Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy.

BACKGROUND: Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS-mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. METHODS: Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 (LZTR1). We generated induced pluripotent stem cell-derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level. RESULTS: Patients' induced pluripotent stem cell-derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS-mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype. CONCLUSIONS: Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell-derived cardiomyocytes from NS patients carrying biallelic variants in LZTR1 and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.

Long-term risk factor management and adverse events in patients with early-onset myocardial infarction-a "real-world" study.

BACKGROUND: International guidelines emphasize the importance of preventive efforts after early-onset myocardial infarction (EOMI); however, data on "real-world" long-term risk factor management and adverse event rates in this special patient group is scarce. METHODS: In this German registry study, 301 patients with MI aged ≤ 45 years were investigated. Risk factor control was assessed at the time of index MI and after 1 year. Major adverse cardiac and cerebrovascular events (MACCE) and its predictors were analyzed during long-term follow-up (median duration 49 months). RESULTS: A majority of patients with EOMI presented with insufficient risk factor control, even during 1-year follow-up. After 1-year 42% of patients were persistent smokers; 74% were physically inactive. The rate of obesity increased significantly from index MI (41%) to 1-year follow-up (46%, p = 0.03) as well as the rate of dysglycemia (index MI: 40%; 1-year follow-up: 51%, p < 0.01) and diabetes mellitus (index MI: 20%; 1-year follow-up: 24%, p < 0.01). 66% of the patients with diabetes mellitus had unsatisfactory HbA1c after 1 year; 69% of the patients did not attain guideline-recommended lipid targets. The rate of MACCE during long-term follow-up was 20% (incidence rate 0.05 per person-year). In a multivariable analysis smoking (HR 2.2, HR 1.3-3.7, p < 0.01) and physical inactivity (HR 2.8, HR 1.2-6.7, p = 0.02) were significant predictors for the occurrence of MACCE. CONCLUSION: Insufficient long-term risk factor control was common in patients with EOMI and was associated with an elevated rate of MACCE. The study reveals that better strategies for prevention in young patients are crucially needed.

Impact of educational attainment on preventive efforts after myocardial infarction: results of the IPP and NET-IPP trials.

AIMS: Educational attainment might impact secondary prevention after myocardial infarction (MI). The purpose of the present study was to compare the rate of risk factors and the efficacy of an intensive prevention program (IPP), performed by prevention assistants and supervised by physicians, in patients with MI and different levels of education. METHODS: In this post hoc analysis of the multicenter IPP and NET-IPP trials, patients with MI were stratified into two groups according to educational attainment: no "Abitur" (no A) vs. "Abitur" or university degree (AUD). The groups were compared at the time of index MI and after 12-month IPP vs. usual care. RESULTS: Out of n = 462 patients with MI, 76.0% had no A and 24.0% had AUD. At the time of index, MI rates of obesity (OR 2.4; 95%CI 1.4-4.0), smoking (OR 2.2, 95%CI 1.4-3.6), and physical inactivity (OR 1.6; 95%CI 1.0-2.5) were significantly elevated in patients with no A. At 12 months after index MI, larger improvements of the risk factors smoking and physical inactivity were observed in patients with IPP and no A than in patients with IPP and AUD or with usual care. LDL cholesterol levels were reduced by IPP compared to usual care, with no difference between no A vs. AUD. A matched-pair analysis revealed that high baseline risk was an important reason for the large risk factor reductions in patients with IPP and no A. CONCLUSION: The study demonstrates that patients with MI and lower educational level have an increased rate of lifestyle-related risk factors and a 12-month IPP, which is primarily performed by non-physician prevention assistants, is effective to improve prevention in this high-risk cohort.

Right Ventricular Cardiac Power Index Predicts 1 Year Outcome After Transcatheter Edge-to-Edge-Repair for Severe Tricuspid Valve Regurgitation.

Tricuspid transcatheter edge-to-edge repair (T-TEER) for severe tricuspid regurgitation (TR) emerged as a novel treatment option for patients not amenable to surgery. However, knowledge regarding independent risk factors for a worse prognosis is rarely available. The study sought to investigate the impact of right ventricular cardiac power index (RVCPi) on 1-year outcomes in patients with severe symptomatic TR who underwent T-TEER. Consecutive patients with severe TR who underwent T-TEER from August 2020 to March 2022 were included and followed prospectively. Baseline clinical and invasive hemodynamic variables, changes in echocardiographic parameters and New York Heart Association functional class, and periprocedural and in-hospital major adverse events were assessed. Primary end point was defined as a composite of all-cause mortality and heart failure hospitalization at 1 year after T-TEER. A multivariable Cox proportional-hazards regression analysis was performed to identify independent risk factors for combined primary end point. RVCPi was calculated as: (cardiac index × mean pulmonary pressure) × K (conversion factor 2.22 × 10-3) = W/m². Receiver operator characteristic analysis was used to determine discriminative capacity of RVCPi. The prognostic value of RVCPi threshold was tested using Kaplan-Meier analysis. In total, 102 patients (mean age 81 ± 6 years, 51% women) at high operative risk underwent T-TEER for severe TR. Primary end point occurred in 30 patients (32%). Receiver operator characteristic curve analysis demonstrated that RVCPi was associated with an area under the curve of 0.69 (95% confidence interval 0.56 to 0.82; p = 0.003). With a RVCPi threshold of 0.17 W/m² (maximally selected rank statistics), the event-free survival was significantly higher in the RVCPi <0.17 W/m² group compared with those with RVCPi ≥0.17 W/m² (71% vs 35%, log-rank p <0.001). In the multivariable Cox regression analysis, RVCPi was an independent predictor for the combined primary end point (hazard ratio 2.6, 95% confidence interval 1.4 to 5.1, p = 0.003). In conclusion, RVCPi is associated with outcome in patients who underwent T-TEER for severe TR and this hemodynamic predictor is useful in risk stratification of T-TEER candidates.