Heart Failure Research Articles

Observational study for multiparametric assessment of cardiac congestion in outpatient worsening heart failure (EVOLUTION).

We sought to characterize the clinical course of patients following worsening heart failure (WHF) treated in an outpatient setting and to identify factors associated with a poor response to standard of care with loop diuretics. Between September 2022 and March 2023, 44 eligible patients (mean age 66.3 years, 84% male) with ejection fraction <50% and with WHF symptoms in the preceding week treated in an outpatient setting were enrolled. Patients were assessed weekly over 4 weeks following the WHF episode. At week 4, responses to fluid expansion and furosemide administration were assessed in 39 patients to unmask persistent subclinical congestion. Patients were on stable doses of guideline-directed medical therapy (GDMT) with a mean daily furosemide dose of 47.4 mg. Patient-reported and physician-assessed symptoms and quality of life improved over the 4 weeks. At 1 h following 1 L Ringer solution infused over 2 h, the median (interquartile range) urine volume and urine sodium excreted over 3 h were 300 (200.0-500.0) ml and 39.6 (12.4-63.0) mEq, respectively. Receiver-operating characteristic curves suggest that cystatin C >1.2 ng/ml, N-terminal pro-B-type natriuretic peptide (NT-proBNP) >1500 pg/ml, and high-sensitivity troponin T >20 pg/ml represent good predictors of non-response to a fluid challenge (diuresis, natriuresis, and rales) following an outpatient WHF, with having all three markers associated with the worst response. Patients with high levels of troponin, or NT-proBNP, or cystatin C who develop WHF despite being treated with a loop diuretic, need novel therapies for WHF.

Long-term weight loss and cardiorenal outcomes by baseline BMI in the VERTIS CV trial.

To assess weight loss and cardiorenal outcomes by baseline body mass index (BMI) in VERTIS CV. Patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease were randomized to ertugliflozin or placebo. These post hoc analyses evaluated cardiometabolic and cardiorenal outcomes (a composite of death from CV causes or hospitalization for heart failure [HHF], CV death, HHF and an exploratory composite kidney outcome including ≥40% estimated glomerular filtration rate [eGFR] decrease) by baseline BMI, using conventional clinical categories and Cox proportional hazards models. In total, 8246 adults were randomized (mean age 64.4 years, diabetes duration 13.0 years, BMI 32.0 kg/m2, 61% with BMI >30 kg/m2). Absolute body weight reduction was greater with ertugliflozin versus placebo at 3 and 5 years in the overall population (p < 0.001) and across BMI subgroups. Ertugliflozin increased the proportion of participants achieving ≥5% and ≥10% body weight reduction (ertugliflozin 34.9% and 13.6%, placebo 19.4% and 4.1%; odds ratio [95% confident interval, CI], 2.21 [1.76-2.77] and 3.65 [2.39-5.57], respectively) at 5 years. No significant difference was observed in the effect of ertugliflozin on HHF across BMI subgroups (Pinteraction = 0.61). Similarly, no significant difference was observed in the effect of ertugliflozin on the kidney composite outcome across BMI subgroups (Pinteraction = 0.39). Results were similar for other CV outcomes, and safety was consistent with the known ertugliflozin profile. Weight loss was observed across baseline BMI and was sustained over 5 years of follow-up. The effects of ertugliflozin on HHF and kidney composite were consistent across baseline BMI.

Striking Cardioprotective Effects of an Adiponectin Receptor Agonist in an Aged Mouse Model of Duchenne Muscular Dystrophy

Adiponectin (ApN) is a hormone with potent effects on various tissues. We previously demonstrated its ability to counteract Duchenne muscular dystrophy (DMD), a severe muscle disorder. However, its therapeutic use is limited. AdipoRon, an orally active ApN mimic, offers a promising alternative. While cardiomyopathy is the primary cause of mortality in DMD, the effects of ApN or AdipoRon on dystrophic hearts have not been investigated. Our recent findings demonstrated the significant protective effects of AdipoRon on dystrophic skeletal muscle. In this study, we investigated whether AdipoRon effects could be extended to dystrophic hearts. As cardiomyopathy develops late in mdx mice (DMD mouse model), 14-month-old mdx mice were orally treated for two months with AdipoRon at a dose of 50 mg/kg/day and then compared with untreated mdx and wild-type (WT) controls. Echocardiography revealed cardiac dysfunction and ventricular hypertrophy in mdx mice, which were fully reversed in AdipoRon-treated mice. AdipoRon also reduced markers of cardiac inflammation, oxidative stress, hypertrophy, and fibrosis while enhancing mitochondrial biogenesis via ApN receptor-1 and CAMKK2/AMPK pathways. Remarkably, treated mice also showed improved skeletal muscle strength and endurance. By offering protection to both cardiac and skeletal muscles, AdipoRon holds potential as a comprehensive therapeutic strategy for better managing DMD.

Characteristics, outcomes and the necessity of continued guideline-directed medical therapy in patients with heart failure with improved ejection fraction

Background Much remains to be learned about patients with heart failure with improved ejection fraction (HFimpEF). Objective This study sheds light on the characteristics and clinical outcomes of HFimpEF patients, including the consequences of halting guideline-directed medical therapy (GDMT). Methods This retrospective study was conducted on patients diagnosed with heart failure with reduced ejection fraction (HFrEF) who underwent a second echocardiogram at least 6 months apart between January 2009 and February 2023. The primary outcomes were major adverse cardiovascular events (MACEs), including all-cause mortality and heart failure hospitalization. The second outcome was recurrent HFrEF. Results Of 4,560 HFrEF patients were included, 3,289 (72.1%) achieved HFimpEF within a median follow-up period of 3.4 years (IQR: 1.8 − 5.9 years). Among these HFimpEF patients, recurrent HFrEF was observed in 941 (28.6%) patients during a median follow-up period of 2.3 years (IQR: 0.8–4.6 years). The proportion of patients who halted GDMT was 70.4%, 53.2%, 59.8% and 63.8% for MRA, beta-blockers, ACEI/ARB/ARNI and SGLT-2 inhibitors. Multivariable Cox analysis revealed ischemic heart disease, chronic kidney disease, coronary heart disease, lower left ventricular ejection fraction, larger left ventricular diastolic dimension and non-use GDMT are associated with recurrent HFrEF. Individuals without GDMT use exhibited lower chances of persistently recovering ejection fraction and high risks of MACEs compared to those who continue use. Conclusions HFimpEF is a common condition across all clinical follow-ups. Prevalent discontinuation of GDMT medications may contribute significantly to recurrent HFrEF, placing patients at a higher risk for poor prognosis.

Irisin Predicts Poor Clinical Outcomes in Patients with Heart Failure with Preserved Ejection Fraction and Low Levels of N-Terminal Pro-B-Type Natriuretic Peptide

Background: Despite existing evidence of the high predictive value of natriuretic peptides (NPs) in patients with heart failure (HF), patients treated with guideline-directed therapy who have low or near-normal NP levels are unlikely to be correctly stratified for risk of clinical outcomes. The aim of this study is to detect plausible predictors for poor one-year clinical outcomes in patients with HFpEF and low NT-proBNP treated with in accordance with conventional guidelines. Methods: A total of 337 patients with HF with preserved ejection fraction (HFpEF) who had low levels of N-terminal natriuretic pro-peptide (NT-proBNP) at discharge due to optimal guideline-based therapy were enrolled in the study. The course of the observation was 3 years. Echocardiography and the assessment of conventional hematological and biochemical parameters, including NT-proBNP, tumor necrosis factor-alpha, high-sensitivity C-reactive protein (hs-CRP), adropin, irisin, visfatin, and fetuin-A, were performed at baseline and at the end of the study. Results: Three-year cumulative clinical endpoints (cardiovascular death, myocardial infarction or unstable angina or acute coronary syndrome, worsening HF, sudden cardiac death, or cardiac-related surgery or all-cause death) were detected in 104 patients, whereas 233 did not meet the endpoint. After adjusting for an age ≥ 64 years and a presence of atrial fibrillation, diabetes mellitus, chronic kidney disease (CKD) stages 1–3 and dilated cardiomyopathy, the multivariable Cox regression analysis showed that an irisin level of ≤7.2 ng/mL was an independent predictor of cumulative clinical endpoint. Moreover, patients with levels of irisin &gt; 7.2 ng/mL had a better Kaplan–Meier survival rate than those with a lower serum irisin level (≤7.2 ng/mL). Conclusions: Multivariable analysis showed that an age ≥ 64 years; the presence of atrial fibrillation, diabetes mellitus, CKD stages 1–3 and dilated cardiomyopathy; an LAVI ≥ 39 mL/m2; and serum levels of hs-CRP ≥ 6.10 mg/L, irisin ≤ 7.2 ng/mL, and visfatin ≤ 1.1 ng/mL were predictors of poor clinical outcomes in HFpEF with low levels of NT-proBNP. A serum level of irisin ≤ 7.2 ng/mL could emerge as valuable biomarker for predicting long-term prognosis among HFpEF patients with low or near-normal levels of NT-proBNP.

Characterization of Cardiac Troponin Fragment Composition Reveals Potential for Differentiating Etiologies of Myocardial Injury.

Increased cardiac troponin (cTn) concentrations occur in acute myocardial injury and chronic diseases. Characterization of cTn composition in the circulation may assist in differentiating etiologies of myocardial injury. Our goal was to study cTn composition and kinetics in patients following type 1 myocardial infraction (T1MI), cardiac procedures, and chronic heart diseases to establish the relationship between cTn composition and clinical diagnosis. Plasma samples were collected from 201 patients with T1MI, 78 undergoing cardiac surgeries, and 218 with chronic cardiomyopathy or chronic heart failure. Major cTn forms in the circulation and their ratios were analyzed using cTn composition immunoassays, targeting (a) the long-cTnT cTnI-cTnT-TnC (ITC) ternary complex, short-cTnT ITC complex cleaved at amino acids residues 189-223 of cTnT, and the binary cTnI-TnC (IC) complex, and designated the "high-sensitivity (hs)-cTnI assay;" (b) the long-cTnT ITC complex, and designated the "long-cTnT ITC complex assay;" (c) the long-cTnT ITC complex and short-cTnT ITC complex, and designated the "hs-total ITC complex assay;" and (d) the central part of cTnT of both the long-cTnT ITC complex and free cTnT, and designated the "hs-cTnT assay." Early-stage T1MI patients showed a high ratio of long-cTnT ITC complex to cTnI (long-cTnT ITC complex/cTnI, R1). Similarly, patients after acute cardiac surgery exhibited increased cTn concentrations with high R1, which decreased rapidly. In chronic disease, cTn composition exhibited stable and low R1 and high ratios of cTnT to cTnI (cTnT/cTnI, R3). Kinetic differences in multiple cTn forms contribute to the differentiation between acute injury and chronic disease, with a high proportion of long-cTnT ITC complex implying occurrence of acute injury.

Evaluation of left atrial function and the relationship between left atrial stiffness index and exercise capacity in hypertension-related heart failure with preserved ejection fraction

ObjectiveThe left atrial stiffness index (LASI) holds significance in the atrioventricular coupling function and heart failure progression. To assess left atrial function and evaluate the relationship between LASI and exercise capacity in hypertension-related heart failure with preserved ejection fraction (HT-HFpEF).MethodsThe study involved 62 healthy subjects and 163 patients with HT (112 patients in simple HT group and 51 patients in HT-HFpEF group). Each patient performed exercise stress test and standard ultrasonic images were evaluated. A comprehensive evaluation of atrioventricular function, along with investigation into the correlation between these functional parameters and exercise capacity. And further to investigate the feasibility of predicting exercise intolerance using three-dimensional derived left atrial strain index (LASI) (E/e'/LASr and E/e'/LASr-c).ResultsCompared to healthy subjects, HT group demonstrated the elevation in left atrial volume accompanied by decrease in strain value (P &amp;lt; 0.05). In HT-HFpEF group, further significant reductions were observed in both longitudinal (LASr) and circumferential strain (LASr-c, LASct-c) (P &amp;lt; 0.05). Univariate regression demonstrated that both E/e'/LASr and E/e'/LASr-c were significantly correlated with metabolic equivalents (METs) (r = −0.462, P &amp;lt; 0.001; r = −0.381, P &amp;lt; 0.001). The E/e'/LASr demonstrates comparable diagnostic efficacy to exercise-E/e' in assessing exercise intolerance in HT-HFpEF patients (AUC: 0.836 vs. 0.867, P = 0.239).ConclusionProgressive LA remodeling contributes to decreased atrioventricular compliance in HT and HT-HFpEF patients.E/e'/LASr serves as an independent indicator of exercise intolerance in patients with HT-HFpEF.

Wnt Signaling Inhibitors as Therapeutic Approach in Ischemic Heart Disease

Wnt (wingless-type MMTV integration site family) signaling is an evolutionary conserved system highly active during embryogenesis, but in adult hearts has low activities under normal conditions. It is essential for a variety of physiological processes including stem cell regeneration, proliferation, migration, cell polarity, and morphogenesis, thereby ensuring homeostasis and regeneration of cardiac tissue. Its dysregulation and excessive activation during pathological conditions leads to morphological and functional changes in the heart resulting in impaired myocardial regeneration under pathological conditions such as myocardial infarction, heart failure, and coronary artery disease. Several groups of Wnt inhibitors have demonstrated the ability to modulate the Wnt pathway and thereby significantly reduce fibrosis and improve cardiac function after myocardial ischemia. Their inhibitory effect can be realized at multiple levels, which include the inhibition of Wnt ligands, the inhibition of Frizzled receptors, the stabilization of the β-catenin destruction complex, and the disruption of nuclear β-catenin interactions. In this review, we overview the function of Wnt signaling in responses of cardiac cells to pathological conditions, especially ischemic heart disease, with an emphasis on the use of inhibitors of this signaling as a therapeutic approach. Finally, we summarize the current knowledge about the potential of the targeting of Wnt signaling in therapeutic applications.

Advanced Speckle-Tracking Echocardiography Could Play a Crucial Role in the Diagnosis of Post-Implanted Cardiomyopathy Associated with a Leadless Pacemaker System

Background: A leadless pacemaker (LP) is a modern alternative to a transvenous pacemaker, allowing certain complications to be avoided; however, some cannot be eliminated. Aim: To highlight the essential role of advanced speckle-tracking echocardiography (STE) in diagnosing pacing-induced cardiomyopathy (PICM) caused by an LP. Clinical case: A 79-year-old male, after LP implantation a year earlier, was admitted due to heart failure (HF). Left ventricular ejection fraction (LVEF) was 40%, global longitudinal strain (GLS) was −10%, and interventricular mechanical delay (IVMD) was 42 ms. All these parameters were significantly better before the operation. Myocardial work indices confirmed dyssynchrony due to the right ventricular (RV) stimulation pattern, and PICM was considered. To verify the impact of RV pacing on the LV, measurements were taken after restoring the native rhythm, showing an improvement in LVEF (45%), GLS (−13%), IVMD (7 ms), and myocardial work indices. After the next HF exacerbation with further deterioration of the LV function, a decision to convert the LP to a standard CRT-P system was made, with immediate relief in clinical symptoms and improved echocardiographic parameters. Conclusions: This case highlights the essential role of STE echocardiography in identifying the detrimental impact of RV pacing, diagnosing PICM, and selecting the appropriate treatment for patients with LPs.

Mechanisms and Therapeutic Potential of Multiple Forms of Cell Death in Myocardial Ischemia–Reperfusion Injury

Programmed cell death, especially programmed necrosis such as necroptosis, ferroptosis, and pyroptosis, has attracted significant attention recently. Traditionally, necrosis was thought to occur accidentally without signaling pathways, but recent discoveries have revealed that molecular pathways regulate certain forms of necrosis, similar to apoptosis. Accumulating evidence indicates that programmed necrosis is involved in the development of various diseases, including myocardial ischemia–reperfusion injury (MIRI). MIRI occurs when blood flow and oxygen return to an ischemic area, causing excessive production of reactive oxygen species. While this reperfusion is critical for treating myocardial infarction, it inevitably causes cellular damage via oxidative stress. Furthermore, this cellular damage triggers multiple forms of cardiomyocyte death, which is the primary cause of inflammation, cardiac tissue remodeling, and ensuing heart failure. Therefore, understanding the molecular mechanisms of various forms of cell death in MIRI is crucial for therapeutic target discovery. Developing therapeutic strategies to inhibit multiple cell death pathways simultaneously could provide effective protection against MIRI. In this paper, we review the fundamental molecular pathways and MIRI-specific mechanisms of apoptosis, necroptosis, ferroptosis, and pyroptosis. Additionally, we suggest that the simultaneous suppression of multiple cell death pathways could be an effective therapy and identify potential therapeutic targets for implementing this strategy.

Advances and challenges of prenatal interventions for fetal tachyarrhythmias

It is estimated that 1%–2% of pregnancies are complicated by fetal arrhythmias, with most arrhythmias considered benign and not requiring further treatment or intervention. However, persistent tachyarrhythmias can lead to fetal heart failure, preterm birth, stillbirth, and increased risks during the perinatal period. Therefore, timely treatment during pregnancy is often necessary. Currently, prenatal treatment for fetal tachyarrhythmias (FTs) is primarily drug based, aiming to restore normal fetal heart rate, prevent or reverse fetal heart failure, and avoid adverse outcomes such as preterm birth and stillbirth. Despite decades of clinical experience, the lack of prospective, multicenter randomized clinical trials on the safety and efficacy of drugs means that there is still no universally accepted prenatal treatment regimen for FTs, and treatment relies on series of observational studies or clinical cases. Moreover, all drug treatments carry potential risks to the mother, fetus, and pregnancy, hence the need for more clinical diagnostic and therapeutic experience to provide more clinical evidence for prenatal treatment of FTs.

Cellular Immunology of Myocarditis: Lights and Shades—A Literature Review

Myocarditis is an inflammatory disease of the myocardium with heterogeneous etiology, clinical presentation, and prognosis; when it is associated with myocardial dysfunction, this identifies the entity of inflammatory cardiomyopathy. In the last few decades, the relevance of the immune system in myocarditis onset and progression has become evident, thus having crucial clinical relevance in terms of treatment and prognostic stratification. In fact, the advances in cardiac immunology have led to a better characterization of the cellular subtypes involved in the pathogenesis of inflammatory cardiomyopathy, whether the etiology is infectious or autoimmune/immune-mediated. The difference in the clinical course between spontaneous recovery to acute, subacute, or chronic progression to end-stage heart failure may be explained not only by classical prognostic markers but also through immune-pathological mechanisms at a cellular level. Nevertheless, much still needs to be clarified in terms of immune characterization and molecular mechanisms especially in biopsy-proven myocarditis. The aims of this review are to (1) describe inflammatory cardiomyopathy etiology, especially immune-mediated/autoimmune forms, (2) analyze recent findings on the role of different immune cells subtypes in myocarditis, (3) illustrate the potential clinical relevance of such findings, and (4) highlight the need of further studies in pivotal areas of myocarditis cellular immunology.

Wearable Cardioverter Defibrillator as a Treatment in Patients with Heart Failure of Various Aetiologies—A Series of Ten Cases Within the BIA-VEST Registry

Background/Objectives: Sudden cardiac death (SCD) remains a major global health concern and represents one of the most common causes of mortality due to cardiovascular diseases. The wearable cardioverter–defibrillator (WCD) is an innovative, non-invasive medical device designed to provide continuous heart monitoring and immediate defibrillation in patients at risk for SCD. The study aimed to assess the efficacy of WCD usage in patients awaiting decision on therapy with implantable cardioverter–defibrillators (ICDs). Methods: We explored the clinical applications, benefits, and limitations of WCD usage within the BIA-VEST registry in Poland over the years 2021–2023. The study included 10 patients with a mean age of 49.1 ± 12.02 years. Results: All patients demonstrated good tolerance and compliance with the LifeVest WCD, wearing it for an average of 93.1 days, about 22.8 h per day (95.7% of the time). No interventions from LifeVests were recorded, and there were no effective, ineffective, or inadequate discharges. After the first follow-up echocardiography, five patients still required ICDs. Due to improved LVEF and overall condition in six out of ten patients undergoing WCD bridge therapy, ICD implantation was finally waived. Conclusions: The WCD acts as a bridge to therapy, such as ICD implantation or cardiac surgery, and may be particularly beneficial for patients with transient or evolving conditions, such as structural heart diseases and life-threatening ventricular arrhythmias.

Heart failure phenotypes in people with type 1 diabetes.

Heart failure phenotypes in people with type 1 diabetes.

Learning about heart failure from the news on a college campus: The effects of health attitude, healthy lifestyle, and health efficacy

ABSTRACT Literature on how people learn from health news is limited. While heart-related diseases top the list of 10 leading causes of death and major health expenditures in the U.S. literature on how people learn about heart-related illness is scarce. As a result, this study aimed to examine how people learn about heart failure from a news article, drawing on Bandura’s social cognitive theory (SCT) as the theoretical framework. Health news learning, the dependent measure, was assessed by a one-group posttest only design on the comprehension and recall of information about heart failure from the news story. Health attitude, healthy lifestyle, and health efficacy were the independent measures. Three hundred and fifty-six students and staff from a college in the northeast of the United States participated in this study. It was found that whether people think their health is important (health attitude), healthy lifestyle choices, and health efficacy were significant predictors of health news learning. A path model was constructed, and health efficacy emerged as an important mediator of the path model. SCT was found to be a valuable conceptual framework in assessing health news learning. Limitations for the study were discussed.

A clinical challenge of cardiomyopathies: Beyond the heart

Introduction: The relation between the cancer and the heart is diverse. It can be affected all parts of the heart directly or indirectly caused by the systemic manifestation of the cancer or by cancer therapy. Paraneoplastic dermatomyositis and tumor lysis syndrome (TLS) are two examples of systemic manifestations of cancer. Being systemic, the cardiovascular system can be affected. Heart failure and arrhythmias are the main cardiac manifestations. Case Report: A 68-year-old man with a recent diagnosis of diffuse large B-cell lymphoma waiting to begin chemotherapy, and paraneoplastic dermatomyositis, presented at the emergency department (ED) with palpitations and dyspnea with a week of evolution. At the physical examination, he presented with pulmonary edema and the novo rapid atrial fibrillation. Also, an Nt-pro BNP of 8957 pg/mL, and echocardiography with severe dilated left ventricle, with a severe reduced ejection fraction. Already in the ward, the patient developed a spontaneous TLS. The etiological interpretation was that paraneoplastic dermatomyositis and TLS were the triggers of atrial fibrillation (AF). Then, the combination of them was responsible for development of the dilated cardiomyopathy (tachymyocardiopathy). The chemotherapy regimen was changed to R-CEOP (Rituximab, cyclophosphamide, etoposide, vincristine sulfate, and prednisone). Conclusion: This clinical case perfectly shows how the world of cardiomyopathies can be challenging and hard to understand all the complexity of the patients.

Left Ventricular Strain in Heart Failure with Preserved Ejection Fraction: A Fast Dive into Diagnosis, Response to Exercise and Afterload Challenge

Left Ventricular Strain in Heart Failure with Preserved Ejection Fraction: A Fast Dive into Diagnosis, Response to Exercise and Afterload Challenge

Sacubitril/Valsartan and Dapagliflozin in Patients with a Failing Systemic Right Ventricle: Effects on the Arrhythmic Burden

Background/Objectives: Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose co-transporter 2 inhibitors (SGLT2i) are essential medications in heart failure (HF) therapy, and their potential antiarrhythmic effects have been reported. Recently, ARNI and SGLT2i use for HF in adult congenital heart disease (ACHD) has been studied. However, whether any beneficial effects may be achieved on the arrhythmic burden in the complex population of ACHD with a systemic right ventricle (sRV) is still to be determined. Methods: We retrospectively collected all significant arrhythmic events from a cohort of patients with a failing sRV attending our tertiary care center on optimal guideline-directed medical therapy (GDMT) with ARNI and/or SGLT2i. Results: A total of 46 patients (mean age 38.2 ± 10.7 years, 58% male) on sacubitril/valsartan were included. Twenty-three (50%) patients were also started on dapagliflozin. After a median follow-up of 36 [Q1–Q3: 34–38] months, arrhythmic events occurred globally in 13 (28%) patients. Survival analysis showed significant reduction of clinically relevant atrial and ventricular arrhythmia at follow-up (p = 0.027). Conclusions: Our findings suggest that GDMT including sacubitril/valsartan and dapagliflozin may also offer an antiarrhythmic effect in ACHD patients with a failing sRV, by reducing the incidence of arrhythmic events at follow-up.

Trained innate immunity as a potential link between preeclampsia and future cardiovascular disease

Preeclampsia (PE) is a complex pregnancy syndrome characterized by hypertension with or without proteinuria, affecting 2–6% of pregnancies globally. PE is characterized by excessive release of damage-associated molecular patterns (DAMPs) into the maternal circulation. This DAMP-rich milieu acts on innate immune cells, inducing a proinflammatory state characterized by elevated cytokines such as IL-1β and IL-18. This proinflammatory state in the mother and placenta results in the endothelial dysfunction strongly associated with cardiovascular disorders. While the immediate maternal and fetal risks of PE are well-documented, accumulating evidence indicates that PE also confers long-term cardiovascular risks to the mother, including hypertension, coronary heart disease, stroke, and heart failure. The underlying mechanisms connecting PE to these chronic cardiovascular conditions remain unclear. This article explores the potential role of trained innate immunity (TRIM) as a mechanistic link between PE and increased long-term cardiovascular risk. We propose that the persistent exposure to DAMPs during PE may epigenetically reprogram maternal innate immune cells and their progenitors, leading to TRIM. This reprogramming enhances the inflammatory response to subsequent stimuli, potentially contributing to endothelial dysfunction and chronic inflammation that predispose women to cardiovascular diseases later in life. Understanding the role of TRIM in PE could provide novel insights into the pathophysiology of PE-related cardiovascular complications and identify potential targets for therapeutic intervention. Further research is warranted to investigate the epigenetic and metabolic alterations in innate immune cells induced by PE and to determine how these changes may influence long-term maternal cardiovascular health.

Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing

AbstractTrifunctional protein deficiency (TFP) is a disorder of fatty acid beta‐oxidation associated with metabolic, cardiac, and liver dysfunction in severe forms. We present two siblings diagnosed by newborn screening and confirmed by biochemical testing at birth. Their clinical course was complicated by recurrent rhabdomyolysis, retinopathy, and hypoparathyroidism. Both siblings were also diagnosed with focal segmental glomerulosclerosis (FSGS) and bone marrow failure and ultimately died of hypoxemic respiratory failure. Initial sequencing of the TFP‐associated genes HADHA and HADHB showed only a paternally inherited variant in HADHB, NM_000183.3:c.1059del (p.Gly354AspfsTer10). Subsequent evaluation by the Undiagnosed Diseases Network with genome and transcriptome sequencing revealed a rare maternally inherited 17 base pair deletion in HADHB, NM_000183.3:c.1390‐515_1390‐499del, located in the final intron and resulting in a pseudoexon that harbors a premature termination codon. Both sisters were compound heterozygous for this and the paternal premature termination codon. No other variants were detected that were potentially causative for the FSGS and bone marrow failure on genome sequencing. A review of the literature at that time revealed several case reports of the uncommon clinical findings of FSGS, bone marrow failure, and pulmonary involvement in patients with TFP, confirming this clinical diagnosis as the complete explanation for these siblings.