Microvascular Dysfunction in Dilated Cardiomyopathy

Gulati, Ankur; Ismail, Tevfik F; Ali, Aamir; Hsu, Li‐Yueh; Gonçalves, Carla; Ismail, Nizar; Krishnathasan, Kaushiga; Davendralingam, Natasha; Ferreira, Pedro F.; Halliday, Brian P; Jones, Daniel A.; Wage, Ricardo; Newsome, Simon; Gatehouse, Peter; Firmin, David N.; Jabbour, Andrew; Assomull, Ravi; Mathur, Anthony; Pennell, Dudley J.; Arai, Andrew E; Prasad, Sanjay K.

doi:10.1016/j.jcmg.2018.10.032

Cited by 55 publications

(30 citation statements)

References 39 publications

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“…Finally, we analyzed cardiac pericytes, since they are the second most common cell type in the heart [42], whose involvement in cardiac pathology is emerging. Indeed, pericytes are important regulators of the cardiac microvascular blood flow [43], whose dysfunction also characterizes DCM [44], plays a role in fibrosis [45], and are possible sentinels of the innate immunity [46]. We observed that E DCM -CPc are characterized by increased senescence rates, lysosomal dysfunction, and lipofuscin accumulation, coupled with mitochondrial dysfunction, miR22 upregulation, and IL1β secretion.…”

Section: Discussionmentioning

confidence: 92%

Autophagy and Inflammasome Activation in Dilated Cardiomyopathy

Caragnano

Aleksova

Bulfoni

et al. 2019

JCM

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Background: The clinical outcome of patients affected by dilated cardiomyopathy (DCM) is heterogeneous, since its pathophysiology is only partially understood. Interleukin 1β levels could predict the mortality and necessity of cardiac transplantation of DCM patients. Objective: To investigate mechanisms triggering sterile inflammation in dilated cardiomyopathy (DCM). Methods: Hearts explanted from 62 DCM patients were compared with 30 controls, employing immunohistochemistry, cellular and molecular biology, as well as metabolomics studies. Results: Although misfolded protein accumulation and aggresome formation characterize DCM hearts, aggresomes failed to trigger the autophagy lysosomal pathway (ALP), with consequent accumulation of both p62SQSTM1 and dysfunctional mitochondria. In line, DCM hearts are characterized by accumulation of lipoperoxidation products and activation of both redox responsive pathways and inflammasome. Consistently with the fact that mTOR signaling may impair ALP, we observed, an increase in DCM activation, together with a reduction in the nuclear localization of Transcription Factor EB -TFEB- (a master regulator of lysosomal biogenesis). These alterations were coupled with metabolomic alterations, including accumulation of branched chain amino acids (BCAAs), known mTOR activators. Consistently, reduced levels of PP2Cm, a phosphatase that regulates the key catabolic step of BCAAs, coupled with increased levels of miR-22, a regulator of PP2Cm levels that triggers senescence, characterize DCM hearts. The same molecular defects were present in clinically relevant cells isolated from DCM hearts, but they could be reverted by downregulating miR-22. Conclusion: We identified, in human DCM, a complex series of events whose key players are miR-22, PP2Cm, BCAA, mTOR, and ALP, linking loss of proteostasis with inflammasome activation. These potential therapeutic targets deserve to be further investigated.

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Section: Discussionmentioning

confidence: 92%

Autophagy and Inflammasome Activation in Dilated Cardiomyopathy

Caragnano

Aleksova

Bulfoni

et al. 2019

JCM

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“…Further, non-ischemic cardiomyopathy was associated with the highest mortality compared to other mechanisms of MINOCA ( 74 ). Using stress CMRI, underlying microvascular dysfunction has been reported in patients with dilated cardiomyopathy ( 75 ).…”

Section: Underlying Pathophysiologic Mechanisms In Minocamentioning

confidence: 99%

Myocardial infarction with non-obstructive coronary arteries (MINOCA)

Yildiz

Ashokprabhu

Shewale

et al. 2022

Front. Cardiovasc. Med.

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Myocardial infarction with non-obstructive coronary arteries (MINOCA) is evident in up to 15% of all acute myocardial infarctions (AMI) and disproportionally affects females. Despite younger age, female predominance, and fewer cardiovascular risk factors, MINOCA patients have a worse prognosis than patients without cardiovascular disease and a similar prognosis compared to patients with MI and obstructive coronary artery disease (CAD). MINOCA is a syndrome with a broad differential diagnosis that includes both ischemic [coronary artery plaque disruption, coronary vasospasm, coronary microvascular dysfunction, spontaneous coronary artery dissection (SCAD), and coronary embolism/thrombosis] and non-ischemic mechanisms (Takotsubo cardiomyopathy, myocarditis, and non-ischemic cardiomyopathy)—the latter called MINOCA mimickers. Therefore, a standardized approach that includes multimodality imaging, such as coronary intravascular imaging, cardiac magnetic resonance, and in selected cases, coronary reactivity testing, including provocation testing for coronary vasospasm, is necessary to determine underlying etiology and direct treatment. Herein, we review the prevalence, characteristics, prognosis, diagnosis, and treatment of MINOCA -a syndrome often overlooked.

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“…However, these findings are less consistent between studies, with one PET (positron emission tomography) study showing no difference between controls and DCM groups, 28 and another CMR study showing higher resting MBF in DCM compared with controls. 29 Resting MBF is subject to multiple factors which can be difficult to control in clinical studies, which may explain the heterogeneity of reported correlations between resting MBF and EF.…”

Section: Discussionmentioning

confidence: 99%

“…28 The correlation between EF and stress MBF that we have demonstrated supports this hypothesis, although cannot provide evidence of a causal relationship. Previous studies have shown decreased stress MBF in DCM 29,30 and severe systolic HF, which has been presumed to be secondary to microvascular disease. In addition, impaired stress MBF is associated with poor prognosis in patients with LV dysfunction, independent of the level of impairment.…”

Section: Myocardial Perfusionmentioning

confidence: 92%

Cardiovascular magnetic resonance phenotyping of heart failure with mildly reduced ejection fraction

Brown

Ikongo

Saunderson

et al. 2022

European Heart Journal - Cardiovascular Imaging

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Aims The 2016 European Society of Cardiology Heart Failure Guidelines defined a new category: heart failure with mid-range ejection fraction (HFmrEF) of 40–49%. This new category was highlighted as having limited evidence and research was advocated into underlying characteristics, pathophysiology, and diagnosis. We used multi-parametric cardiovascular magnetic resonance (CMR) to define the cardiac phenotype of presumed non-ischaemic HFmrEF. Methods and results Patients (N = 300, 62.7 ± 13 years, 63% males) with a clinical diagnosis of heart failure with no angina symptoms, history of myocardial infarction, or coronary intervention were prospectively recruited. Patients underwent clinical assessment and CMR including T1 mapping, extracellular volume (ECV) mapping, late gadolinium enhancement, and measurement of myocardial blood flow at rest and maximal hyperaemia. Of 273 patients in the final analysis, 93 (34%) patients were categorized as HFmrEF, 46 (17%) as heart failure with preserved ejection fraction (HFpEF), and 134 (49%) as heart failure with reduced ejection fraction (HFrEF). Nineteen (20%) patients with HFmrEF had evidence of occult ischaemic heart disease. Diffuse fibrosis and hyperaemic myocardial blood flow were similar in HFmrEF and HFpEF, but HFmrEF showed significantly lower native T1 (1311 ± 32 vs. 1340 ± 45 ms, P < 0.001), ECV (24.6 ± 3.2 vs. 26.3 ± 3.1%, P < 0.001), and higher myocardial perfusion reserve (2.75 ± 0.84 vs. 2.28 ± 0.84, P < 0.001) compared with HFrEF. Conclusion Patients with HFmrEF share most phenotypic characteristics with HFpEF, including the degree of microvascular impairment and fibrosis, but have a high prevalence of occult ischaemic heart disease similar to HFrEF. Further work is needed to confirm how the phenotype of HFmrEF responds to medical therapy.

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Microvascular Dysfunction in Dilated Cardiomyopathy

Cited by 55 publications

References 39 publications

Autophagy and Inflammasome Activation in Dilated Cardiomyopathy

Autophagy and Inflammasome Activation in Dilated Cardiomyopathy

Myocardial infarction with non-obstructive coronary arteries (MINOCA)

Cardiovascular magnetic resonance phenotyping of heart failure with mildly reduced ejection fraction

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