Molecular and Cellular Basis of Viable Dysfunctional Myocardium

Bayeva, Marina; Sawicki, Konrad Teodor; Butler, Javed; Gheorghiade, Mihai; Ardehali, Hossein

doi:10.1161/circheartfailure.113.000912

Cited by 48 publications

(34 citation statements)

References 151 publications

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“…These biological abnormalities are related to the myocytes, e.g. the signalling pathway, myofibrillar function, mitochondrial energetics, calcium handling etc., microvascular dysfunction, or the interstitium . Omics technology provides an unprecedented opportunity to understand disease biology and selectively target interventions.…”

Section: Blaming the Diseasementioning

confidence: 99%

“…the signalling pathway, myofibrillar function, mitochondrial energetics, calcium handling etc., microvascular dysfunction, or the interstitium. 11 Omics technology provides an unprecedented opportunity to understand disease biology and selectively target interventions. However, currently it is unclear which abnormalities in which groups of patients and in what combination should be targeted.…”

Section: Blaming the Diseasementioning

confidence: 99%

See 1 more Smart Citation

Heart failure at the crossroads: moving beyond blaming stakeholders to targeting the heart

Senni

Gavazzi

Gheorghiade

et al. 2015

European J of Heart Fail

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Section: Blaming the Diseasementioning

confidence: 99%

Section: Blaming the Diseasementioning

confidence: 99%

Heart failure at the crossroads: moving beyond blaming stakeholders to targeting the heart

Senni

Gavazzi

Gheorghiade

et al. 2015

European J of Heart Fail

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“…Numerous studies have shown that a significant proportion of patients hospitalized for decompensated HF have an elevated troponin concentration indicating myocardial injury . A significant number of patients with either ischaemic or non‐ischaemic cardiomyopathy with reduced systolic function have viable but non‐contractile or dysfunctional myocardium, which may be due to excessive neurohumoral stimulation, haemodynamic overload, and/or ischaemia . Depressed contractility in HF may be an important compensatory mechanism to reduce energy usage by the failing myocardium .…”

Section: Discussionmentioning

confidence: 99%

Haemodynamic monitoring of cardiac status using heart sounds from an implanted cardiac device

Thakur

Swanson

et al. 2017

ESC Heart Failure

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AimThe aim of this study was to evaluate the haemodynamic correlates of heart sound (HS) parameters such as third HS (S3), first HS (S1), and HS‐based systolic time intervals (HSTIs) from an implantable cardiac device.Methods and resultsTwo unique animal models (10 swine with myocardial ischaemia and 11 canines with pulmonary oedema) were used to evaluate haemodynamic correlates of S1, S3, and HSTIs, namely, HS‐based pre‐ejection period (HSPEP), HS‐based ejection time (HSET), and the ratio HSPEP/HSET during acute haemodynamic perturbations. The HS was measured using implanted cardiac resynchronization therapy defibrillator devices simultaneously with haemodynamic references such as left atrial (LA) pressure and left ventricular (LV) pressure. In the ischaemia model, S1 amplitude (r = 0.76 ± 0.038; P = 0.002), HSPEP (r = −0.56 ± 0.07; P = 0.002), and HSPEP/HSET (r = −0.42 ± 0.1; P = 0.002) were significantly correlated with LV dP/dtmax. In contrast, HSET was poorly correlated with LV dP/dtmax (r = 0.14 ± 0.14; P = 0.23). In the oedema model, a physiological delayed response was observed in S3 amplitude after acute haemodynamic perturbations. After adjusting for the delay, S3 amplitude significantly correlated with LA pressure in individual animals (r = 0.71 ± 0.07; max: 0.92; min: 0.17) as well as in aggregate (r = 0.62; P < 0.001). The S3 amplitude was able to detect elevated LA pressure, defined as >25 mmHg, with a sensitivity = 58% and specificity = 90%.ConclusionsThe HS parameters such as S1, S3, and HSTIs measured using implantable devices significantly correlated with haemodynamic changes in acute animal models, suggesting potential utility for remote heart failure patient monitoring.

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“…Free heme is a major source of redox‐active iron, which causes cellular damage by catalyzing the Fenton reaction to produce toxic free hydroxyl radicals from hydrogen peroxide . Heme‐driven production of ROS leads to cellular dysfunction by damaging lipid membranes, proteins, and nucleic acids . To confirm that the deleterious effects of ALAS2 expression on cardiomyocyte viability are through excess heme production, we performed studies in cultured cardiomyoblasts using 2 approaches: (1) ALAS2 knockdown and (2) ALAS2 overexpression with ALAS1 knockdown.…”

Section: Discussionmentioning

confidence: 99%

“…11 Heme-driven production of ROS leads to cellular dysfunction by damaging lipid membranes, proteins, and nucleic acids. [42][43][44] To confirm that the deleterious effects of ALAS2 expression on cardiomyocyte viability are through excess heme production, we performed studies in cultured cardiomyoblasts using 2 approaches: (1) ALAS2 knockdown and (2) ALAS2 overexpression with ALAS1 knockdown. We show that ALAS2 knockdown can reverse the increase in heme content and cell death associated with hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Increased Heme Levels in the Heart Lead to Exacerbated Ischemic Injury

Sawicki

Meng

et al. 2015

JAHA

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BackgroundHeme is an essential iron-containing molecule for cardiovascular physiology, but in excess it may increase oxidative stress. Failing human hearts have increased heme levels, with upregulation of the rate-limiting enzyme in heme synthesis, δ-aminolevulinic acid synthase 2 (ALAS2), which is normally not expressed in cardiomyocytes. We hypothesized that increased heme accumulation (through cardiac overexpression of ALAS2) leads to increased oxidative stress and cell death in the heart.Methods and ResultsWe first showed that ALAS2 and heme levels are increased in the hearts of mice subjected to coronary ligation. To determine the causative role of increased heme in the development of heart failure, we generated transgenic mice with cardiac-specific overexpression of ALAS2. While ALAS2 transgenic mice have normal cardiac function at baseline, their hearts display increased heme content, higher oxidative stress, exacerbated cell death, and worsened cardiac function after coronary ligation compared to nontransgenic littermates. We confirmed in cultured cardiomyoblasts that the increased oxidative stress and cell death observed with ALAS2 overexpression is mediated by increased heme accumulation. Furthermore, knockdown of ALAS2 in cultured cardiomyoblasts exposed to hypoxia reversed the increases in heme content and cell death. Administration of the mitochondrial antioxidant MitoTempo to ALAS2-overexpressing cardiomyoblasts normalized the elevated oxidative stress and cell death levels to baseline, indicating that the effects of increased ALAS2 and heme are through elevated mitochondrial oxidative stress. The clinical relevance of these findings was supported by the finding of increased ALAS2 induction and heme accumulation in failing human hearts from patients with ischemic cardiomyopathy compared to nonischemic cardiomyopathy.ConclusionsHeme accumulation is detrimental to cardiac function under ischemic conditions, and reducing heme in the heart may be a novel approach for protection against the development of heart failure.

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Molecular and Cellular Basis of Viable Dysfunctional Myocardium

Cited by 48 publications

References 151 publications

Heart failure at the crossroads: moving beyond blaming stakeholders to targeting the heart

Heart failure at the crossroads: moving beyond blaming stakeholders to targeting the heart

Haemodynamic monitoring of cardiac status using heart sounds from an implanted cardiac device

Increased Heme Levels in the Heart Lead to Exacerbated Ischemic Injury

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