Impact of Autophagy on Prognosis of Patients With Dilated Cardiomyopathy

Kanamori, Hiromitsu; Yoshida, Akihiro; Naruse, Genki; Endo, Saori; Minatoguchi, Shingo; Watanabe, Takatomo; Kawaguchi, Tomonori; Tanaka, Toshiki; Yamada, Yoshihisa; Takasugi, Nobuhiro; Ishihara, Takuma; Mikami, Atsushi; Miyazaki, Nagisa; Nishigaki, Kazuhiko; Miyazaki, Tatsuhiko; Okura, Hiroyuki

doi:10.1016/j.jacc.2021.11.059

Cited by 31 publications

(31 citation statements)

References 31 publications

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“…139,140 Although excessive stimulation of autophagy may exert deleterious effects on the heart (particularly after acutely imposed massive stresses in the absence of HF), 141,142 measured augmentation of selective autophagy protects the heart against pressure overload, hypoxia, and injury produced by cardiotoxic agents, 143,144 and shields podocytes and renal tubular cells from damage caused by diabetes, ischemia, and nephrotoxic drugs. 145,146 Autophagic vacuoles are increased in patients who show reverse cardiac remodeling or receive mechanical unloading, 147,148 whereas persistent impairment in autophagy flux in the failing human heart is a poor prognostic sign. 149,150 Similarly, autophagic function is blunted in renal tubular cells of patients with diabetic nephropathy 151 and loss of autophagosomes is a marker of chronic graft dysfunction in renal transplant patients.…”

Section: Action Of Nutrient Sensors To Influence Cellular Stress By M...mentioning

confidence: 99%

“…Autophagic vacuoles are increased in patients who show reverse cardiac remodeling or receive mechanical unloading, 147 , 148 whereas persistent impairment in autophagy flux in the failing human heart is a poor prognostic sign. 149 , 150 Similarly, autophagic function is blunted in renal tubular cells of patients with diabetic nephropathy 151 and loss of autophagosomes is a marker of chronic graft dysfunction in renal transplant patients.…”

Section: Actions Of Sglt2 Inhibitors To Promote Nutrient Deprivation ...mentioning

confidence: 99%

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Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

2022

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SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression of cardiomyopathy and nephropathy, which is characterized by a reduction in oxidative and endoplasmic reticulum stress, restoration of mitochondrial health and enhanced mitochondrial biogenesis, a decrease in proinflammatory and profibrotic pathways, and preservation of cellular and organ integrity and viability. A substantial body of evidence indicates that this characteristic pattern of responses can be explained by the action of SGLT2 inhibitors to promote cellular housekeeping by enhancing autophagic flux, an effect that may be related to the action of these drugs to produce simultaneous upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling, as manifested by an increase in the expression and activity of AMPK (adenosine monophosphate–activated protein kinase), SIRT1 (sirtuin 1), SIRT3 (sirtuin 3), SIRT6 (sirtuin 6), and PGC1-α (peroxisome proliferator–activated receptor γ coactivator 1-α) and decreased activation of mTOR (mammalian target of rapamycin). The distinctive pattern of cardioprotective and renoprotective effects of SGLT2 inhibitors is abolished by specific inhibition or knockdown of autophagy, AMPK, and sirtuins. In the clinical setting, the pattern of differentially increased proteins identified in proteomics analyses of blood collected in randomized trials is consistent with these findings. Clinical studies have also shown that SGLT2 inhibitors promote gluconeogenesis, ketogenesis, and erythrocytosis and reduce uricemia, the hallmarks of nutrient deprivation signaling and the principal statistical mediators of the ability of SGLT2 inhibitors to reduce the risk of heart failure and serious renal events. The action of SGLT2 inhibitors to augment autophagic flux is seen in isolated cells and tissues that do not express SGLT2 and are not exposed to changes in environmental glucose or ketones and may be related to an ability of these drugs to bind directly to sirtuins or mTOR. Changes in renal or cardiovascular physiology or metabolism cannot explain the benefits of SGLT2 inhibitors either experimentally or clinically. The direct molecular effects of SGLT2 inhibitors in isolated cells are consistent with the concept that SGLT2 acts as a nutrient surplus sensor, and thus, its inhibition causes enhanced nutrient deprivation signaling and its attendant cytoprotective effects, which can be abolished by specific inhibition or knockdown of AMPK, sirtuins, and autophagic flux.

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Section: Action Of Nutrient Sensors To Influence Cellular Stress By M...mentioning

confidence: 99%

Section: Actions Of Sglt2 Inhibitors To Promote Nutrient Deprivation ...mentioning

confidence: 99%

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

2022

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“…Theoretically, LVRR is caused by a reduction in hemodynamic, energetic, and neurohumoral stresses by OMT (17). The decreased left ventricular volume and increased LVEF suggest morphological and functional recovery of impaired cardiomyocytes (1)(2)(3).…”

Section: Theoretical Bases Of LV Reversibility In Mamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Dilated cardiomyopathy (DCM) is a heterogeneous disease, and it is challenging to predict whether left ventricular functional recovery (left ventricular reverse remodeling [LVRR]) can be achieved (1)(2)(3). LVRR is indicative of a good prognosis and is achieved in about 40% of patients with DCM through optimal medical therapies (OMTs) (1)(2)(3)(4). The early prediction of LVRR in newly-diagnosed DCM patients is desirable when considering the indication for an im-plantable cardioverter-defibrillator or heart transplantation.…”

Section: Introductionmentioning

confidence: 99%

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Baseline Blood Pressure and Left Ventricular Reverse Remodeling in Dilated Cardiomyopathy with Spontaneous Mechanical Alternans

et al. 2023

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Background Spontaneous mechanical alternans (MA), or pulsus alternans, has been observed in heart failure patients with hypertension or tachycardia for 150 years and is considered a sign of a poor prognosis. However, in some dilated cardiomyopathy (DCM) patients with MA, optimal medical therapy (OMT) brings left ventricular reverse remodeling (LVRR), a preferable prognostic indicator. This study examined the probability of LVRR in DCM patients with spontaneous MA and whether or not LVRR can be predicted by the baseline blood pressure or heart rate. Methods and ResultsThirty-three newly diagnosed DCM patients were retrospectively examined. Spontaneous MA was observed during diagnostic cardiac catheterization in at least 1 of the pressure waveforms of the aorta, left ventricle, pulmonary artery, or right ventricle in 10 patients (30%) (MA-group). LVRR after OMT was achieved roughly equally in the MA group (6 of 10, 60%) and the non-MA group (12 of 23, 52%). In the MA group, those who achieved LVRR had a significantly higher baseline systolic aortic pressure (more than 120 mmHg in all 6 patients) than those who did not, although the baseline heart rate did not show a significant correlation with LVRR. In contrast, in the non-MA group, LVRR was unrelated to the baseline aortic pressure or heart rate. Conclusions The probability of LVRR in newly-diagnosed DCM patients with spontaneous MA was similar to that in those without spontaneous MA. Spontaneous MA may not necessarily be a sign of a poor prognosis if observed in patients with a preserved blood pressure.

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Circulating cardiac MicroRNAs safeguard against dilated cardiomyopathy

Cheng

Jian

Xing

et al. 2023

Clinical & Translational Med

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Background Cardiac‐resident or ‐enriched microRNAs (miRNAs) could be released into the bloodstream becoming circulating cardiac miRNAs, which are increasingly recognized as non‐invasive and accessible biomarkers of multiple heart diseases. However, dilated cardiomyopathy (DCM)‐associated circulating miRNAs (DACMs) and their roles in DCM pathogenesis remain largely unexplored. Methods Two human cohorts, consisting of healthy individuals and DCM patients, were enrolled for serum miRNA sequencing (10 vs. 10) and quantitative polymerase chain reaction validation (46 vs. 54), respectively. Rigorous screening strategy was enacted to define DACMs and their potentials for diagnosis. DCM mouse model, different sources of cardiomyocytes, adeno‐associated virus 9 (AAV9), gene knockout, RNAscope miRNA in situ hybridization, mRFP‐GFP‐LC3B reporter, echocardiography and transmission electron microscopy were adopted for mechanistic explorations. Results Serum miRNA sequencing revealed a unique expression pattern for DCM circulating miRNAs. DACMs miR‐26a‐5p, miR‐30c‐5p, miR‐126‐5p and miR‐126‐3p were found to be depleted in DCM circulation as well as heart tissues. Their expressions in circulation and heart tissues were proven to be correlated significantly, and a combination of these miRNAs was suggested potential values for DCM diagnosis. FOXO3, a predicted common target, was experimentally demonstrated to be co‐repressed within cardiomyocytes by these DACMs except miR‐26a‐5p. Delivery of a combination of miR‐30c‐5p, miR‐126‐5p and miR‐126‐3p into the murine myocardium via AAV9 carrying an expression cassette driven by cTnT promoter, or cardiac‐specific knockout of FOXO3 (Myh6‐CreERT2, FOXO3 flox+/+) dramatically attenuated cardiac apoptosis and autophagy involved in DCM progression. Moreover, competitively disrupting the interplay between DACMs and FOXO3 mRNA by specifically introducing their interacting regions into murine myocardium crippled the cardioprotection of DACMs against DCM. Conclusions Circulating cardiac miRNA‐FOXO3 axis plays a pivotal role in safeguarding against myocardial apoptosis and excessive autophagy in DCM development, which may provide serological cues for DCM non‐invasive diagnosis and shed light on DCM pathogenesis and therapeutic targets.

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Impact of Autophagy on Prognosis of Patients With Dilated Cardiomyopathy

Cited by 31 publications

References 31 publications

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

Baseline Blood Pressure and Left Ventricular Reverse Remodeling in Dilated Cardiomyopathy with Spontaneous Mechanical Alternans

Circulating cardiac MicroRNAs safeguard against dilated cardiomyopathy

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