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ESC Heart Failure Jun 2024Atrial fibrillation and heart failure with preserved ejection fraction (HFpEF) are frequent concomitant diseases sharing several pathophysiological mechanisms leading to...
Atrial fibrillation and heart failure with preserved ejection fraction (HFpEF) are frequent concomitant diseases sharing several pathophysiological mechanisms leading to structural remodelling of both atria and ventricles. We present a case of an HFpEF patient with rapid atrial fibrillation who remained symptomatic even after successful cardioversion, initiation of antiarrhythmic therapy, and treatment of comorbidities. Due to asymmetric septal hypertrophy, the stress test was performed to exclude outflow tract obstruction and revealed a low basal heart rate with significant chronotropic insufficiency. In addition to SGLT2 initiation, the beta-blocker dose was reduced, and amiodarone was discontinued. This therapy modification led to a marked improvement in exercise capacity, significant reduction of palpitations, reduction of NT-proBNP, and signs of a decreased left ventricular filling pressure with reverse remodelling of LA. This case shows the importance of both individual tailoring of medical therapy and chronotropic insufficiency in HFpEF patients.
PubMed: 38886855
DOI: 10.1002/ehf2.14897 -
Frontiers in Cardiovascular Medicine 2024The kynurenine pathway (KP) serves as the primary route for tryptophan metabolism in most mammalian organisms, with its downstream metabolites actively involved in... (Review)
Review
The kynurenine pathway (KP) serves as the primary route for tryptophan metabolism in most mammalian organisms, with its downstream metabolites actively involved in various physiological and pathological processes. Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) serve as the initial and pivotal enzymes of the KP, with IDO playing important and intricate roles in cardiovascular diseases. Multiple metabolites of KP have been observed to exhibit elevated concentrations in plasma across various cardiovascular diseases, such as atherosclerosis, hypertension, and acute myocardial infarction. Multiple studies have indicated that kynurenine (KYN) may serve as a potential biomarker for several adverse cardiovascular events. Furthermore, Kynurenine and its downstream metabolites have complex roles in inflammation, exhibiting both inhibitory and stimulatory effects on inflammatory responses under different conditions. In atherosclerosis, upregulation of IDO stimulates KYN production, mediating aromatic hydrocarbon receptor (AhR)-induced exacerbation of vascular inflammation and promotion of foam cell formation. Conversely, in arterial calcification, this mediation alleviates osteogenic differentiation of vascular smooth muscle cells. Additionally, in cardiac remodeling, KYN-mediated AhR activation exacerbates pathological left ventricular hypertrophy and fibrosis. Interventions targeting components of the KP, such as IDO inhibitors, 3-hydroxyanthranilic acid, and anthranilic acid, demonstrate cardiovascular protective effects. This review outlines the mechanistic roles of KP in coronary atherosclerosis, arterial calcification, and myocardial diseases, highlighting the potential diagnostic, prognostic, and therapeutic value of KP in cardiovascular diseases, thus providing novel insights for the development and application of related drugs in future research.
PubMed: 38883986
DOI: 10.3389/fcvm.2024.1406856 -
American Journal of Translational... 2024Heart failure poses a significant threat to global public health within the realm of cardiovascular diseases. Its pathological progression involves various alterations... (Review)
Review
Heart failure poses a significant threat to global public health within the realm of cardiovascular diseases. Its pathological progression involves various alterations in cardiomyocytes, among which autophagy, a crucial intracellular degradation mechanism, plays a pivotal role. Autophagy facilitates the breakdown of damaged organelles and proteins, thereby maintaining cellular homeostasis. In the context of heart failure, autophagy coexists with apoptosis and necrosis, influencing myocardial hypertrophy and ventricular remodeling. However, its impact on heart failure manifests a dual nature: moderate autophagy aids in cardiac repair, whereas excessive autophagy may exacerbate ventricular remodeling and cell demise. This review delves into the fundamental biology of autophagy, elucidating its involvement in the pathological cascade of heart failure and its correlation with cardiac hypertrophy and ventricular remodeling. Furthermore, an analysis of the interplay between autophagy regulatory factors and heart failure sheds light on the potential therapeutic implications of autophagy in the prevention and management of heart failure. This exploration provides a theoretical foundation for novel treatment strategies in combating heart failure.
PubMed: 38883358
DOI: 10.62347/OBXQ9477 -
Circulation Journal : Official Journal... Jun 2024
PubMed: 38880609
DOI: 10.1253/circj.CJ-24-0109 -
Journal of Pharmacological Sciences Aug 2024The atrophic myocardium resulting from mechanical unloading and nutritional deprivation is considered crucial as maladaptive remodeling directly associated with heart...
The atrophic myocardium resulting from mechanical unloading and nutritional deprivation is considered crucial as maladaptive remodeling directly associated with heart failure, as well as interstitial fibrosis. Conversely, myocardial hypertrophy resulting from hemodynamic loading is perceived as compensatory stress adaptation. We previously reported the abundant presence of highly redox-active polysulfide molecules, termed supersulfide, with two or more sulfur atoms catenated in normal hearts, and the supersulfide catabolism in pathologic hearts after myocardial infarction correlated with worsened prognosis of heart failure. However, the impact of supersulfide on myocardial remodeling remains unclear. Here, we investigated the involvement of supersulfide metabolism in cardiomyocyte remodeling, using a model of adenosine 5'-triphosphate (ATP) receptor-stimulated atrophy and endothelin-1 receptor-stimulated hypertrophy in neonatal rat cardiomyocytes. Results revealed contrasting changes in intracellular supersulfide and its catabolite, hydrogen sulfide (HS), between cardiomyocyte atrophy and hypertrophy. Stimulation of cardiomyocytes with ATP decreased supersulfide activity, while HS accumulation itself did not affect cardiomyocyte atrophy. This supersulfide catabolism was also involved in myofibroblast formation of neonatal rat cardiac fibroblasts. Thus, unraveling supersulfide metabolism during myocardial remodeling may lead to the development of novel therapeutic strategies to improve heart failure.
Topics: Animals; Myocytes, Cardiac; Sulfides; Hydrogen Sulfide; Cells, Cultured; Ventricular Remodeling; Adenosine Triphosphate; Rats; Atrophy; Cardiomegaly; Heart Failure; Animals, Newborn; Rats, Sprague-Dawley
PubMed: 38880546
DOI: 10.1016/j.jphs.2024.05.002 -
ESC Heart Failure Jun 2024Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic cardiac disorder characterized by unexplained left ventricular hypertrophy. It can cause a wide...
AIMS
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic cardiac disorder characterized by unexplained left ventricular hypertrophy. It can cause a wide spectrum of clinical manifestations, ranging from asymptomatic to heart failure and sudden cardiac death (SCD). Approximately half of HCM cases are caused by variants in sarcomeric proteins, including α-tropomyosin (TPM1). In this study, we aimed to characterize the clinical and molecular phenotype of HCM in an Iranian pedigree with SCD.
METHODS AND RESULTS
The proband and available family members underwent comprehensive clinical evaluations, including echocardiography, cardiac magnetic resonance (CMR) imaging and electrocardiography (ECG). Whole-exome sequencing (WES) was performed in all available family members to identify the causal variant, which was validated, and segregation analysis was conducted via Sanger sequencing. WES identified a novel missense variant, c.761A>G:p.D254G (NM_001018005.2), in the TPM1 gene, in the proband, his father and one of his sisters. Bioinformatic analysis predicted it to be likely pathogenic. Clinical features in affected individuals were consistent with HCM.
CONCLUSIONS
The identification of a novel TPM1 variant in a family with HCM and SCD underscores the critical role of genetic screening in at-risk families. Early detection of pathogenic variants can facilitate timely intervention and management, potentially reducing the risk of SCD in individuals with HCM.
PubMed: 38874371
DOI: 10.1002/ehf2.14906 -
Coexistence of variant-type transthyretin and immunoglobulin light-chain amyloidosis: a case report.European Heart Journal. Case Reports Jun 2024Determining the type of amyloid deposits is clinically important for choosing the specific therapies for cardiac amyloidosis.
BACKGROUND
Determining the type of amyloid deposits is clinically important for choosing the specific therapies for cardiac amyloidosis.
CASE SUMMARY
A 78-year-old woman who had been experiencing fluid retention and dyspnoea on exertion for 6 months was referred to our hospital for the management of heart failure with left ventricular hypertrophy. Since Tc-hydroxymethylene diphosphonate scintigraphy showed mild cardiac uptake and significant elevation of serum free lambda chain (with a difference of 263 mg/L in free light chain), we suspected immunoglobulin light-chain amyloidosis (AL), and endomyocardial biopsy was performed. The deposit site within the myocardial tissue exhibited positive for Congo red staining and transthyretin immunostaining, however negative or non-specific for light-chain immunostaining including lambda and kappa staining. Genetic testing confirmed a mutation in V122I, variant-type transthyretin amyloidosis (ATTRv). Despite the administration of patisiran, her condition exhibited progressive deterioration. Additionally, she displayed macroglossia, an atypical manifestation in ATTRv amyloidosis. Further biopsies from tongue and abdominal wall fat culminated in a final diagnosis: the coexistence of ATTRv and AL (of the lambda type). Although treatment with melphalan and dexamethasone was started, she passed away 24 months after the initial visit. When the endomyocardial biopsy specimen underwent mass spectrometry as a analysis, both ATTR and AL amyloid were significantly detected.
DISCUSSION
Coexistence of ATTRv and AL within cardiac amyloidosis is extremely uncommon. In situations where incongruities arise between the amyloid type determined via immunohistochemistry findings and the amyloid type assumed based on other clinical findings, mass spectrometry should be considered.
PubMed: 38872953
DOI: 10.1093/ehjcr/ytae264 -
Physiological Reports Jun 2024ERK3/MAPK6 activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in...
ERK3/MAPK6 activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency impairs cardiac fibroblast function. This study determined the effect of reduced ERK3 on cardiac hypertrophy following transverse aortic constriction (TAC) and fibroblast biology in male mice. Three weeks post-surgery, ERK3, but not ERK4 or p38α, co-immunoprecipitated with MK5 from both sham and TAC heart lysates. The increase in left ventricular mass and myocyte diameter was lower in TAC-ERK3 than TAC-ERK3 hearts, whereas ERK3 haploinsufficiency did not alter systolic or diastolic function. Furthermore, the TAC-induced increase in Col1a1 mRNA abundance was diminished in ERK3 hearts. ERK3 immunoreactivity was detected in atrial and ventricular fibroblasts but not myocytes. In both quiescent fibroblasts and "activated" myofibroblasts isolated from adult mouse heart, siRNA-mediated knockdown of ERK3 reduced the TGF-β-induced increase in Col1a1 mRNA. In addition, intracellular type 1 collagen immunoreactivity was reduced following ERK3 depletion in quiescent fibroblasts but not myofibroblasts. Finally, knocking down ERK3 impaired motility in both atrial and ventricular myofibroblasts. These results suggest that ERK3 plays an important role in multiple aspects of cardiac fibroblast biology.
Topics: Animals; Male; Mice; Fibroblasts; Collagen Type I; Collagen Type I, alpha 1 Chain; Myocardium; Mitogen-Activated Protein Kinase 6; Mice, Inbred C57BL; Protein Serine-Threonine Kinases; Intracellular Signaling Peptides and Proteins; Mitogen-Activated Protein Kinase 3; Cells, Cultured; Cardiomegaly; Myocytes, Cardiac
PubMed: 38872461
DOI: 10.14814/phy2.16108 -
Frontiers in Pharmacology 2024Pyroptosis is a type of programmed cell death that is mediated by both typical and atypical pathways and ultimately leads to the lysis and rupture of cell membranes and... (Review)
Review
Pyroptosis is a type of programmed cell death that is mediated by both typical and atypical pathways and ultimately leads to the lysis and rupture of cell membranes and the release of proinflammatory factors, triggering an intense inflammatory response. Heart failure (HF) is a serious and terminal stage of various heart diseases. Myocardial hypertrophy, myocardial fibrosis, ventricular remodeling, oxidative stress, the inflammatory response and cardiomyocyte ionic disorders caused by various cardiac diseases are all risk factors for and aggravate HF. Numerous studies have shown that pyroptosis can induce and exacerbate these reactions, causing progression to HF. Therefore, targeting pyroptosis is a promising strategy to treat HF. This paper summarizes the role of pyroptosis in the development of HF and the underlying mechanism involved. Recent research progress on the ability of traditional Chinese medicine (TCM) extracts and formulas to inhibit pyroptosis and treat HF was summarized, and some traditional Chinese medicine extracts and formulas can alleviate different types of HF, including heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with midrange ejection fraction (HFmrEF), by targeting pyroptosis. These findings may provide new ideas and evidence for the treatment or adjuvant treatment of HF by targeting pyroptosis.
PubMed: 38868667
DOI: 10.3389/fphar.2024.1377359 -
Diabetes, Metabolic Syndrome and... 2024The evidence on the association between insulin resistance (IR) and the prevalence or incidence of cardiac dysfunction has been controversial, and the relationship...
The Relationship Between Insulin Resistance Indicated by Triglyceride and Glucose Index and Left Ventricular Hypertrophy and Decreased Left Ventricular Diastolic Function with Preserved Ejection Fraction.
AIM
The evidence on the association between insulin resistance (IR) and the prevalence or incidence of cardiac dysfunction has been controversial, and the relationship between pre-diabetic IR and cardiac function is lacking. Large sample studies in the Chinese general population are urgently needed to explore the association between IR and the risk of left ventricular hypertrophy (LVH) and decreased left ventricular diastolic function with preserved ejection fraction (LVDFpEF).
METHODS
Based on a National Health Check-up database in China, we conducted a multicenter cross-sectional retrospective study in 344,420 individuals. Furthermore, at a single center, we performed two retrospective longitudinal studies encompassing 8270 and 5827 individuals to investigate the association between IR and the development of new-onset LVH and LVDFpEF, respectively. The median follow-up duration exceeded 2.5 years. The triglyceride and glucose (TyG) index, known for its high sensitivity in detecting IR, serves as a reliable alternative marker of IR. The logistic and cox proportional hazard regression models were used to determine the relationships.
RESULTS
In the cross-sectional study, IR showed a positive association with the prevalence of LVH and decreased LVDFpEF after adjusting for confounders. In the longitudinal cohort, IR was also correlated with the new onset of LVH and decreased LVDFpEF, with hazard ratios (HR) of 1.986 (95% CI: 1.307, 3.017) and 1.386 (95% CI: 1.167, 1.647) in the fourth quartile of TyG levels compared to the lowest quartile, respectively, after adjusting for confounders. The subgroup analysis in non-hypertensive or non-diabetic people and the sensitivity analysis in the population with homeostasis model assessment of insulin resistance (HOMA-IR) further verified the above-mentioned results.
CONCLUSION
IR was associated with LVH and decreased LVDFpEF. Effective management of IR may prevent or delay the development of adverse LVH and decreased LVDFpEF.
PubMed: 38868630
DOI: 10.2147/DMSO.S454876