Agalsidase alfa long-term effect on left ventricular hypertrophy in Fabry disease.

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder affecting glycosphingolipid metabolism. Most FD patients have cardiac involvement, mainly manifested as left ventricular hypertrophy (LVH), leading to early death due to complications (arrhythmias, valvular disease, vascular involvement). Early initiation of enzyme replacement therapy (ERT) before fibrosis development has been associated with better cardiac outcomes in terms of left ventricular mass index (LVMI) and functional parameters. METHODS: A retrospective observational study was conducted in patients with FD treated with agalsidase alfa for at least 2 years. The primary objectives were: [a] to assess the annual rate of change in LVMI; [b] to define the overall incidence of stability, regression or progression of LVMI. RESULTS: Forty-nine patients were included in the final analysis, with a median follow-up of 7 years. The overall change in LVMI was 0.38 g/m2.73/year, without significant influence of baseline LVH, gender, age at ERT initiation, LV ejection fraction, body mass index, renal disease, and classical cardiovascular risk factors. Long-term ERT with agalsidase alfa was associated with stabilization of LVMI in 98% of patients with FD and was independent of the same covariables. CONCLUSION: Our results are in line with previous literature of comparable FD populations and probably represent the first study of its kind in Argentina. We here highlight the importance of cardiac morphometric stability as a positive outcome of ERT.

Introducción: La enfermedad de Fabry (EF) es una enfermedad de almacenamiento lisosomal ligada al cromosoma X que afecta el metabolismo de glicoesfingolípidos. La mayoría de pacientes EF tienen afectación cardíaca, manifestada principalmente como hipertrofia ventricular izquierda (HVI), que conduce a muerte prematura secundaria a complicaciones (arritmias, valvulopatías, afectación vascular). El tratamiento de reemplazo enzimático (TRE) precoz, iniciado antes del desarrollo de la fibrosis, se relaciona con mejores resultados cardíacos en términos del índice de masa ventricular izquierda (IMVI) y parámetros funcionales. Métodos: Se realizó un estudio retrospectivo observacional en que se incluyeron pacientes con EF tratados con agalsidasa alfa por al menos 2 años. Los objetivos primarios fueron: [a] evaluar el cambio anual del IMVI; [b] definir la incidencia global de estabilidad, regresión o progresión del IMVI. Resultados: Se incluyeron 49 pacientes, con seguimiento (mediana) de 7 años. El cambio global en el IMVI fue 0.38 g/m2.73/año, sin influencia significativa de HVI basal, sexo, edad de inicio de TRE, fracción de eyección del VI, índice de masa corporal, insuficiencia renal y factores de riesgo cardiovascular clásicos. La TRE a largo plazo con agalsidasa alfa se relacionó con la estabilización del IMVI en el 98% de los pacientes con EF, independientemente de las mismas covariables. Conclusión: Nuestros resultados están en línea con la bibliografía previa de poblaciones comparables y, probablemente, representan el primer estudio de este tipo en Argentina. Se destaca la importancia de la estabilidad morfométrica cardíaca como resultado positivo de la TRE.

Semaglutide ameliorates pressure overload-induced cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome.

Pathological cardiac hypertrophy is an important cause of heart failure(HF). Recent studies reveal that glucagon-like peptide-1 receptor (GLP1R) agonists can improve mortality and left ventricular ejection fraction in the patients with type 2 diabetes and HF. The present study aims to investigate whether semaglutide, a long-acting GLP1R agonist, can ameliorate cardiac hypertrophy induced by pressure overload, and explore the potential mechanism. The rats were performed transverse aortic constriction (TAC) to mimic pressure overload model. The rats were divided into four groups including Sham, TAC, TAC + semaglutide, and TAC + semaglutide + HCQ (hydroxychloroquine, an inhibitor of mitophagy). The rats in each experimental group received their respective interventions for 4 weeks. The parameters of left ventricular hypertrophy(LVH) were measured by echocardiography, Hematoxylin-eosin (HE) staining, western-blot and immunohistochemistry (IHC), respectively. The changes of mitophagy were reflected by detecting cytochrome c oxidase subunit II (COXII), LC3II/LC3I, mitochondria, and autophagosomes. Meanwhile, NLRP3, Caspase-1, and interleukin-18 were detected to evaluate the activation of NLRP3 inflammasome in each group. The results suggest that LVH, impaired mitophagy, and activation of NLRP3 inflammasome were present in TAC rats. Semaglutide significantly reduced LVH, improve mitophagy, and down-regulated NLRP3 inflammatory signal pathway in TAC rats. However, the reversed effect of semaglutide on cardiac hypertrophy was abolished by HCQ, which restored the activation of NLRP3 inflammasome suppressed by improved mitophagy. In conclusion, semaglutide ameliorates the cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome. Semaglutide may be a novel potential option for intervention of cardiac hypertrophy induced by pressure overload.

Effects of Long-Term Administration of Bovine Bone Gelatin Peptides on Myocardial Hypertrophy in Spontaneously Hypertensive Rats.

The research purpose was to investigate the effects and the underlying molecular mechanisms of bovine bone gelatin peptides (BGP) on myocardial hypertrophy in spontaneously hypertensive rats (SHR). BGP relieved myocardial hypertrophy and fibrosis in SHR rats in a dose-dependent manner by reducing the left ventricular mass index, myocardial cell diameter, myocardial fibrosis area, and levels of myocardial hypertrophy markers (atrial natriuretic and brain natriuretic peptide). Label-free quantitative proteomics analysis showed that long-term administration of BGP changed the left ventricle proteomes of SHR. The 37 differentially expressed proteins in the high-dose BGP group participated in multiple signaling pathways associated with cardiac hypertrophy and fibrosis indicating that BGP could play a cardioprotective effect on SHR rats by targeting multiple signaling pathways. Further validation experiments showed that a high dose of BGP inhibited the expression of phosphoinositide 3-kinase (Pi3k), phosphorylated protein kinase B (p-Akt), and transforming growth factor-beta 1 (TGF-ß1) in the myocardial tissue of SHR rats. Together, BGP could be an effective candidate for functional nutritional supplements to inhibit myocardial hypertrophy and fibrosis by negatively regulating the TGF-ß1 and Pi3k/Akt signaling pathways.

Effects of Agalsidase Alfa Enzyme Replacement Therapy on Left Ventricular Hypertrophy on Electrocardiogram in a Female Patient with Fabry Disease.

Fabry disease is an X-linked lysosomal storage disorder caused by defective enzyme activity of α-galactosidase A and treated with enzyme replacement therapy (ERT) with recombinant α-galactosidase. ERT reduces left ventricular mass assessed by echocardiography or magnetic resonance imaging. However, electrocardiogram changes during ERT have not been fully elucidated. In the present case, ERT with agalsidase alfa for 4 years decreased QRS voltage and negative T depth along with a reduction of left ventricular mass and wall thickness and improvement of symptoms in a female patient with Fabry disease. Long-term observation of electrocardiogram changes might be useful for determining the efficacy of ERT in this case.

Regression of left ventricular hypertrophy after tafamidis therapy in a patient with transthyretin amyloidosis variant.

Transthyretin amyloidosis (ATTR) variant is a life-threatening hereditary disease predominantly affecting the peripheral nervous system and heart. Tafamidis, which prevents the deposition of amyloid by stabilizing transthyretin, is available for the treatment of neuropathy and cardiomyopathy of ATTR. However, whether tafamidis could eliminate established amyloid deposits and improve cardiac function remains unknown. We reported a case of regression of left ventricular hypertrophy after tafamidis therapy in a patient with an ATTR variant. J. Med. Invest. 69 : 320-322, August, 2022.

Impact of Sacubitril/Valsartan Compared With Ramipril on Cardiac Structure and Function After Acute Myocardial Infarction: The PARADISE-MI Echocardiographic Substudy.

BACKGROUND: Angiotensin-converting enzyme inhibitors attenuate left ventricular (LV) enlargement after acute myocardial infarction (AMI). Preclinical data suggest similar benefits with combined angiotensin receptor neprilysin inhibition, but human data are conflicting. The PARADISE-MI Echo Study (Prospective ARNI Versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction) tested the effect of sacubitril/valsartan compared with ramipril on LV function and adverse remodeling after high risk-AMI. METHODS: In a prespecified substudy, 544 PARADISE-MI participants were enrolled in the Echo Study to undergo protocol echocardiography at randomization and after 8 months. Patients were randomized within 0.5 to 7 days of presentation with their index AMI to receive a target dose of sacubitril/valsartan 200 mg or ramipril 5 mg twice daily. Echocardiographic measures were performed at a core laboratory by investigators blinded to treatment assignment. The effect of treatment on change in echo measures was assessed with ANCOVA with adjustment for baseline value and enrollment region. The primary end points were change in LV ejection fraction (LVEF) and left atrial volume (LAV), and prespecified secondary end points included changes in LV end-diastolic and end-systolic volumes. RESULTS: Mean age was 64±12 years; 26% were women; mean LVEF was 42±12%; and LAV was 49±17 mL. Of 544 enrolled patients, 457 (84%) had a follow-up echo at 8 months (228 taking sacubitril/valsartan, 229 taking ramipril). There was no significant difference in change in LVEF (P=0.79) or LAV (P =0.62) by treatment group. Patients randomized to sacubitril/valsartan demonstrated less increase in LV end-diastolic volume (P=0.025) and greater decline in LV mass index (P=0.037), increase in tissue Doppler e'lat (P=0.005), decrease in E/e'lat (P=0.045), and decrease in tricuspid regurgitation peak velocity (P=0.024) than patients randomized to ramipril. These differences remained significant after adjustment for differences in baseline characteristics. Baseline LVEF, LV end-diastolic volume, LV end-systolic volume, LV mass index, LAV, and Doppler-based diastolic indices were associated with risk of cardiovascular death or incident heart failure. CONCLUSIONS: Treatment with sacubitril/valsartan compared with ramipril after AMI did not result in changes in LVEF or LAV at 8 months. Patients randomized to sacubitril/valsartan had less LV enlargement and greater improvement in filling pressure. Measures of LV size, systolic function, and diastolic properties were predictive of cardiovascular death and incident heart failure after AMI in this contemporary, well-treated cohort. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02924727.

[Treatment of patients with heart failure and preserved ejection fraction: reliance on clinical phenotypes].

The article discusses the problem of improving the effectiveness of treatment of heart failure with preserved left ventricular ejection fraction (HFpEF). The relative "failure" of early studies with renin-angiotensin-aldosterone system inhibitors was largely due to the lack of understanding that patients with HFpEF represent a heterogeneous group with various etiological factors and pathogenetic mechanisms of the disease. Therefore, the so-called personalized approach should be used in the treatment of these patients. This approach is based on the identification of clearly defined disease phenotypes, each characterized by a set of demographic, pathogenetic, and clinical characteristics. Based on the literature and own experience, the authors consider four main phenotypes of HFpEF: 1) phenotype with brain natriuretic peptide "deficiency" syndrome associated with moderate/severe left ventricular hypertrophy; 2) cardiometabolic phenotype; 3) phenotype with mixed pulmonary hypertension and right ventricular failure; and 4) cardiac amyloidosis phenotype. In the treatment of patients with phenotype 1, it seems preferable to use the valsartan + sacubitril (possibly in combination with spironolactone) combination treatment; with phenotype 2, the empagliflozin treatment is the best; with phenotype 3, the phosphodiesterase type 5 inhibitor sildenafil; and with phenotype 4, transthyretin stabilizers. Certain features of different phenotypes overlap and may change as the disease progresses. Nevertheless, the isolation of these phenotypes is advisable to prioritize the choice of drug therapy. Thus, the diuretic treatment (preferably torasemide) should be considered in the presence of congestion, regardless of the HFpEF phenotype; the valsartan + sacubitril and spironolactone treatment is appropriate not only in the shortage of brain natriuretic peptide but also in the presence of concentric left ventricular hypertrophy (except for the amyloidosis phenotype); and the treatment with empagliflozin and statins may be considered in all situations where pro-inflammatory mechanisms are involved.

Lessons from effect of etelcalcetide on left ventricular hypertrophy in patients with end-stage kidney disease.

PURPOSE OF REVIEW: Patients with end-stage kidney disease (ESKD) frequently develop left ventricular hypertrophy (LVH), which is associated with an exceptionally high risk of cardiovascular events and mortality. This review focuses on interventional studies that modify levels of fibroblast growth factor 23 (FGF23) and examine effects on myocardial hypertrophy, cardiovascular events and mortality. RECENT FINDINGS: Quantitative evaluations of trials of calcimimetics found no effects on cardiovascular events and cardiovascular and all-cause mortality when compared with placebo. However, a recent randomized, controlled trial of etelcalcetide versus alfacalcidol showed that etelcalcetide effectively inhibited the progression of LVH in comparison to vitamin D in patients on haemodialysis after 1 year of treatment. Prior to that, oral calcimimetic treatment has already been shown to reduce left ventricular mass in patients on haemodialysis, whereas treatment with active vitamin D or mineralocorticoids was ineffective in patients with ESKD. SUMMARY: Data from a recent trial of etelcalcetide on LVH suggest that FGF23 may be a possible therapeutic target for cardiac risk reduction in patients on haemodialysis. If these findings are confirmed by further research, it might be speculated that a treatment shift from active vitamin D towards FGF23-lowering therapy may occur in patients on haemodialysis.

Fabry Disease and the Effectiveness of Enzyme Replacement Therapy (ERT) in Left Ventricular Hypertrophy (LVH) Improvement: A Review and Meta-Analysis.

Background: Fabry disease is an inherited lysosomal storage disease affecting multiple organs with complications, including cardiomyopathy such as left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) has been the main treatment for Fabry patients since 2001. However, the indications of ERT are not clearly defined. We performed a meta-analysis according to previous studies to review the benefit of ERT for LVH improvement in Fabry patients. Methods: We performed a literature search from the National Center for Biotechnology Information (NCBI) and PubMed database without restriction of years for systematic review purposes. We performed a systematic review of clinical cohort studies and trials using a pooled analysis of proportions. We calculated the pooled proportions and the confidence intervals (CI) for left ventricular mass index (LVMI) for both ERT treatment and ERT treatment-naïve groups. The results for before ERT treatment and after ERT treatment are also investigated. Results: A total of 5 cohort studies and 2 randomized controlled trials (RCTs), involving a total of 552 participants (267 on ERT treatment versus 285 on naïve treatment), met the inclusion criteria. The pooled proportions analysis showed that the difference in means of LVMI between the ERT treatment group and the ERT treatment-naïve group was -0.149 [95% CI: -0.431, 0.132]. Effect differences favored the ERT treatment group over the ERT treatment-naïve group (p = 0.034). Another analysis included 3 cohort studies and 1 RCT with 442 participants (228 on before ERT and 214 on 4 years after ERT). The pooled proportions analysis showed that the difference in means of LVMI between the before ERT treatment group and the after ERT treatment group was -0.448 [95% CI: -0.787, -0.108]. It favored the 4 years after ERT group over the before ERT group (p = 0.037). Conclusions: Based on the currently available data, our meta-analysis showed that there are beneficial effects on LVH improvement with ERT in Fabry disease patients. It is better to start ERT as soon as we have diagnoses in female carriers and atypically affected males. Further research is needed to investigate the role of ERT in LVH improvement.

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease.

Radiation-induced heart disease (RIHD) is a potential late side-effect of thoracic radiotherapy resulting in left ventricular hypertrophy (LVH) and fibrosis due to a complex pathomechanism leading to heart failure. Angiotensin-II receptor blockers (ARBs), including losartan, are frequently used to control heart failure of various etiologies. Preclinical evidence is lacking on the anti-remodeling effects of ARBs in RIHD, while the results of clinical studies are controversial. We aimed at investigating the effects of losartan in a rat model of RIHD. Male Sprague-Dawley rats were studied in three groups: (1) control, (2) radiotherapy (RT) only, (3) RT treated with losartan (per os 10 mg/kg/day), and were followed for 1, 3, or 15 weeks. At 15 weeks post-irradiation, losartan alleviated the echocardiographic and histological signs of LVH and fibrosis and reduced the overexpression of chymase, connective tissue growth factor, and transforming growth factor-beta in the myocardium measured by qPCR; likewise, the level of the SMAD2/3 protein determined by Western blot decreased. In both RT groups, the pro-survival phospho-AKT/AKT and the phospho-ERK1,2/ERK1,2 ratios were increased at week 15. The antiremodeling effects of losartan seem to be associated with the repression of chymase and several elements of the TGF-ß/SMAD signaling pathway in our RIHD model.

Resveratrol Confers Protection Against Ischemia/Reperfusion Injury by Increase of Angiotensin (1-7) Expression in a Rat Model of Myocardial Hypertrophy.

ABSTRACT: Left ventricular hypertrophy (LVH) makes the heart vulnerable to ischemia/reperfusion (IR) injury. Angiotensin (Ang) (1-7) is recognized as a cardioprotective peptide. We investigated the effect of polyphenol resveratrol on myocardial IR injury after hypertrophy and examined cardiac content of Ang (1-7) and transcription of its receptor (MasR). Rats were divided into sham-operated, LVH, IR, LVH + IR, and resveratrol + LVH + IR groups. Myocardial hypertrophy and IR models were created by abdominal aortic banding and left coronary artery occlusion, respectively. To evaluate the electrocardiogram parameters and incidence of arrhythmias, electrocardiogram was recorded by subcutaneous leads (lead II). Blood pressure was measured through the left carotid artery. Infarct size was determined by the triphenyl tetrazolium chloride staining. The Ang (1-7) level was evaluated by immunohistochemistry. The Mas receptor mRNA level was assessed by the real-time real time reverse transcription polymerase chain reaction technique. QT-interval duration, infarct size, and incidence of ischemia-induced arrhythmia were significantly higher in the LVH + IR group. However, in the resveratrol-treated group, these parameters were decreased significantly. The cardiac level of Ang (1-7) was decreased in untreated hypertrophied hearts (LVH and LVH + IR groups). Pretreatment with resveratrol normalized the cardiac level of Ang (1-7). The mRNA level of Mas receptor was increased in all of hypertrophied hearts in the presence or absence of resveratrol. Resveratrol can decrease IR injury in rats with LVH. The anti-ischemic effect of resveratrol may be related to the enhancement of Ang (1-7)/MasR axis.

The GABAA Receptor Influences Pressure Overload-Induced Heart Failure by Modulating Macrophages in Mice.

Background: Myocardial macrophages have key roles in cardiac remodeling and dysfunction. The gamma-aminobutyric acid subtype A (GABAA) receptor was recently found to be distributed in macrophages, allowing regulation of inflammatory responses to various diseases. This study aimed to clarify the role of GABAA receptor-mediated macrophage responses in pressure overload-induced heart failure. Methods and Results: C57BL/6J mice underwent transverse aortic constriction for pressure-overload hypertrophy (POH) and were intraperitoneally treated with a specific GABAA receptor agonist (topiramate) or antagonist (bicuculline). Echocardiography, histology, and flow cytometry were performed to evaluate the causes and effects of myocardial hypertrophy and fibrosis. Activation of the GABAA receptor by topiramate reduced ejection fraction and fractional shortening, enlarged the end-diastolic and end-systolic left ventricular internal diameter, aggravated myocardial hypertrophy and fibrosis, and accelerated heart failure in response to pressure overload. Mechanistically, topiramate increased the number of Ly6Clow macrophages in the heart during POH and circulating Ly6Chigh classic monocyte infiltration in late-phase POH. Further, topiramate drove Ly6Clow macrophages toward MHCIIhigh macrophage polarization. As a result, Ly6Clow macrophages activated the amphiregulin-induced AKT/mTOR signaling pathway, and Ly6ClowMHCIIhigh macrophage polarization increased expression levels of osteopontin and TGF-ß, which led to myocardial hypertrophy and fibrosis. Conversely, GABAA receptor blockage with bicuculline reversed these effects. Conclusions: Control of the GABAA receptor activity in monocytes/macrophages plays an important role in myocardial hypertrophy and fibrosis after POH. Blockade of the GABAA receptor has the potential to improve pressure overload-induced heart failure.

Nutraceutical, Dietary, and Lifestyle Options for Prevention and Treatment of Ventricular Hypertrophy and Heart Failure.

Although well documented drug therapies are available for the management of ventricular hypertrophy (VH) and heart failure (HF), most patients nonetheless experience a downhill course, and further therapeutic measures are needed. Nutraceutical, dietary, and lifestyle measures may have particular merit in this regard, as they are currently available, relatively safe and inexpensive, and can lend themselves to primary prevention as well. A consideration of the pathogenic mechanisms underlying the VH/HF syndrome suggests that measures which control oxidative and endoplasmic reticulum (ER) stress, that support effective nitric oxide and hydrogen sulfide bioactivity, that prevent a reduction in cardiomyocyte pH, and that boost the production of protective hormones, such as fibroblast growth factor 21 (FGF21), while suppressing fibroblast growth factor 23 (FGF23) and marinobufagenin, may have utility for preventing and controlling this syndrome. Agents considered in this essay include phycocyanobilin, N-acetylcysteine, lipoic acid, ferulic acid, zinc, selenium, ubiquinol, astaxanthin, melatonin, tauroursodeoxycholic acid, berberine, citrulline, high-dose folate, cocoa flavanols, hawthorn extract, dietary nitrate, high-dose biotin, soy isoflavones, taurine, carnitine, magnesium orotate, EPA-rich fish oil, glycine, and copper. The potential advantages of whole-food plant-based diets, moderation in salt intake, avoidance of phosphate additives, and regular exercise training and sauna sessions are also discussed. There should be considerable scope for the development of functional foods and supplements which make it more convenient and affordable for patients to consume complementary combinations of the agents discussed here. Research Strategy: Key word searching of PubMed was employed to locate the research papers whose findings are cited in this essay.

Randomized Trial of Etelcalcetide for Cardiac Hypertrophy in Hemodialysis.

[Figure: see text].

Pygo1 regulates pathological cardiac hypertrophy via a ß-catenin-dependent mechanism.

Wnt/ß-catenin signaling plays a key role in pathological cardiac remodeling in adults. The identification of a tissue-specific Wnt/ß-catenin interaction factor may provide a tissue-specific clinical targeting strategy. Drosophila Pygo encodes the core interaction factor of Wnt/ß-catenin. Two Pygo homologs (Pygo1 and Pygo2) have been identified in mammals. Different from the ubiquitous expression profile of Pygo2, Pygo1 is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease is yet to be elucidated. In this study, we found that Pygo1 was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios, and increased cell size. The canonical ß-catenin/T-cell transcription factor 4 (TCF4) complex was abundant in Pygo1-overexpressing transgenic (Pygo1-TG) cardiac tissue, and the downstream genes of Wnt signaling, that is, Axin2, Ephb3, and c-Myc, were upregulated. A tail vein injection of ß-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodeling in Pygo1-TG mice. Furthermore, in vivo downregulated pygo1 during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/ß-catenin-dependent manner, which may provide new clues for tissue-specific clinical treatment via targeting this pathway.NEW & NOTEWORTHY In this study, we found that Pygo1 is associated with human pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy. Meanwhile, cardiac function was improved when expression of Pygo1 was interfered in hypertrophy-model mice. Our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/ß-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.

Mitochondrial protective effects of PARP-inhibition in hypertension-induced myocardial remodeling and in stressed cardiomyocytes.

AIMS: During oxidative stress mitochondria become the main source of endogenous reactive oxygen species (ROS) production. In the present study, we aimed to clarify the effects of pharmacological PARP-1 inhibition on mitochondrial function and quality control processes. MAIN METHODS: L-2286, a quinazoline-derivative PARP inhibitor, protects against cardiovascular remodeling and heart failure by favorable modulation of signaling routes. We examined the effects of PARP-1 inhibition on mitochondrial quality control processes and function in vivo and in vitro. Spontaneously hypertensive rats (SHRs) were treated with L-2286 or placebo. In the in vitro model, 150 µM H2O2 stress was applied on neonatal rat cardiomyocytes (NRCM). KEY FINDINGS: PARP-inhibition prevented the development of left ventricular hypertrophy in SHRs. The interfibrillar mitochondrial network were less fragmented, the average mitochondrial size was bigger and showed higher cristae density compared to untreated SHRs. Dynamin related protein 1 (Drp1) translocation and therefore the fission of mitochondria was inhibited by L-2286 treatment. Moreover, L-2286 treatment increased the amount of fusion proteins (Opa1, Mfn2), thus preserving structural stability. PARP-inhibition also preserved the mitochondrial genome integrity. In addition, the mitochondrial biogenesis was also enhanced due to L-2286 treatment, leading to an overall increase in the ATP production and improvement in survival of stressed cells. SIGNIFICANCE: Our results suggest that the modulation of mitochondrial dynamics and biogenesis can be a promising therapeutical target in hypertension-induced myocardial remodeling and heart failure.

Water-soluble alkaloids extracted from Aconiti Radix lateralis praeparata protect against chronic heart failure in rats via a calcium signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Many studies have shown the beneficial effects of aconite water-soluble alkaloid extract (AWA) in experimental models of heart disease, which have been ascribed to the presence of aconine, hypaconine, talatisamine, fuziline, neoline, and songorine. This study evaluated the effects of a chemically characterized AWA by chemical content, evaluated its effects in suprarenal abdominal aortic coarctation surgery (AAC)-induced chronic heart failure (CHF) in rats, and revealed the underlying mechanisms of action by proteomics. METHODS: Rats were distributed into different groups: sham, model, and AWA-treated groups (10, 20, and 40 mg/kg/day). Sham rats received surgery without AAC, whereas model rats an AWA-treated groups underwent AAC surgery. after 8 weeks, the treatment group was fed AWA for 4 weeks, and body weight was assessed weekly. At the end of the treatment, heart function was tested by echocardiography. AAC-induced chronic heart failure, including myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis, was evaluated in heart tissue and plasma by RT-qPCR, ELISA, hematoxylin and eosin (H&E) staining, Masson's trichrome staining, TUNEL staining, and immunofluorescence staining of α-SMA, Col Ⅰ, and Col Ⅲ. Then, a proteomics approach was used to explore the underlying mechanisms of action of AWA in chronic heart failure. RESULTS: AWA administration reduced body weight gain, myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis, and rats showed improvement in cardiac function compared to model group. The extract significantly ameliorated the AAC-induced altered expression of heart failure markers such as ANP, NT-proBNP, and ß-MHC, as well as fibrosis, hypertrophy markers MMP-2 and MMP-9, and other heart failure-related factors including plasma levels of TNF-α and IL-6. Furthermore, the extract reduced the protein expression of α-SMA, Col Ⅰ, and Col Ⅲ in the left ventricular (LV), thus inhibiting the LV remodeling associated with CHF. In addition, proteomics characterization of differentially expressed proteins showed that AWA administration inhibited left ventricular remodeling in CHF rats via a calcium signaling pathway, and reversed the expression of RyR2 and SERCA2a. CONCLUSIONS: AWA extract exerts beneficial effects in an AAC-induced CHF model in rats, which was associated with an improvement in LV function, hypertrophy, fibrosis, and apoptotic status. These effects may be related to the regulation of calcium signaling by the altered expression of RyR2 and SERCA2a.

[Eosinophilic Granulomatosis with Polyangiitis with Pulmonary and Cardiac Involvement]. / Eosinophile Granulomatose mit Polyangiitis mit pulmonaler und kardialer Beteiligung.

A 62-year-old patient with bronchial asthma and chronic rhinosinusitis underwent inguinal hernia surgery. After the operation, sudden circulatory arrest occurred, requiring cardiopulmonary resuscitation. Coronary angiography revealed a 99 % proximal stenosis of right coronary artery (RCA) with unsuspicious and smooth coronary vessel walls. In the further course, several similar events occurred, but without pathological findings in the coronary angiography. Initially, echocardiography showed slightly reduced left ventricular ejection fraction of 45 %. Chest radiography revealed bilateral pulmonary infiltrates, and white blood cell count showed severe eosinophilia (37 %). Serological antibody testing including ANA, ENA and c-/p-ANCA was negative. Myeloproliferative pathologies were excluded by bone marrow puncture. The patient suffered from emerging dyspnea, weakness, and ongoing weight loss. A methylprednisolone pulse of 250 mg/d for 3 days remained without significant effect, so that the patient was eventually referred to our university hospital due to ongoing clinical deterioration. On admission, the patient suffered from weakness, progressive muscular atrophy, and dyspnea on exertion. Physical examination revealed a right-sided peroneal paralysis. Bronchial lavage detected severe eosinophil alveolitis (37 %), and laboratory findings showed elevated cardiac enzymes and NT-proBNP (Troponin-T > 700 ng/l, NT-proBNP > 10.000 ng/l). Echocardiography revealed a dramatic deterioration of cardiac function (LVEF 16 %). Interdisciplinary discussion between pulmonologists and cardiologists lead to the diagnosis of ANCA-negative eosinophilic granulomatosis with polyangiitis (EGPA) with pulmonary and cardiac involvement. Initiation of immunosuppressive therapy with methylprednisolone 1000 mg/d for 3 days followed by cyclophosphamide therapy (6 pulses, administered every 4 weeks) led to substantial symptomatic improvement, complete regression of pulmonary infiltrates and marked recovery of cardiac function (LVEF 47 %). CONCLUSION: Serological detection of elevated ANCAs is not necessary for diagnosis of EGPA. Only 30 - 70 % of patients are positive for these, particularly if neurological and/or renal rather than cardiac and/or pulmonary involvement is present. This may be a pitfall in establishing the correct diagnosis. Induction therapy with cyclophosphamide is the preferred treatment for steroid-refractory EGPA with life-threatening organ involvement.

A Contemporary Approach to Hypertensive Cardiomyopathy: Reversing Left Ventricular Hypertrophy.

PURPOSE OF REVIEW: To highlight pharmacological and non-pharmacological approaches to reversing hypertensive left ventricular hypertrophy (LVH). We identify high-risk phenotypes that may benefit from aggressive blood pressure (BP) management to prevent incident outcomes such as the development of atherosclerotic cardiovascular disease, stroke, and heart failure. RECENT FINDINGS: LVH is a modifiable risk factor. Intensive BP lowering (systolic BP < 120 mmHg) induces greater regression of electrocardiographic LVH than standard BP targets. The optimal agents for inducing LVH regression include renin-angiotensinogen-aldosterone system inhibitors and calcium channel blockers, although recent meta-analyses have demonstrated superior efficacy of non-hydrochlorothiazide diuretics. Novel agents (such as sacubitril/valsartan) and non-pharmacological approaches (like bariatric surgery) hold promise but longitudinal studies assessing their impact on clinical outcomes are needed. LVH regression is achievable with appropriate therapy with first-line antihypertensive agents. Additional studies are warranted to assess if intensive BP lowering in high-risk groups (such as blacks, women, and malignant LVH) improves outcomes.

ß-adrenergic activation may promote myosin light chain kinase degradation through calpain in pressure overload-induced cardiac hypertrophy: ß-adrenergic activation results in MLCK degradation.

BACKGROUND: ß-adrenergic activation is able to exacerbate cardiac hypertrophy. Myosin light chain kinase (MLCK) and its phosphorylated substrate, phospho-myosin light chain 2 (p-MLC2), play vital roles in regulating cardiac hypertrophy. However, it is not yet clear whether there is a relationship between ß-adrenergic activation and MLCK in the progression of cardiac hypertrophy. Therefore, we explored this relationship and the underlying mechanisms in this work. METHODS: Cardiac hypertrophy and cardiomyocyte hypertrophy were induced by pressure overload and isoproterenol (ISO) stimulation, respectively. Echocardiography, histological analysis, immunofluorescence and qRT-PCR were used to confirm the successful establishment of the models. A ß-blocker (metoprolol) and a calpain inhibitor (calpeptin) were administered to inhibit ß-adrenergic activity in rats and calpain in cardiomyocytes, respectively. The protein expression levels of MLCK, myosin light chain 2 (MLC2), p-MLC2, myosin phosphatase 2 (MYPT2), calmodulin (CaM) and calpain were measured using western blotting. A cleavage assay was performed to assess the degradation of recombinant human MLCK by recombinant human calpain. RESULTS: The ß-blocker alleviated cardiac hypertrophy and dysfunction, increased MLCK and MLC2 phosphorylation and decreased calpain expression in pressure overload-induced cardiac hypertrophy. Additionally, the calpain inhibitor calpeptin attenuated cardiomyocyte hypertrophy, upregulated MLCK and p-MLC2 and reduced MLCK degradation in ISO-induced cardiomyocyte hypertrophy. Recombinant human calpain degraded recombinant human MLCK in vitro in concentration- and time-dependent manners, and this degradation was inhibited by the calpain inhibitor calpeptin. CONCLUSION: Our study suggested that ß-adrenergic activation may promote the degradation of MLCK through calpain in pressure overload-induced cardiac hypertrophy.