Target population for a selective cardiac myosin inhibitor in hypertrophic obstructive cardiomyopathy: Real-life estimation from the French register of hypertrophic cardiomyopathy (REMY).

BACKGROUND: The efficacy of current pharmacological therapies in hypertrophic cardiomyopathy is limited. A cardiac myosin inhibitor, mavacamten, has recently been approved as a first-in-class treatment for symptomatic hypertrophic obstructive cardiomyopathy. AIMS: To assess the profile and burden of cardiac myosin inhibitor candidates in the hypertrophic cardiomyopathy prospective Register of hypertrophic cardiomyopathy (REMY) held by the French Society of Cardiology. METHODS: Data were collected at baseline and during follow-up from patients with hypertrophic cardiomyopathy enrolled in REMY by the three largest participating centres. RESULTS: Among 1059 adults with hypertrophic cardiomyopathy, 461 (43.5%) had obstruction; 325 (30.7%) of these were also symptomatic, forming the "cardiac myosin inhibitor candidates" group. Baseline features of this group were: age 58±15years; male sex (n=196; 60.3%); diagnosis-to-inclusion delay 5 (1-12)years; maximum wall thickness 20±6mm; left ventricular ejection fraction 69±6%; family history of hypertrophic cardiomyopathy or sudden cardiac death (n=133; 40.9%); presence of a pathogenic sarcomere gene mutation (n=101; 31.1%); beta-blocker or verapamil treatment (n=304; 93.8%), combined with disopyramide (n=28; 8.7%); and eligibility for septal reduction therapy (n=96; 29%). At the end of a median follow-up of 66 (34-106) months, 319 (98.2%) were treated for obstruction (n=43 [13.2%] received disopyramide), 46 (14.2%) underwent septal reduction therapy and the all-cause mortality rate was 1.9/100 person-years (95% confidence interval 1.4-2.6) (46 deaths). Moreover, 41 (8.9%) patients from the initial hypertrophic obstructive cardiomyopathy group became eligible for a cardiac myosin inhibitor. CONCLUSIONS: In this cohort of patients with hypertrophic cardiomyopathy selected from the REMY registry, one third were eligible for a cardiac myosin inhibitor.

First-in-man use of a cardiovascular cell-derived secretome in heart failure. Case report.

BACKGROUND: There is increased evidence that the effects of stem cells can mostly be duplicated by administration of their secretome which might streamline the translation towards the clinics. METHODS: The 12-patient SECRET-HF phase 1 trial has thus been designed to determine the feasibility and safety of repeated intravenous injections of the extracellular vesicle (EV)-enriched secretome of cardiovascular progenitor cells differentiated from pluripotent stem cells in severely symptomatic patients with drug-refractory left ventricular (LV) dysfunction secondary to non-ischemic dilated cardiomyopathy. Here we report the case of the first treated patient (baseline NYHA class III; LV Ejection Fraction:25%) in whom a dose of 20 × 109 particles/kg was intravenously infused three times three weeks apart. FINDINGS: In addition to demonstrating the feasibility of producing a cardiac cell secretome compliant with Good Manufacturing Practice standards, this case documents the excellent tolerance of its repeated delivery, without any adverse events during or after infusions. Six months after the procedure, the patient is in NYHA Class II with improved echo parameters, a reduced daily need for diuretics (from 240 mg to 160 mg), no firing from the previously implanted automatic internal defibrillator and no alloimmunization against the drug product, thereby supporting its lack of immunogenicity. INTERPRETATION: The rationale underlying the intravenous route is that the infused EV-enriched secretome may act by rewiring endogenous immune cells, both circulating and in peripheral organs, to take on a reparative phenotype. These EV-modified immune cells could then traffic to the heart to effect tissue repair, including mitigation of inflammation which is a hallmark of cardiac failure. FUNDING: This trial is funded by the French Ministry of Health (Programme Hospitalier de Recherche CliniqueAOM19330) and the "France 2030" National Strategy Program (ANR-20-F2II-0003). It is sponsored by Assistance Publique-Hôpitaux de Paris.

Association of Impaired Left Ventricular Mitral Filling from 4D Flow Cardiac MRI and Prognosis of Hypertrophic Cardiomyopathy.

Purpose To investigate whether the peak early filling rate normalized to the filling volume (PEFR/FV) estimated from four-dimensional (4D) flow cardiac MRI may be used to assess impaired left ventricular (LV) filling and predict clinical outcomes in individuals with hypertrophic cardiomyopathy (HCM). Materials and Methods Cardiac MRI with a 4D flow sequence and late gadolinium enhancement (LGE), as well as echocardiography, was performed in 88 individuals: 44 participants with HCM from a French prospective registry (ClinicalTrials.gov; NCT01091480) and 44 healthy volunteers matched for age and sex. In participants with HCM, a composite primary end point was assessed at follow-up, including unexplained syncope, new-onset atrial fibrillation, hospitalization for congestive heart failure, ischemic stroke, sustained ventricular arrhythmia, septal reduction therapy, and cardiac death. A Cox proportional hazard model was used to analyze associations with the primary end point. Results PEFR/FV was significantly lower in the HCM group (mean age, 51.8 years ± 18.5 [SD]; 29 male participants) compared with healthy volunteers (mean, 3.35 sec-1 ± 0.99 [0.90-5.20] vs 4.42 sec-1 ± 1.68 [2.74-11.86]; P < .001) and correlated with both B-type natriuretic peptide (BNP) level (r = -0.31; P < .001) and the ratio of pulsed Doppler early transmitral inflow to Doppler tissue imaging annulus velocities (E/E'; r = -0.54; P < .001). At a median follow-up of 2.3 years (IQR, 1.7-3.3 years), the primary end point occurred in 14 (32%) participants. A PEFR/FV of 2.61 sec-1 or less was significantly associated with occurrence of the primary end point (hazard ratio, 9.46 [95% CI: 2.61, 45.17; P < .001] to 15.21 [95% CI: 3.51, 80.22; P < .001]), independently of age, BNP level, E/E', LGE extent, and LV and left atrial strain according to successive bivariate models. Conclusion In HCM, LV filling evaluated with 4D flow cardiac MRI correlated with Doppler and biologic indexes of diastolic dysfunction and predicted clinical outcomes. Keywords: Diastolic Function, Left Ventricular Filling, Hypertrophic Cardiomyopathy, Cardiac MRI, 4D Flow Sequence Clinical trial registration no. NCT01091480 Supplemental material is available for this article. © RSNA, 2024.

Does Atrial Septal Anatomy Still Matter in the Etiological Evaluation of Ischemic Stroke Beyond the Age of 60?

BACKGROUND: Patent foramen ovale (PFO) is causally associated with stroke in some patients younger than 60 years, especially when it is large or associated with an atrial septal aneurysm (ASA). After 60 years of age, this association is less well understood. We assessed the relationships between detailed atrial septal anatomy and the cryptogenic nature of stroke in this population. METHODS AND RESULTS: We reviewed all patients aged 60 to 80 years admitted to our stroke center for ischemic stroke who underwent contrast echocardiography between 2016 and 2021. The atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection (ASCOD) classification was used to reevaluate the etiological workup. Associations between cryptogenic stroke and (1) PFO presence or (2) categories of PFO anatomy (nonlarge PFO without ASA, nonlarge PFO with ASA, large PFO without ASA, and large PFO with ASA) were assessed using logistic regression. Among 533 patients (median National Institutes of Health Stroke Scale score=1), PFO was present in 152 (prevalence, 28.5% [95% CI, 24.9-32.5]). Compared with noncryptogenic stroke, cryptogenic stroke (n=218) was associated with PFO presence (44.5% versus 17.5%; P<0.0001). Among patients with a PFO, septal anatomy categories were associated with cryptogenic stroke (P=0.02), with a strong association for patients with both large PFO and ASA (38.1% versus 14.5%, P=0.002). CONCLUSIONS: PFO presence remains strongly associated with cryptogenic stroke between 60 and 80 years of age. Large PFO, ASA, and their association were strongly associated with cryptogenic stroke in this age group. Our results support performing contrast echocardiography even after 60 years of age, although the optimal secondary prevention therapy in this population remains to be determined in randomized trials.

Transbronchial cryobiopsy proven amyloid diffuse cystic lung disease complicating a transthyretin mutated (ATTRm) amyloidosis: a case report.

We present a case report of transbronchial cryobiopsy proven diffuse amyloid cystic lung disease complicating a homozygous Val122Ile (V122I) transthyretin mutated amyloidosis (ATTRm). To the best of our knowledge, this is the first case in the literature reporting such pulmonary lesions in ATTRm amyloidosis, and notably diagnosed through cryobiopsy. A 51-year-old man from Mali with a past medical history of bilateral carpal tunnel syndrome presented erectile dysfunction, asthenia and worsening dyspnoea over the past year. He presented signs of cardiac failure; histological and radiological investigations diagnosed cardiac amyloidosis. He was found homozygote for the V122I mutation in transthyretin. A diffuse cystic lung disease (DCLD) was noted on computed tomography (CT) scan. We performed a transbronchial pulmonary cryobiopsy that revealed histological transthyretin amyloid deposits. This case report illustrates the safety and usefulness of cryobiopsy in the setting of DCLD and extends ATTRm amyloidosis as a possible cause of DCLD.

Transcatheter Tricuspid Repair for Tricuspid Regurgitation After Heart Transplantation.

A 67-year-old patient with history of heart transplantation was referred for symptomatic severe tricuspid regurgitation. Diagnostic workup showed chordal ruptures on the septal and anterior leaflets, most likely related to endomyocardial biopsies. Given the high surgical risk, the patient was treated percutaneously, with good results persisting at 3 months. (Level of Difficulty: Intermediate.).

Initiation and development of a percutaneous left atrial appendage closure programme: A French centre's experience and literature review.

BACKGROUND: Percutaneous left atrial appendage closure may be considered in selected patients with atrial fibrillation at significant risk of both thromboembolism and haemorrhage. AIMS: To report the experience of a tertiary French centre in percutaneous left atrial appendage closure and to discuss the outcomes compared with previously published series. METHODS: This was a retrospective observational cohort study of all patients referred for percutaneous left atrial appendage closure between 2014 and 2020. Patient characteristics, procedural management and outcomes were reported, and the incidence of thromboembolic and bleeding events during follow-up were compared with historical incidence rates. RESULTS: Overall, 207 patients had left atrial appendage closure (mean age 75.3±8.6 years; 68% men; CHA2DS2-VASc score 4.8±1.5 ; HAS-BLED score 3.3±1.1), with a 97.6% (n=202) success rate. Twenty (9.7%) patients had at least one significant periprocedural complication, including six (2.9%) tamponades and three (1.4%) thromboembolisms. Periprocedural complication rates decreased from earlier to more recent periods (from 13% before 2018 to 5.9% after; P=0.07). During a mean follow-up of 23.1±20.2 months, 11 thromboembolic events were observed (2.8% per patient-year), a 72% risk reduction compared with the estimated theoretical annual risk. Conversely, 21 (10%) patients experienced bleeding during follow-up, with almost half of the events occurring during the first 3 months. After the first 3 months, the risk of major bleeding was 4.0% per patient-year, a 31% risk reduction compared with the expected estimated risk. CONCLUSION: This real-world evaluation emphasizes the feasibility and benefit of left atrial appendage closure, but also illustrates the need for multidisciplinary expertise to initiate and develop this activity.

Staging Heart Failure Patients With Secondary Mitral Regurgitation Undergoing Transcatheter Edge-to-Edge Repair.

BACKGROUND: Secondary mitral regurgitation (SMR) is a progressive disease with characteristic pathophysiological changes that may influence prognosis. Although the staging of SMR patients suffering from heart failure with reduced ejection fraction (HFrEF) according to extramitral cardiac involvement has prognostic value in medically treated patients, such data are so far lacking for edge-to-edge mitral valve repair (M-TEER). OBJECTIVES: This study sought to classify M-TEER patients into disease stages based on the phenotype of extramitral cardiac involvement and to assess its impact on symptomatic and survival outcomes. METHODS: Based on echocardiographic and clinical assessment, patients were assigned to 1 of the following HFrEF-SMR groups: left ventricular involvement (Stage 1), left atrial involvement (Stage 2), right ventricular volume/pressure overload (Stage 3), or biventricular failure (Stage 4). A Cox regression model was implemented to investigate the impact of HFrEF-SMR stages on 2-year all-cause mortality. The symptomatic outcome was assessed with New York Heart Association functional class at follow-up. RESULTS: Among a total of 849 eligible patients who underwent M-TEER for relevant SMR from 2008 until 2019, 9.5% (n = 81) presented with left ventricular involvement, 46% (n = 393) with left atrial involvement, 15% (n = 129) with right ventricular pressure/volume overload, and 29% (n = 246) with biventricular failure. An increase in HFrEF-SMR stage was associated with increased 2-year all-cause mortality after M-TEER (HR: 1.39; CI: 1.23-1.58; P < 0.01). Furthermore, higher HFrEF-SMR stages were associated with significantly less symptomatic improvement at follow-up. CONCLUSIONS: The classification of M-TEER patients into HFrEF-SMR stages according to extramitral cardiac involvement provides prognostic value in terms of postinterventional survival and symptomatic improvement.

Left atrial volume index and outcome after transcatheter edge-to-edge valve repair for secondary mitral regurgitation.

AIMS: To investigate the role of left atrial volume index (LAVi) in patients with secondary mitral regurgitation (SMR) undergoing transcatheter edge-to-edge mitral valve repair (TEER). METHODS AND RESULTS: Outcomes were evaluated in SMR patients of a European multicentre registry according to baseline LAVi. Main analysis was performed for all-cause mortality; residual mitral regurgitation (MR) and New York Heart Association (NYHA) class improvement were analysed for patients available. A total of 1074 patients were included with a median LAVi (interquartile range) of 58 ml/m2 (46-73). Postprocedural reduction of MR grade to ≤2+ was similar across LAVi quintiles, ranging 91%-96% (p = 0.26). Symptomatic benefit (≥1 NYHA class improvement) also did not differ by LAVi quintiles (61%-68% of patients) (p = 0.66). The risk of mortality increased by 23%-42% in the four upper quintiles compared to the bottom quintile (LAVi <42 ml/m2 ). The hazard ratio (HR) of mortality was 1.35 (95% confidence interval [CI] 1.02-1.78, p = 0.035) associated with a LAVi >42 ml/m2 , which was attenuated after multivariable adjustment (HR 1.18, 95% CI 0.83-1.67, p = 0.36). A significant interaction was found for MR severity and pulmonary hypertension, with an increased risk of death associated with enlarged LAVi in patients with inframedian effective regurgitant orifice area (HR 1.99, 95% CI 1.06-3.74, p = 0.032) and in patients with systolic pulmonary pressure ≤50 mmHg (HR 1.67, 95% CI 1.02-2.75, p = 0.042) in multivariable analysis. CONCLUSION: Procedural success and symptomatic benefit were high throughout the whole range of LAVi. The prognostic impact of left atrial enlargement was relevant in patients with less severe SMR and without pulmonary hypertension, reinforcing the need to identify patients in the early course of backward congestion to achieve good long-term outcome after TEER.

Epidemiology, Pathophysiology, and Management of Native Atrioventricular Valve Regurgitation in Heart Failure Patients.

Atrioventricular regurgitation is frequent in the setting of heart failure. It is due to atrial and ventricular remodelling, as well as rhythmic disturbances and loss of synchrony. Once atrioventricular regurgitation develops, it can aggravate the underlying heart failure, and further participate and aggravate its own severity. Its presence is therefore concomitantly a surrogate of advance disease and a predictor of mortality. Heart failure management, including medical therapy, cardiac resynchronization therapy, and restoration of sinus rhythm, are the initial steps to reduce atrioventricular regurgitation. In the current review, we analyse the current data assessing the epidemiology, pathophysiology, and impact of non-valvular intervention on atrioventricular regurgitation including medical treatment, cardiac resynchronization and atrial fibrillation ablation.

Management and outcomes of hypertrophic cardiomyopathy in young adults.

BACKGROUND: Management of young adults with hypertrophic cardiomyopathy (HCM) is challenging. AIMS: To evaluate the profile of young adults (16-25 years) with HCM included in the French prospective HCM registry. METHODS: Patients were compared according to occurrence of major adverse cardiac events (MACE), comprising sudden cardiac death (SCD) events (implantable cardioverter defibrillator [ICD] discharge, SCD, sustained ventricular tachycardia), atrial fibrillation/embolic stroke, heart failure hospitalisation and unexplained syncope, at a mean follow-up of 4.4±2.2 years. RESULTS: At baseline, among 61 patients (20.5±3.0 years; 16 women, 26.2%), 13 (21.3%) had a prophylactic ICD, 24.6% a family history of SCD, 29.5% obstruction, 86.0% magnetic resonance imaging myocardial fibrosis, 11.8% abnormal exercise blood pressure and 52.8% a European Society of Cardiology (ESC) 5-year SCD score<4% (24.5%≥6%). At follow-up, 15 patients (24.6%; seven women; all with fibrosis) presented 17 MACE, comprising: SCD events (n=7, 41.2%; including three patients with an ICD, five with at least one SCD major classical risk factor and an ESC score≥5% and two with no risk factors and an ESC score<4%); atrial fibrillation/stroke (n=6, 35.3%); heart failure (n=1, 5.9%); syncope (n=3, 17.6%). An ICD was implanted in 11 patients (four for secondary prevention), but in only 61.5% of patients with a score≥6%. Only obstruction significantly increased MACE risk (odds ratio 3.96; P=0.035), with a non-significant trend towards a lower risk in men (OR 0.29; P=0.065). CONCLUSIONS: In young adults with HCM, MACE are common in the short term, especially in obstructive HCM and women, mostly arrhythmic in origin. Prophylactic ICD implantation is frequent and does not strictly follow the guidelines, while the use of European/USA guidelines is helpful but imperfect in identifying SCD risk.

Predictive Factor for COVID-19 Worsening: Insights for High-Sensitivity Troponin and D-Dimer and Correlation With Right Ventricular Afterload.

Background: Coronavirus disease 2019 (COVID-19) has been associated with cardiovascular complications and coagulation disorders. Objectives: To explore clinical and biological parameters of COVID-19 patients with hospitalization criteria that could predict referral to intensive care unit (ICU). Methods: Analyzing the clinical and biological profiles of COVID-19 patients at admission. Results: Among 99 consecutive patients that fulfilled criteria for hospitalization, 48 were hospitalized in the medicine department, 21 were first admitted to the medicine ward department and referred later to ICU, and 30 were directly admitted to ICU from the emergency department. At admission, patients requiring ICU were more likely to have lymphopenia, decreased SpO2, a D-dimer level above 1,000 ng/mL, and a higher high-sensitivity cardiac troponin (Hs-cTnI) level. A receiver operating characteristic curve analysis identified Hs-cTnI above 9.75 pg/mL as the best predictive criteria for ICU referral [area under the curve (AUC), 86.4; 95% CI, 76.6-96.2]. This cutoff for Hs-cTnI was confirmed in univariate [odds ratio (OR), 22.8; 95% CI, 6.0-116.2] and multivariate analysis after adjustment for D-dimer level (adjusted OR, 20.85; 95% CI, 4.76-128.4). Transthoracic echocardiography parameters subsequently measured in 72 patients showed an increased right ventricular (RV) afterload correlated with Hs-cTnI (r = 0.42, p = 0.010) and D-dimer (r = 0.18, p = 0.047). Conclusion: Hs-cTnI appears to be the best relevant predictive factor for referring COVID-19 patients to ICU. This result associated with the correlation of D-dimer with RV dilatation probably reflects a myocardial injury due to an increased RV wall tension. This reinforces the hypothesis of a COVID-19-associated microvascular thrombosis inducing a higher RV afterload.

Prognostic value of the 12-lead surface electrocardiogram in sarcomeric hypertrophic cardiomyopathy: data from the REMY French register.

AIMS: To identify independent electrocardiogram (ECG) predictors of long-term clinical outcome based on standardized analysis of the surface ECG in a large multicentre cohort of patients with sarcomeric hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Retrospective observational study from the REMY French HCM clinical research observatory. Primary endpoint was a composite of all-cause mortality, major non-fatal arrhythmic events, hospitalization for heart failure (HF), and stroke. Secondary endpoints were components of the primary endpoint. Uni- and multivariable Cox proportional hazard regression analysis was performed to identify independent predictors. Among 994 patients with HCM, only 1.8% had a strictly normal baseline ECG. The most prevalent abnormalities were inverted T waves (63.7%), P-wave abnormalities (30.4%), and abnormal Q waves (25.5%). During a mean follow-up of 4.0 ± 2.0 years, a total of 272 major cardiovascular events occurred in 217 patients (21.8%): death or heart transplant in 98 (9.8%), major arrhythmic events in 40 (4.0%), HF hospitalization in 115 (11.6%), and stroke in 23 (2.3%). At multivariable analysis using ECG covariates, prolonged QTc interval, low QRS voltage, and PVCs of right bundle branch block pattern predicted worse outcome, but none remained independently associated with the primary endpoint after adjustment on main demographic and clinical variables. For secondary endpoints, abnormal Q waves independently predicted all-cause death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.23-4.47; P = 0.009] and prolonged QTc the risk of HF hospitalization (HR 1.006, 95% CI 1.001-1.011; P = 0.024). CONCLUSION: The 12-lead surface ECG has no independent value to predict the primary outcome measure in patients with HCM. The 12-lead surface ECG has been widely used as a screening tool in HCM but its prognostic value remains poorly known. The value of baseline surface ECG to predict long-term clinical outcomes was studied in a cohort of 994 patients with sarcomeric HCM. The surface ECG has no significant additional value to predict outcome in this patient population.