impaired cardiac function
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2021 ◽  
Author(s):  
Raquel F Videira ◽  
Anne-Marie C Koop ◽  
Lara Ottaviani ◽  
Ella M Poels ◽  
Jordy M M Kocken ◽  
...  

Abstract Aims Research on the pathophysiology of right ventricular (RV) failure has, in spite of the associated high mortality and morbidity, lagged behind compared to the left ventricle (LV). Previous work from our lab revealed that the embryonic basic helix-loop-helix transcription factor heart and neural crest derivatives expressed-2 (Hand2) is re-expressed in the adult heart and activates a ‘foetal gene programme’ contributing to pathological cardiac remodelling under conditions of LV pressure overload. As such, ablation of cardiac expression of Hand2 conferred protection to cardiac stress and abrogated the maladaptive effects that were observed upon increased expression levels. In this study, we aimed to understand the contribution of Hand2 to RV remodelling in response to pressure overload induced by pulmonary artery banding (PAB). Methods and results In this study, Hand2F/F and MCM- Hand2F/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic- and MRI-derived haemodynamic parameters as well as molecular remodelling were assessed for all experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of Hand2 expression increased in the control-banded animals but, as expected, remained absent in the knockout hearts. Despite the dramatic differences in Hand2 expression, pressure overload resulted in impaired cardiac function independently of the genotype. In fact, Hand2 depletion seems to sensitize the RV to pressure overload as these mice develop more hypertrophy and more severe cardiac dysfunction. Higher expression levels of HAND2 were also observed in RV samples of human hearts from patients with pulmonary hypertension. In turn, the LV of RV pressure-overloaded hearts was also dramatically affected as reflected by changes in shape, decreased LV mass, and impaired cardiac function. RNA-sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV. Conclusion Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressu re overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodelling of the RV in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hongfei Ge ◽  
Gongxin Liu ◽  
Tracy M. Yamawaki ◽  
Caroline Tao ◽  
Shawn T. Alexander ◽  
...  

AbstractHeart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death.


2021 ◽  
Author(s):  
Hongfei Ge ◽  
Gongxin Liu ◽  
Tracy M. Yamawaki ◽  
Caroline Tao ◽  
Shawn T. Alexander ◽  
...  

Abstract Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Both pharmacological and genetic inhibition of phytosterol absorption prevented the induction of both pathways. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These phytosterolemia-associated comorbidities provide novel insight into the underlying pathophysiological mechanism that predispose these patients to increased risk of sudden cardiac death.


2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Maren Leifheit-Nestler ◽  
Matilda Bariani ◽  
Miriam A Wagner ◽  
Isabel Vogt ◽  
Fiona Eitner ◽  
...  

Abstract Background and Aims Left ventricular hypertrophy (LVH) is a major complication of CKD and associates with increased levels of the phosphaturic hormone fibroblast growth factor (FGF) 23. FGF23 induces hypertrophic growth of cardiac myocytes in vitro and LVH in rodents, suggesting that FGF23 can directly affect the heart. Besides the bone, cardiac myocytes express FGF23, too, and recent studies demonstrate that its expression is increased in cardiac and kidney injury, suggesting that cardiotoxicity of FGF23 may be at least partly due to the paracrine effects of heart-derived FGF23. However, it is still questioned whether elevated FGF23 per se is able to induce pathologic alterations in the heart or whether additional factors in CKD, such as Klotho deficiency or hyperphosphatemia are required for FGF23 to tackle the heart. By generating a mouse model with cardiac-specific overexpression of FGF23 via myocardial gene transfer using adeno-associated virus (AAV), we elucidated the cardiotoxic properties of elevated FGF23 in (1) unchallenged mice, unbiased of alterations usually associated with CKD, and (2) in the presence of high dietary phosphate intake, mimicking the exposure of enhanced serum phosphate. Method First, an adeno-associated virus that expresses murine Fgf23 (AAV-Fgf23) under the control of the cardiac troponin T promotor was injected subcutaneously into eight-week-old male C57BL/6 wildtype mice. After four months, cardiac function and geometry was assessed by cardiac magnetic resonance imaging (MRI) and echocardiography and heart tissue was analysed by qPCR, immunoblot and histological analyses. The biological activity of AAV-Fgf23-derived cardiac Fgf23 was determined using isolated neonatal rat ventricular myocytes (NRVM) in vitro. Second, AAV-Fgf23 and control mice were fed a 2% high phosphate diet (HPD) or a 0.8% normal phosphate diet (NPD) and cardiac phenotype was investigated after six months. Results AAV-Fgf23 mice showed increased cardiac-specific Fgf23 expression and synthesis of intact Fgf23 (iFgf23) protein in the heart resulting in enhanced circulating iFgf23 compared to control. Serum of AAV-Fgf23 mice stimulated hypertrophic growth of isolated NRVM and induced pro-hypertrophic gene expression in vitro, indicating that cardiac iFgf23 is biologically active. Likewise, AAV-Fgf23 mice revealed an activation of renal FGFR1/Klotho/MAPK signalling and subsequent down-regulation of renal sodium phosphate transporters NaPi-2a and NaPi-2c, causing reduced tubular phosphate reabsorption. Nevertheless, in unchallenged AAV-Fgf23 mice, impaired cardiac function, LVH and LV fibrosis were lacking. In contrast, HPD stimulated the bone expression of Fgf23 in both AAV-Fgf23 and Ctrl mice, while intra-cardiac Fgf23 mRNA levels were only increased in both AAV-Fgf23 groups irrespective of NPD or HPD. However, HPD in AAV-Fgf23 mice promoted O-glycosylation of cardiac iFgf23, suggesting stabilization of biologically active Fgf23 protein. Echocardiography showed impaired cardiac function in AAV-Fgf23 on HPD compared to its NPD group, demonstrated by enhanced end-systolic and end-diastolic volumes, increased systolic and diastolic LV diameters as well as enlarged LV inner diameters, respectively. Pressure-volume analysis using Millar catheter showed higher end-systolic and end-diastolic blood pressure (ESP, EDP) in AAV-Fgf23 mice on HPD compared to NPD. HPD in Ctrl only enhanced EDP, although this did not reach the level of statistical significance. Conclusion Chronic exposure to biologically active cardiac iFgf23 per se does not tackle the heart, while high intra-cardiac Fgf23 synthesis in the presence of high dietary phosphate promotes cardiotoxicity of Fgf23, which could pose a significant health risk to the general population.


Author(s):  
Kendrick Lee ◽  
Steven R. Laviolette ◽  
Daniel B. Hardy

Abstract Background Cannabis use in pregnancy leads to fetal growth restriction (FGR), but the long-term effects on cardiac function in the offspring are unknown, despite the fact that fetal growth deficits are associated with an increased risk of developing postnatal cardiovascular disease. We hypothesize that maternal exposure to Δ9-tetrahydrocannabinol (Δ9-THC) during pregnancy will impair fetal development, leading to cardiac dysfunction in the offspring. Methods Pregnant Wistar rats were randomly selected and administered 3 mg/kg of Δ9-THC or saline as a vehicle daily via intraperitoneal injection from gestational days 6 to 22, followed by echocardiogram analysis of cardiac function on offspring at postnatal days 1 and 21. Heart tissue was harvested from the offspring at 3 weeks for molecular analysis of cardiac remodelling. Results Exposure to Δ9-THC during pregnancy led to FGR with a significant decrease in heart-to-body weight ratios at birth. By 3 weeks, pups exhibited catch-up growth associated with significantly greater left ventricle anterior wall thickness with a decrease in cardiac output. Moreover, these Δ9-THC-exposed offsprings exhibited increased expression of collagen I and III, decreased matrix metallopeptidase-2 expression, and increased inactivation of glycogen synthase kinase-3β, all associated with cardiac remodelling. Conclusions Collectively, these data suggest that Δ9-THC-exposed FGR offspring undergo postnatal catch-up growth concomitant with cardiac remodelling and impaired cardiac function early in life. Impact To date, the long-term effects of perinatal Δ9-THC (the main psychoactive component) exposure on the cardiac function in the offspring remain unknown. We demonstrated, for the first time, that exposure to Δ9-THC alone during rat pregnancy results in significantly smaller hearts relative to body weight. These Δ9-THC-exposed offsprings exhibited postnatal catch-up growth concomitant with cardiac remodelling and impaired cardiac function. Given the increased popularity of cannabis use in pregnancy along with rising Δ9-THC concentrations, this study, for the first time, identifies the risk of perinatal Δ9-THC exposure on early postnatal cardiovascular health.


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