodynamic and isolated working heart measurements confirmed LV systolic and diastolic dysfunction (late stage, p<0.05 vs Control, respectively). Interestingly, heart rate and aortic flow were predominantly declined in cachectic animals (p<0.05 vs Control). Importantly, cardiac dysfunction was associated with a significant reduction in both BAG3 and Hsp70 in the myocardium independently of cachexia. Conclusions: Cancer rather than CAC is a main driver for the development of cardiac contractile dysfunction prior to CCT exposure. In addition, our data suggest that targeting BAG3-Hsp70 complex in the cardiomyocytes may provide a novel strategy to improve the cancer associated cardiac dysfunction.