RESUMEN
The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.
Asunto(s)
Modelos Animales de Enfermedad , Insuficiencia Cardíaca , Mitocondrias Cardíacas , Animales , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Masculino , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/genética , Proteómica , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/genética , Disfunción Ventricular Derecha/patología , Función Ventricular Derecha , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/patología , Ratas , Función Ventricular Izquierda , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/genética , Transcriptoma , Ratas Sprague-Dawley , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genéticaRESUMEN
BACKGROUND: Left ventricular ejection fraction (LVEF) is the most commonly clinically used imaging parameter for assessing cancer therapy-related cardiac dysfunction (CTRCD). However, LVEF declines may occur late, after substantial injury. This study sought to investigate cardiovascular magnetic resonance (CMR) imaging markers of subclinical cardiac injury in a miniature swine model. METHODS: Female Yucatan miniature swine (n = 14) received doxorubicin (2 mg/kg) every 3 weeks for 4 cycles. CMR, including cine, tissue characterization via T1 and T2 mapping, and late gadolinium enhancement (LGE) were performed on the same day as doxorubicin administration and 3 weeks after the final chemotherapy cycle. In addition, magnetic resonance spectroscopy (MRS) was performed during the 3 weeks after the final chemotherapy in 7 pigs. A single CMR and MRS exam were also performed in 3 Yucatan miniature swine that were age- and weight-matched to the final imaging exam of the doxorubicin-treated swine to serve as controls. CTRCD was defined as histological early morphologic changes, including cytoplasmic vacuolization and myofibrillar loss of myocytes, based on post-mortem analysis of humanely euthanized pigs after the final CMR exam. RESULTS: Of 13 swine completing 5 serial CMR scans, 10 (77%) had histological evidence of CTRCD. Three animals had neither histological evidence nor changes in LVEF from baseline. No absolute LVEF <40% or LGE was observed. Native T1, extracellular volume (ECV), and T2 at 12 weeks were significantly higher in swine with CTRCD than those without CTRCD (1178 ms vs. 1134 ms, p = 0.002, 27.4% vs. 24.5%, p = 0.03, and 38.1 ms vs. 36.4 ms, p = 0.02, respectively). There were no significant changes in strain parameters. The temporal trajectories in native T1, ECV, and T2 in swine with CTRCD showed similar and statistically significant increases. At the same time, there were no differences in their temporal changes between those with and without CTRCD. MRS myocardial triglyceride content substantially differed among controls, swine with and without CTRCD (0.89%, 0.30%, 0.54%, respectively, analysis of variance, p = 0.01), and associated with the severity of histological findings and incidence of vacuolated cardiomyocytes. CONCLUSION: Serial CMR imaging alone has a limited ability to detect histologic CTRCD beyond LVEF. Integrating MRS myocardial triglyceride content may be useful for detection of early potential CTRCD.
Asunto(s)
Cardiotoxicidad , Modelos Animales de Enfermedad , Doxorrubicina , Imagen por Resonancia Cinemagnética , Miocardio , Valor Predictivo de las Pruebas , Volumen Sistólico , Porcinos Enanos , Función Ventricular Izquierda , Animales , Femenino , Miocardio/patología , Miocardio/metabolismo , Porcinos , Función Ventricular Izquierda/efectos de los fármacos , Volumen Sistólico/efectos de los fármacos , Factores de Tiempo , Espectroscopía de Resonancia Magnética , Antibióticos Antineoplásicos/efectos adversos , Medios de Contraste , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/metabolismoRESUMEN
Preclinical data strongly suggest that myocardial steatosis leads to adverse cardiac remodelling and left ventricular dysfunction. Using 1 H cardiac magnetic resonance spectroscopy, similar observations have been made across the spectrum of health and disease. The purpose of this brief review is to summarize these recent observations. We provide a brief overview of the determinants of myocardial triglyceride accumulation, summarize the current evidence that myocardial steatosis contributes to cardiac dysfunction, and identify opportunities for further research.
Asunto(s)
Cardiopatías , Disfunción Ventricular Izquierda , Humanos , Miocardio/patología , Corazón , Espectroscopía de Resonancia Magnética , Disfunción Ventricular Izquierda/patología , Triglicéridos , Función Ventricular IzquierdaRESUMEN
Background: Type 2 diabetes (T2D) and obesity induce left ventricular (LV) dysfunction. The underlying pathophysiological mechanisms remain unclear, but myocardial triglyceride content (MTGC) could be involved. Objectives: This study aimed to determine which clinical and biological factors are associated with increased MTGC and to establish whether MTGC is associated with early changes in LV function. Methods: A retrospective study was conducted using five previous prospective cohorts, leading to 338 subjects studied, including 208 well-phenotyped healthy volunteers and 130 subjects living with T2D and/or obesity. All the subjects underwent proton magnetic resonance spectroscopy and feature tracking cardiac magnetic resonance imaging to measure myocardial strain. Results: MTGC content increased with age, body mass index (BMI), waist circumference, T2D, obesity, hypertension, and dyslipidemia, but the only independent correlate found in multivariate analysis was BMI (p=0.01; R²=0.20). MTGC was correlated to LV diastolic dysfunction, notably with the global peak early diastolic circumferential strain rate (r=-0.17, p=0.003), the global peak late diastolic circumferential strain rate (r=0.40, p<0.0001) and global peak late diastolic longitudinal strain rate (r=0.24, p<0.0001). MTGC was also correlated to systolic dysfunction via end-systolic volume index (r=-0.34, p<0.0001) and stroke volume index (r=-0.31, p<0.0001), but not with longitudinal strain (r=0.009, p=0.88). Interestingly, the associations between MTGC and strain measures did not persist in multivariate analysis. Furthermore, MTGC was independently associated with LV end-systolic volume index (p=0.01, R²=0.29), LV end-diastolic volume index (p=0.04, R²=0.46), and LV mass (p=0.002, R²=0.58). Conclusions: Predicting MTGC remains a challenge in routine clinical practice, as only BMI independently correlates with increased MTGC. MTGC may play a role in LV dysfunction but does not appear to be involved in the development of subclinical strain abnormalities.
Asunto(s)
Diabetes Mellitus Tipo 2 , Disfunción Ventricular Izquierda , Humanos , Función Ventricular Izquierda/fisiología , Estudios Retrospectivos , Diabetes Mellitus Tipo 2/diagnóstico por imagen , Triglicéridos , Espectroscopía de Protones por Resonancia Magnética , Imagen por Resonancia Magnética , Disfunción Ventricular Izquierda/patología , Obesidad/complicaciones , Obesidad/diagnóstico por imagenRESUMEN
Duchenne muscular dystrophy (DMD) is the most common form of muscle degenerative hereditary disease. Muscular replacement by fibrosis and calcification are the principal causes of progressive and severe musculoskeletal, respiratory, and cardiac dysfunction. To date, the D2.B10-Dmdmdx/J (D2-mdx) model is proposed as the closest to DMD, but the results are controversial. In this study, the cardiac structure and function was characterized in D2-mdx mice from 16-17 up to 24-25 weeks of age. Echocardiographic assessment in conscious mice, gross pathology, and histological and cardiac biomarker analyses were performed. At 16-17 weeks of age, D2-mdx mice presented mild left ventricular function impairment and increased pulmonary vascular resistance. Cardiac fibrosis was more extended in the right ventricle, principally on the epicardium. In 24-25-week-old D2-mdx mice, functional and structural alterations increased but with large individual variation. High-sensitivity cardiac Troponin T, but not N-terminal pro-atrial natriuretic peptide, plasma levels were increased. In conclusion, left ventricle remodeling was mild to moderate in both young and adult mice. We confirmed that right ventricle epicardial fibrosis is the most outstanding finding in D2-mdx mice. Further long-term studies are needed to evaluate whether this mouse model can also be considered a model of DMD cardiomyopathy.
Asunto(s)
Cardiomiopatías , Distrofia Muscular de Duchenne , Disfunción Ventricular Izquierda , Animales , Ratones , Ratones Endogámicos mdx , Corazón , Distrofia Muscular de Duchenne/patología , Cardiomiopatías/patología , Disfunción Ventricular Izquierda/patología , Fibrosis , Modelos Animales de Enfermedad , Músculo Esquelético/patologíaRESUMEN
OBJECTIVE: The aim of this retrospective study was to determine whether regional epicardial adipose tissue (EAT) exerts localized effects on adjacent myocardial left ventricular (LV) function. METHODS: Cardiac magnetic resonance imaging (MRI), echocardiography, dual-energy x-ray absorptiometry, and exercise testing were performed in 71 patients with obesity with elevated cardiac biomarkers and visceral fat. Total and regional (anterior, inferior, lateral, right ventricular) EAT was quantified by MRI. Diastolic function was quantified by echocardiography. MRI was used to quantify regional longitudinal LV strain. RESULTS: EAT was associated with visceral adiposity (r = 0.47, p < 0.0001) but not total fat mass. Total EAT was associated with markers of diastolic function (early tissue Doppler relaxation velocity [e'], mitral inflow velocity ratio [E/A], early mitral inflow/e' ratio [E/e']), but only E/A remained significant after adjustment for visceral adiposity (r = -0.30, p = 0.015). Right ventricular and LV EAT had similar associations with diastolic function. There was no evidence for localized effects of regional EAT deposition on adjacent regional longitudinal strain. CONCLUSIONS: There was no association between regional EAT deposition and corresponding regional LV segment function. Furthermore, the association between total EAT and diastolic function was attenuated after adjustment for visceral fat, indicating that systemic metabolic impairments contribute to diastolic dysfunction in high-risk middle-aged adults.
Asunto(s)
Pericardio , Disfunción Ventricular Izquierda , Adulto , Persona de Mediana Edad , Humanos , Estudios Retrospectivos , Pericardio/diagnóstico por imagen , Tejido Adiposo , Función Ventricular Izquierda , Diástole , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/patologíaRESUMEN
BACKGROUND: The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation to increase oxygen efficiency of adenosine triphosphate production, with mixed results. METHODS: To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MVo2), invasive arteriovenous sampling and pressure-volume loops were performed (n=9). RESULTS: At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; P=0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased (LCFA 73±17% of total substrate versus 19±26% total during I+G; P=0.009). Myocardial energetics were better with Intralipid compared with I+G (phosphocreatine/adenosine triphosphate 1.86±0.25 versus 2.01±0.33; P=0.02), and systolic and diastolic function were improved (LVEF 34.9±9.1 baseline, 33.7±8.2 I+G, 39.9±9.3 Intralipid; P<0.001). During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism. CONCLUSIONS: Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies.
Asunto(s)
Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Humanos , Volumen Sistólico , Metabolismo Energético , Función Ventricular Izquierda , Miocardio/metabolismo , Insuficiencia Cardíaca/patología , Adenosina Trifosfato/metabolismo , Disfunción Ventricular Izquierda/patología , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Oxígeno/metabolismoRESUMEN
BACKGROUND: Left ventricular (LV) diastolic function is primarily assessed by means of echocardiography, which has limited utility in detecting fibrosis. Cardiac magnetic resonance (CMR) readily detects and quantifies fibrosis. OBJECTIVES: In this study, the authors sought to determine the association of LV diastolic function by echocardiography with CMR-determined global fibrosis burden and the incremental value of fibrosis with diastolic function grade in prediction of total mortality and heart failure hospitalizations. METHODS: A total of 549 patients underwent comprehensive echocardiography and CMR within 30 days. Echocardiography was used to assess LV diastolic function, and CMR was used to determine LV volumes, mass, ejection fraction, replacement fibrosis, and percentage extracellular volume fraction (ECV). RESULTS: Normal diastolic function was present in 142 patients; the rest had diastolic dysfunction grades I to III, except for 18 (3.3%) with indeterminate results. The event rate was higher in patients with diastolic dysfunction compared with patients with normal diastolic function (33.4% vs 15.5; P < 0.001). The model including LV diastolic function grades II and III predicted composite outcome (C-statistic: 0.71; 95% CI: 0.67-0.76), which increased by adding global fibrosis burden (C-statistic: 0.74, 95% CI: 0.70-0.78; P = 0.02). For heart failure hospitalizations, the competing risk model with LV diastolic function grades II and III was good (C-statistic: 0.78; 95% CI: 0.74-0.83) and increased significantly with the addition of global fibrosis burden (C-statistic: 0.80; 95% CI: 0.76-0.85; P = 0.03). CONCLUSIONS: Higher grades of diastolic dysfunction are seen in patients with replacement fibrosis and increased ECV. Fibrosis burden as determined with the use of CMR provides incremental prognostic information to echocardiographic evaluation of LV diastolic function.
Asunto(s)
Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Humanos , Imagen por Resonancia Cinemagnética/métodos , Valor Predictivo de las Pruebas , Función Ventricular Izquierda , Insuficiencia Cardíaca/diagnóstico por imagen , Diástole , Fibrosis , Medición de Riesgo , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/patología , Volumen SistólicoRESUMEN
PURPOSE: Data derived by cardiac magnetic resonance (CMR) feature tracking suggest that not only left ventricular but also left atrial function is impaired in patients with acute myocarditis. Therefore, we investigated the diagnostic value of speckle tracking echocardiography of the left ventricle and left atrium in patients with acute myocarditis and normal left ventricular ejection fraction (LVEF). METHODS AND RESULTS: 30 patients with acute myocarditis confirmed by CMR according to the Lake Louise criteria and 20 healthy controls were analyzed including global longitudinal strain (GLS) and left atrial (LA) strain parameters. Although preserved LVEF was present in both groups, GLS was significantly lower in patients with acute myocarditis (GLS - 19.1 ± 1.8% vs. GLS - 22.1 ± 1.7%, p < 0.001). Further diastolic dysfunction measured by E/e' mean was significantly deteriorated in the myocarditis group compared to the control group (E/e' mean 6.4 ± 1.6 vs. 5.5 ± 1.0, p = 0.038). LA reservoir function (47.6 ± 10.4% vs. 55.5 ± 10.8%, p = 0.013) and LA conduit function (-33.0 ± 9.6% vs. -39.4 ± 9.5%, p = 0.024) were significantly reduced in patients with acute myocarditis compared to healthy controls. Also left atrial stiffness index (0.15 ± 0.05 vs. 0.10 ± 0.03, p = 0.003) as well as left atrial filling index (1.67 ± 0.47 vs. 1.29 ± 0.34, p = 0.004) were deteriorated in patients with myocarditis compared to the control group. CONCLUSION: In patients with acute myocarditis and preserved LVEF not only GLS but also LA reservoir function, LA conduit function and left atrial stiffness index as well as left atrial filling index were impaired compared to healthy controls indicating ventricular diastolic dysfunction and elevated LV filling pressures.
Asunto(s)
Fibrilación Atrial , Miocarditis , Disfunción Ventricular Izquierda , Disfunción Ventricular , Humanos , Función Ventricular Izquierda , Volumen Sistólico , Valor Predictivo de las Pruebas , Atrios Cardíacos/diagnóstico por imagen , Ecocardiografía/métodos , Disfunción Ventricular/patología , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/patologíaRESUMEN
Restrictive cardiomyopathy (RCM) is a heterogeneous group of diseases characterized by restrictive left ventricular pathophysiology, i.e. a rapid rise in ventricular pressure with only small increases in filling volume due to increased myocardial stiffness. More precisely, the defining feature of RCM is the coexistence of persistent restrictive pathophysiology, diastolic dysfunction, non-dilated ventricles, and atrial dilatation, regardless of ventricular wall thickness and systolic function. Beyond this shared haemodynamic hallmark, the phenotypic spectrum of RCM is wide. The disorders manifesting as RCM may be classified according to four main disease mechanisms: (i) interstitial fibrosis and intrinsic myocardial dysfunction, (ii) infiltration of extracellular spaces, (iii) accumulation of storage material within cardiomyocytes, or (iv) endomyocardial fibrosis. Many disorders do not show restrictive pathophysiology throughout their natural history, but only at an initial stage (with an evolution towards a hypokinetic and dilated phenotype) or at a terminal stage (often progressing from a hypertrophic phenotype). Furthermore, elements of both hypertrophic and restrictive phenotypes may coexist in some patients, making the classification challenge. Restrictive pathophysiology can be demonstrated by cardiac catheterization or Doppler echocardiography. The specific conditions may usually be diagnosed based on clinical data, 12-lead electrocardiogram, echocardiography, nuclear medicine, or cardiovascular magnetic resonance, but further investigations may be needed, up to endomyocardial biopsy and genetic evaluation. The spectrum of therapies is also wide and heterogeneous, but disease-modifying treatments are available only for cardiac amyloidosis and, partially, for iron overload cardiomyopathy.
Asunto(s)
Cardiomiopatía Restrictiva , Disfunción Ventricular Izquierda , Humanos , Cardiomiopatía Restrictiva/diagnóstico , Cardiomiopatía Restrictiva/patología , Ecocardiografía Doppler , Disfunción Ventricular Izquierda/patología , Miocardio/patología , EcocardiografíaRESUMEN
BACKGROUND: Chronic heart valve regurgitation induces left ventricular (LV) volume overload, leading to the development of hypertrophy and progressive dilatation of the ventricle to maintain physiological cardiac output. In order to prevent potential irreversible LV structural changes, the identification of the best timing for treatment is pivotal. OBJECTIVE: To assess the presence and extent of fibrosis in myocardial tissue in asymptomatic patients with valvular heart disease (VHD) and preserved LV dimensions and function undergoing cardiac surgery. METHODS: Thirty-nine patients were enrolled. Sixteen patients were affected by aortic or mitral regurgitation: they were all asymptomatic, undergoing valve surgery according to VHD European Society of Cardiology guidelines. Twenty-three patients with end-stage nonischemic dilated cardiomyopathy (DCM) and severe LV dysfunction undergoing cardiac surgery for implantation of a durable left ventricular assist device (LVAD) served as controls. During surgery, VHD patients underwent three myocardial biopsies at the level of the septum, the lateral wall and LV apex, while in LVAD patients the coring of the apex of the LV was used. For both groups, the tissue samples were analyzed on one section corresponding to the apical area. All slides were stained with hematoxylin and eosin and Masson's trichrome staining and further digitalized. The degree of fibrosis was then calculated as a percentage of the total area. RESULTS: Of 39 patients, 23 met the inclusion criteria: 12 had mitral or aortic insufficiency with a preserved ejection fraction and 11 had idiopathic dilated cardiomyopathy. Quantitative analysis of apical sections revealed a myocardial fibrosis amount of 10â±â6% in VHD patients, while in LVAD patients the mean apical myocardial fibrosis rate was 38â±â9%. In VHD patients, fibrosis was also present in the lateral wall (9â±â4%) and in the septum (9â±â6%). CONCLUSION: Our case series study highlights the presence of tissue remodeling with fibrosis in asymptomatic patients with VHD and preserved LV function. According to our results, myocardial fibrosis is present at an early stage of the disease, well before developing detectable LV dysfunction and symptoms. Since the relationship between the progressive magnitude of myocardial fibrosis and potential prognostic implications are not yet defined, further studies on this topic are warranted.
Asunto(s)
Insuficiencia de la Válvula Aórtica , Cardiomiopatías , Cardiomiopatía Dilatada , Enfermedades de las Válvulas Cardíacas , Insuficiencia de la Válvula Mitral , Disfunción Ventricular Izquierda , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/etiología , Insuficiencia de la Válvula Aórtica/cirugía , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/cirugía , Fibrosis , Humanos , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/cirugía , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/patología , Función Ventricular IzquierdaRESUMEN
Renewal of the myocardium by preexisting cardiomyocytes is a powerful strategy for restoring the architecture and function of hearts injured by myocardial infarction. To advance this strategy, we show that combining two clinically approved drugs, but neither alone, muscularizes the heart through cardiomyocyte proliferation. Specifically, in adult murine cardiomyocytes, metoprolol, a cardioselective ß1-adrenergic receptor blocker, when given with triiodothyronine (T3, a thyroid hormone) accentuates the ability of T3 to stimulate ERK1/2 phosphorylation and proliferative signaling by inhibiting expression of the nuclear phospho-ERK1/2-specific phosphatase, dual-specificity phosphatase-5. While short-duration metoprolol plus T3 therapy generates new heart muscle in healthy mice, in mice with myocardial infarction-induced left ventricular dysfunction and pathological remodeling, it remuscularizes the heart, restores contractile function and reverses chamber dilatation; outcomes that are enduring. If the beneficial effects of metoprolol plus T3 are replicated in humans, this therapeutic strategy has the potential to definitively address ischemic heart failure.
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Infarto del Miocardio , Disfunción Ventricular Izquierda , Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Antagonistas de Receptores Adrenérgicos beta 1/uso terapéutico , Animales , Metoprolol/farmacología , Metoprolol/uso terapéutico , Ratones , Infarto del Miocardio/patología , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Triyodotironina/metabolismo , Triyodotironina/farmacología , Disfunción Ventricular Izquierda/patología , Remodelación VentricularRESUMEN
Cardiovascular diseases remain the leading cause of death worldwide, with pathological fibrotic remodeling mediated by activated cardiac myofibroblasts representing a unifying theme across etiologies. Despite the profound contributions of myocardial fibrosis to cardiac dysfunction and heart failure, there currently exist limited clinical interventions that effectively target the cardiac fibroblast and its role in fibrotic tissue deposition. Exploration of novel strategies designed to mitigate or reverse myofibroblast activation and cardiac fibrosis will likely yield powerful therapeutic approaches for the treatment of multiple diseases of the heart, including heart failure with preserved or reduced ejection fraction, acute coronary syndrome, and cardiovascular disease linked to type 2 diabetes. In this Review, we provide an overview of classical regulators of cardiac fibrosis and highlight emerging, next-generation epigenetic regulatory targets that have the potential to revolutionize treatment of the expanding cardiovascular disease patient population.
Asunto(s)
Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Diabetes Mellitus Tipo 2/patología , Fibroblastos/patología , Fibrosis , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/terapia , Humanos , Miocardio/patología , Miofibroblastos/patología , Disfunción Ventricular Izquierda/patologíaRESUMEN
In the present study, we investigated the cardiotoxic potential of Micrurus frontalis venom. Twelve guinea pigs (Cavia porcellus) were distributed in two groups (n = 6), named control and envenomed. Control groups received 0.2 ml of PBS/BSA, while envenomed group received 0.2 ml of the same solution containing 450 µg/kg of M. frontalis venom. Both were intramuscular injections. Electrocardiography, echocardiogram, blood count, and serum biochemistry were performed before and 2 h after inoculation. Necropsy was performed, and histological and ultrastructural analysis of the heart were conducted. First clinical signs were presented as early as 18 min after venom inoculation. All poisoned animals presented flaccid paralysis of both hind and forelimbs, followed by fasciculations and respiratory arrythmia. However, the animals did not die in the first 2 h of poisoning. ECG of the poisoned animals revealed severe ventricular arrythmias, corroborated by reduction of both ejection and shortening fractions, increase in CK, CK-MB, troponin, cardiomyocyte degeneration, fragmentation and mitochondrial damage. M. frontalis venom causes severe heart damage, eliciting both morphological and arrhythmogenic effects after only 2 h of envenomation.
Asunto(s)
Arritmias Cardíacas/inducido químicamente , Cardiomiopatías/inducido químicamente , Venenos Elapídicos/toxicidad , Frecuencia Cardíaca/efectos de los fármacos , Miocardio/patología , Disfunción Ventricular Izquierda/inducido químicamente , Función Ventricular Izquierda/efectos de los fármacos , Animales , Arritmias Cardíacas/sangre , Arritmias Cardíacas/patología , Arritmias Cardíacas/fisiopatología , Biomarcadores/sangre , Cardiomiopatías/sangre , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Cardiotoxicidad , Serpientes de Coral , Cobayas , Masculino , Miocardio/metabolismo , Necrosis , Factores de Tiempo , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/patologíaRESUMEN
BACKGROUND: Aging is associated with metabolic and structural changes causing heart failure with preserved ejection fraction (HFpEF). Interleukin-1 (IL-1) is a pro-inflammatory cytokine involved in aging-related inflammation. OBJECTIVE: We sought to determine whether IL-1 mediates aging-related changes in the heart, as seen in HFpEF. METHODS: We studied age-matched young (4-month-old), middle-aged (14-month-old), and old (23-month-old) wild-type (WT) C57BL/6J and IL-1 receptor type I deficient (IL1RI-KO) male mice. Echocardiography was used to evaluate left ventricular (LV) dimensions and systolic/diastolic function, and a pressure transducer was used to measure the LV end-diastolic pressure. Picrosirius red stain was used to assess for myocardial interstitial fibrosis (MIF) at pathology. RESULTS: WT and IL-1RIKO mice showed a normal cardiac phenotype at young age, without any differences between the two groups. With aging, the WT mice developed LV concentric hypertrophy (as measured by a significant increase in LV mass [+42%, P < 0.01] and relative wall thickness [+34%, P < 0.01]), whereas the aging IL-1RI-KO mice did not. With aging, the WT mice also developed diastolic dysfunction (as measured by a significant increase in isovolumetric relaxation time [+148%, P < 0.01] and a significantly higher LV end-diastolic pressure [+174%, P < 0.01]), whereas the aging IL1RI-KO did not. Aged WT mice showed a significant increase in MIF (+124%, P < 0.01) at cardiac pathology, whereas the aging IL-1RI-KO did not. CONCLUSIONS: Genetically-modified mice lacking the IL-1RI receptor, not responsive to IL-1, are protected from aging-related LV hypertrophy, fibrosis, and diastolic dysfunction. These data support a central role of IL-1 in the pathophysiology of aging-related HFpEF.
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Cardiomiopatías , Insuficiencia Cardíaca , Receptores Tipo I de Interleucina-1 , Factores de Edad , Envejecimiento , Animales , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores Tipo I de Interleucina-1/metabolismo , Volumen Sistólico/fisiología , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patologíaRESUMEN
Systemic inflammation is a key mediator of left ventricular dysfunction (LV) in prediabetes via the activation of myeloid differentiation factor 2 (MD2)/toll-like receptor 4 complex. The MD2 inhibitor L6H21 effectively reduced systemic and cardiac inflammation in obese mice. However, its effects on cardiac function and regulated cell death pathways in the heart in prediabetes are still unknown. The prediabetic rats were divided into 3 subgroups to receive vehicle, L6H21 (10, 20, 40 mg/kg) or metformin (300 mg/kg) for 1, 2 and 4 weeks. Then, metabolic parameters, cardiac sympathovagal balance, LV function, cardiac mitochondrial function, oxidative stress, inflammation, apoptosis, necroptosis, and ferroptosis were determined. All prediabetic rats exhibited cardiac sympathovagal imbalance, LV dysfunction, and cardiac mitochondrial dysfunction. All doses of L6H21 treatment for 2- and 4-weeks attenuated insulin resistance. L6H21 at 40 mg/kg attenuated cardiac autonomic imbalance and LV dysfunction after 1 week of treatment. Both 10 and 20 mg/kg of L6H21 required longer treatment duration to show these benefits. Mechanistically, all doses of L6H21 reduced cardiac mitochondrial dysfunction after 1 week of treatment, resulting in alleviated oxidative stress and inflammation. L6H21 also effectively suppressed cardiac apoptosis and ferroptosis, but it did not affect necroptosis in prediabetic rats. L6H21 provided the cardioprotective efficacy in dose- and time-dependent manners in prediabetic rats via reduction in apoptosis and ferroptosis.
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Chalconas/farmacología , Ferroptosis , Cardiopatías/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Antígeno 96 de los Linfocitos/antagonistas & inhibidores , Mitocondrias Cardíacas/efectos de los fármacos , Estado Prediabético/fisiopatología , Animales , Dieta Alta en Grasa , Cardiopatías/metabolismo , Cardiopatías/patología , Inflamación/metabolismo , Inflamación/patología , Resistencia a la Insulina , Masculino , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Ratas , Ratas Wistar , Disfunción Ventricular Izquierda/tratamiento farmacológico , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patologíaRESUMEN
BACKGROUND: Systolic dysfunction in pectus excavatum (PEX) is usually very subtle and mainly focused on the right ventricle (RV), leading to normal or unremarkable cardiac imaging findings unless involving exercise stress. OBJECTIVES: We evaluated systolic function in PEX using longitudinal strain cardiac magnetic resonance (CMR), a validated parameter for the assessment of the systolic deformation of subendocardial fibers. METHODS: This prospective registry comprised consecutive patients with PEX who were referred to CMR to define treatment strategies or to establish surgical candidacy. We also included a control group of 15 healthy volunteers without chest wall abnormalities. Using dedicated software, we evaluated the endocardial global longitudinal strain (GLS) of both ventricles and the endocardial global circumferential strain (GCS) of the left ventricle (LV). RESULTS: A total of 50 patients with PEX comprised the study population, with a mean age of 19.9 ± 8.0 years. The right ventricular ejection fraction (RVEF) of patients with PEX was significantly lower compared to the control group both at end-expiration (59.5 ± 6.8 vs. 64.7 ± 4.7%, p = 0.008) and end-inspiration (56.7 ± 7.2%, vs. 62.7 ± 4.4, p = 0.004); as well as the pulmonary stroke distance (12.6 ± 2.5, vs. 15.0 ± 2.0 cm, p = 0.001). The LV volumetric analysis revealed no differences between PEX and the control group (p > 0.05 for all) regardless of the respiratory cycle, with a mean expiratory LV ejection fraction (LVEF) of 61.4 ± 6.0%. In contrast, the GLS of the LV was significantly lower in PEX compared to controls (-21.2 ± 3.2 vs. -23.7 ± 3.0%, p = 0.010), whereas GCS was similar either at expiration (-28.5 ± 4.0%, vs. -29.5 ± 2.8, p = 0.38) or inspiration (-29.3 ± 4.1%, vs.-28.9 ± 2.3, p = 0.73). CONCLUSIONS: In this study, we demonstrated that longitudinal strain analysis might enable the detection of very subtle left ventricular systolic function abnormalities in patients with PEX, that are commonly overlooked using the conventional assessment. LEVEL OF EVIDENCE: II.
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Tórax en Embudo , Cardiopatías Congénitas , Disfunción Ventricular Izquierda , Adolescente , Adulto , Niño , Tórax en Embudo/complicaciones , Tórax en Embudo/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Espectroscopía de Resonancia Magnética , Volumen Sistólico , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/patología , Función Ventricular Derecha , Adulto JovenRESUMEN
AIMS: The glucose-driven enzymatic modification of myocardial proteins by the sugar moiety, ß-N-acetylglucosamine (O-GlcNAc), is increased in pre-clinical models of diabetes, implicating protein O-GlcNAc modification in diabetes-induced heart failure. Our aim was to specifically examine cardiac manipulation of the two regulatory enzymes of this process on the cardiac phenotype, in the presence and absence of diabetes, utilising cardiac-targeted recombinant-adeno-associated viral-vector-6 (rAAV6)-mediated gene delivery. METHODS AND RESULTS: In human myocardium, total protein O-GlcNAc modification was elevated in diabetic relative to non-diabetic patients, and correlated with left ventricular (LV) dysfunction. The impact of rAAV6-delivered O-GlcNAc transferase (rAAV6-OGT, facilitating protein O-GlcNAcylation), O-GlcNAcase (rAAV6-OGA, facilitating de-O-GlcNAcylation), and empty vector (null) were determined in non-diabetic and diabetic mice. In non-diabetic mice, rAAV6-OGT was sufficient to impair LV diastolic function and induce maladaptive cardiac remodelling, including cardiac fibrosis and increased Myh-7 and Nppa pro-hypertrophic gene expression, recapitulating characteristics of diabetic cardiomyopathy. In contrast, rAAV6-OGA (but not rAAV6-OGT) rescued LV diastolic function and adverse cardiac remodelling in diabetic mice. Molecular insights implicated impaired cardiac PI3K(p110α)-Akt signalling as a potential contributing mechanism to the detrimental consequences of rAAV6-OGT in vivo. In contrast, rAAV6-OGA preserved PI3K(p110α)-Akt signalling in diabetic mouse myocardium in vivo and prevented high glucose-induced impairments in mitochondrial respiration in human cardiomyocytes in vitro. CONCLUSION: Maladaptive protein O-GlcNAc modification is evident in human diabetic myocardium, and is a critical regulator of the diabetic heart phenotype. Selective targeting of cardiac protein O-GlcNAcylation to restore physiological O-GlcNAc balance may represent a novel therapeutic approach for diabetes-induced heart failure.
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Antígenos de Neoplasias/metabolismo , Cardiomiopatías Diabéticas/enzimología , Histona Acetiltransferasas/metabolismo , Hialuronoglucosaminidasa/metabolismo , Miocitos Cardíacos/enzimología , N-Acetilglucosaminiltransferasas/metabolismo , Procesamiento Proteico-Postraduccional , Disfunción Ventricular Izquierda/enzimología , Función Ventricular Izquierda , Remodelación Ventricular , Anciano , Animales , Antígenos de Neoplasias/genética , Línea Celular , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Femenino , Fibrosis , Regulación de la Expresión Génica , Glicosilación , Histona Acetiltransferasas/genética , Humanos , Hialuronoglucosaminidasa/genética , Masculino , Ratones , Persona de Mediana Edad , Miocitos Cardíacos/patología , N-Acetilglucosaminiltransferasas/genética , Fenotipo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Disfunción Ventricular Izquierda/genética , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
BACKGROUND: Duchenne muscular dystrophy is associated with progressive deterioration in left ventricular (LV) function. The golden retriever muscular dystrophy (GRMD) dog model recapitulates the pathology and clinical manifestations of Duchenne muscular dystrophy. Importantly, they develop progressive LV dysfunction starting at early age. OBJECTIVES: The authors tested the cardioprotective effect of chronic administration of the ARM036, a small molecule that stabilizes the closed conformation of the cardiac sarcoplasmic reticulum ryanodine receptor/calcium release channel (RyR2) in young GRMD-dogs. METHODS: Two-month-old GRMD-dogs were treated with ARM036 or placebo for 4 months. Healthy-dogs of the same genetic background served as controls. Cardiac function was evaluated by conventional and 2-dimensional speckle-tracking echocardiography. Cardiac cellular and molecular analyses were performed at 6 months old. RESULTS: Conventional echocardiography showed normal LV dimensions and ejection fraction in 6-month-old GRMD dogs. Interestingly, 2-dimensional speckle-tracking echocardiography revealed decreased global longitudinal strain and the presence of hypokinetic segments in placebo-treated GRMD dogs. Single-channel measurements revealed higher RyR2 open probability at low resting Ca2+ in GRMD cardiomyocytes than in controls. ARM036 prevented those in vivo and in vitro dysfunctions in GRMD dogs. Myofilament Ca2+-sensitivity was increased in permeabilized GRMD cardiomyocytes at short sarcomere length. ARM036 had no effect on this parameter. Cross-bridge cycling kinetics were altered in GRMD myocytes and recovered with ARM036 treatment, which coincided with the level of myosin binding protein-C-S glutathionylation. CONCLUSIONS: GRMD-dogs exhibit early LV dysfunction associated with altered myofilament contractile properties. These abnormalities were prevented pharmacologically by stabilizing RyR2 with ARM036.
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Distrofia Muscular de Duchenne/complicaciones , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Disfunción Ventricular Izquierda/etiología , Función Ventricular Izquierda/fisiología , Animales , Biopsia , Modelos Animales de Enfermedad , Perros , Ecocardiografía , Distrofia Muscular de Duchenne/diagnóstico , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miofibrillas/metabolismo , Miofibrillas/patología , Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/patología , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/patologíaRESUMEN
INTRODUCTION: Cardiomyopathies are diseases of the heart muscle and are important causes of heart failure. Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy that can be acquired, syndromic or non-syndromic. The current study was conducted to explore the genetic defects in a Pakistani family with cardiac disease and features of Marfan's syndrome (MFS). METHODS: A family with left ventricle (LV) diastolic dysfunction and MFS phenotype was assessed in Pakistan. The clinical information and blood samples from the patients were collected after physical, cardiovascular, and ophthalmologic examinations. An affected individual (proband) was subjected to whole-exome sequencing (WES). The findings were further validated through Sanger sequencing in the family. RESULTS: Through WES and sanger validation, we identified a novel variant NM_000138.4; c.1402A>G in the Fibrillin-1 (FBN1) gene that segregates with LV diastolic dysfunction and MFS. Furthermore, bioinformatic evaluation suggested that the novel variant is deleterious and disease-causing. CONCLUSIONS: This study identified for the first time a novel FBN1 variant in a family with LV diastolic dysfunction and MFS in Pakistan.