Objective: Prosthesis–patient mismatch (PPM) occurs after aortic valve replacement (AVR) when the effective orifice area of the implanted prosthetic valve is small relative to the patient’s body surface area. Beyond simply elevating transvalvular gradient, PPM profoundly affects cardiac remodeling, coronary physiology, and ultimately patient survival. This comprehensive review synthesizes current evidence regarding PPM pathophysiology, clinical consequences, and therapeutic strategies. Methods: We conducted a narrative review of PPM in surgical (SAVR) and transcatheter (TAVR) aortic valve replacement. PubMed and Embase were systematically searched using terms related to AVR and PPM and reference lists of key studies and reviews were screened. Studies addressing PPM prevalence, hemodynamic impact, clinical outcomes, and mitigation strategies were included. Results: PPM, defined as an iEOA ≤ 0.85 cm²/m² (moderate) or ≤0.65 cm²/m² (severe), demonstrates variable prevalence across studies, typically ranging from 5 to 30% after SAVR and 2–35% after TAVR. It is associated with increased transvalvular gradients, reduced left ventricular mass regression, persistent coronary flow abnormalities, higher rates of heart failure, and both early and late mortality. Supra-annular self-expanding transcatheter aortic valve replacement (TAVR) devices and newer generation stentless or bovine pericardial surgical valves exhibit lower PPM rates than older stented or porcine valves. Valve-in-valve (ViV) TAVR and bioprosthetic valve fracture (BVF) can improve outcomes in failed surgical valves but are less effective in small annuli. TAVR-in-TAVR procedures are limited by anatomic and technical constraints, especially in maintaining coronary access and minimizing residual gradients. Conclusions: PPM remains a common and clinically consequential complication of AVR that compromises long-term outcomes. It is largely preventable through accurate preoperative imaging, valve sizing, and consideration of annular enlargement. Optimal outcomes require matching valve characteristics to individual patient anatomy and physiology. In an era of expanding TAVR use, preventing PPM during the index procedure is critical to optimizing survival and preserving future reintervention options.

Background and Aims: We examined familial patterns and phenotypes of thoracic aortic aneurysms and dissections (TAAD) in the 3746 patients currently populating our Yale Aortic Institute Database. Methods: Patient charts and electronic medical records were retrospectively reviewed for the entire cohort. TAAD disease was categorized as syndromic (with extra-aortic manifestations) or non-syndromic (without) for each patient. Family patterns and whole exome sequencing results were assessed. Family history was considered ‘proven’ when a patient’s relative(s) had an arterial aneurysm or dissection confirmed by an imaging study, surgical treatment, or postmortem examination. Family history was termed ‘likely’ when at least one relative suffered sudden death at ages ≤50 for males and ≤60 for females, and ‘possible’ with a history of sudden death at any age. Results: Of the 3746 patients in the database, family history of aneurysm or dissection and connective tissue status was able to be determined for 3113 patients, divided into 109 (3.5%) syndromic and 3004 (96.5%) non-syndromic TAAD patients. Findings were as follows: (1) In the syndromic group, 46 (42.2%) patients had a ‘proven’ family history, 6 (5.5%) had a ‘likely’ family history, 4 (3.7%) had a ‘possible’ family history, and 18 (16.5%) had ‘none’. For 35 patients (32.1%) their family history was unknown. (2) In the non-syndromic group, 587 (19.5%) patients had ‘proven’ family history, 147 (4.9%) had ‘likely’ family history, 210 (7.0%) had ‘possible’ family history and 1444 (48.1%) had no family history, thus representing sporadic TAAD. A total of 616 (20.5%) had an unknown family history. (3) There was a significant difference between the rate for ‘proven’ and ‘none’ family history between the syndromic and non-syndromic groups (42.2% vs. 19.5% and 16.5% vs. 48.1%, respectively; p < 0.001). (4) Syndromic patients presented at a significantly younger age than non-syndromic or sporadic patients (41.2 vs. 63.3 or 63.6; p < 0.001). (5) There was no significant difference in age of presentation between familial non-syndromic (patients with ‘proven’, ‘likely’, and ‘possible’ family history) and sporadic patients (63.3 vs. 63.6; p = 0.64). (6) Overall, of the 3746 patients in the database, 631 patients (25 syndromic, 552 non-syndromic, and 54 with unknown status) underwent Whole Exome Sequencing (WES). Sequencing revealed 170 disease-causing or suspicious variants [13 pathogenic, 16 likely pathogenic, 7 not classified, and 134 Variants of Uncertain Significance (VUS)] found in the exomes of 141 (22.3%) patients (12 syndromic, 103 non-syndromic TAAD patients plus a remaining 26 of unknown connective tissue status). Seventy (49.6%) of these patients had a ‘proven’ family history. (7) Familial TAAD patients were more likely to find a variant in their WES result than patients without a family history (70 vs. 26; p < 0.001). Recognition of these strong familial patterns, even in non-syndromic cases, encourages intensive investigation of family in order to save lives by detecting silent TAA disease. Conclusions: Our large-scale, clinical and sequencing-based study clearly demonstrates the strongly familial and genetically mediated nature of thoracic aortic disease. We vividly demonstrate and characterize this familial nature of TAAD, both clinically and by genetic sequencing. Our findings strongly support vigorous family investigation when a new patient is diagnosed with thoracic aortic aneurysm, as well as vigorous application of whole exome sequencing for these families.

Background: ACTA2 encodes smooth muscle alpha-actin and is one of the most common genetic causes of inherited non-syndromic thoracic aortic aneurysm and dissection. Although murine models have provided important mechanistic insight, complementary vertebrate systems may enable more rapid in vivo phenotyping and future therapeutic screening. Methods: Utilizing a CRISPR/Cas9-based approach, we developed zebrafish acta2 mutant models and assessed phenotypes at larval and adult stages. At 3 days post-fertilization, larvae were screened by brightfield microscopy for edema, axis defects, hemorrhage, and a composite endpoint (any phenotype) under basal conditions and after exposure to 0.2 mM epinephrine. Phenotype occurrence was summarized as group-specific proportions across a 2 × 2 design defined by genotype (wild-type vs. acta2-deficient mutant) and treatment (DMSO control vs. epinephrine), with prespecified pairwise comparisons using Pearson’s chi-squared tests. Pooled fish-level logistic regression models were also fit for each endpoint. Adult follow-up was performed by genotyping all available acta2 fish at the facility and tracking staggered tank-level cohorts longitudinally. Results: Initial gross morphologic assessment did not reveal overt external phenotypic differences between heterozygous or homozygous acta2 mutant larvae and wild-type controls. In larval analyses, the mutant genotype was associated with a greater burden of adverse phenotypes than treatment exposure. For the composite endpoint, mutant larvae demonstrated higher proportions than normal larvae under both control (28.3% vs. 17.4%, p = 0.007) and epinephrine conditions (26.9% vs. 17.4%, p = 0.023), whereas epinephrine did not significantly alter composite phenotype frequency within either genotype. Similar genotype-associated trends were observed for axis defects and hemorrhage. In pooled logistic regression, acta2 deficiency was associated with increased odds of axis defects (OR 2.64, 95% CI 1.48–4.89, p = 0.001), hemorrhage (OR 2.40, 95% CI 1.09–5.68, p = 0.036), and the composite endpoint (OR 1.88, 95% CI 1.19–3.00, p = 0.008), whereas epinephrine exposure did not demonstrate a consistent independent effect across endpoints. Adult staggered follow-up showed greater attrition in homozygous mutant cohorts than in wild-type or heterozygous cohorts, with aggregated losses of 24%, 12%, and 3%, respectively. Conclusions: This preliminary zebrafish acta2 model demonstrated that acta2 deficiency is associated with increased adverse larval phenotype burden and suggested reduced long-term persistence of homozygous mutant fish in adulthood. The strongest signal in the current study was genotype-associated phenotype burden rather than a robust epinephrine-dependent effect. These findings support the feasibility of zebrafish-based ACTA2 phenotyping while highlighting the need for more specific vascular endpoints, refined longitudinal follow-up, and future variant-specific modeling.

The aortic arch remains one of the most complex segments of the thoracic aorta to treat, demanding strategies that safeguard cerebral and spinal perfusion while achieving durable proximal and distal repair. Contemporary management strategies include open hemi/total arch replacement, hybrid approaches such as frozen elephant trunk (FET) or debranching with thoracic endovascular aortic repair (TEVAR), and fully endovascular repair using branched or fenestrated devices. Updated guidelines (American College of Cardiology/American Heart Association [ACC/AHA] 2022; European Society of Cardiology [ESC] 2024) emphasize multidisciplinary, patient-specific decision-making grounded in standardized imaging, genetics, and lifelong surveillance. Procedurally, selective antegrade cerebral perfusion with moderate-to-low hypothermia has replaced routine deep hypothermic circulatory arrest for most open arch operations. Zone-based planning using Ishimaru’s map, complemented by the Modified Arch Landing Areas Nomenclature (MALAN), improves feasibility assessment and risk stratification, while entry-focused schemas like TEM (Type, Entry, Malperfusion) further refine management. Emerging data indicate that open repair remains the durability benchmark in younger populations and those with connective tissue disease, and FET enables single-stage treatment capability with acceptable early outcomes but requires vigilant neurologic protection and reintervention surveillance. An integrated, zone-driven approach guided by center expertise optimizes patient selection for open, hybrid, or endovascular options to maximize safety and durability.