Current and Future Applications of Artificial Intelligence in Cardiac CT.

PURPOSE OF REVIEW: In this review, we aim to summarize state-of-the-art artificial intelligence (AI) approaches applied to cardiovascular CT and their future implications. RECENT FINDINGS: Recent studies have shown that deep learning networks can be applied for rapid automated segmentation of coronary plaque from coronary CT angiography, with AI-enabled measurement of total plaque volume predicting future heart attack. AI has also been applied to automate assessment of coronary artery calcium on cardiac and ungated chest CT and to automate the measurement of epicardial fat. Additionally, AI-based prediction models integrating clinical and imaging parameters have been shown to improve prediction of cardiac events compared to traditional risk scores. Artificial intelligence applications have been applied in all aspects of cardiovascular CT - in image acquisition, reconstruction and denoising, segmentation and quantitative analysis, diagnosis and decision assistance and to integrate prognostic risk from clinical data and images. Further incorporation of artificial intelligence in cardiovascular imaging holds important promise to enhance cardiovascular CT as a precision medicine tool.

Knockin mouse model of the human CFL2 p.A35T mutation results in a unique splicing defect and severe myopathy phenotype.

Cofilin-2 is an actin-binding protein that is predominantly expressed in skeletal and cardiac muscles and belongs to the AC group of proteins, which includes cofilin-1 and destrin. In humans, cofilin-2 (CFL2) mutations have been associated with congenital myopathies that include nemaline and myofibrillar myopathy. To understand the pathogenicity of the human CFL2 mutation, p.A35T, that first linked cofilin-2 with the human disease, we created a knock-in mouse model. The Cfl2A35T/A35T (KI) mice were indistinguishable from their wild-type littermates at birth, but they rapidly worsened and died by postnatal day 9. The phenotypic, histopathologic and molecular findings mimicked the constitutive Cfl2-knockout (KO) mice described previously, including sarcomeric disruption and actin accumulations in skeletal muscles and negligible amounts of cofilin-2 protein. In addition, KI mice demonstrated a marked reduction in Cfl2 mRNA levels in various tissues including skeletal muscles. Further investigation revealed evidence of alternative splicing with the presence of two alternate transcripts of smaller size. These alternate transcripts were expressed at very low levels in the wild-type mice and were significantly upregulated in the mutant mice, indicating that pre-translational splicing defects may be a critical component of the disease mechanism associated with the mutation. Evidence of reduced expression of the full-length CFL2 transcript was also observed in the muscle biopsy sample of the patient with p.A35T mutation.

Patient factors predict complications after partial nephrectomy: validation and calibration of the Preoperative Risk Evaluation for Partial Nephrectomy (PREP) score.

OBJECTIVES: To develop and validate the Preoperative Risk Evaluation for Partial Nephrectomy (PREP) score to predict the probability of major postoperative complications after partial nephrectomy (PN) based on patient comorbidities. PATIENTS AND METHODS: The Premier Healthcare Database was used to identify patients who had undergone elective PN. Through review of International Classification of Diseases ninth revision codes, we identified patient comorbidities and major surgical complications (Clavien-Dindo Grade III-V). Multivariable logistic regression was used to identify predictors of major complications. We used half of the set as the training cohort to develop our risk score and the other half as a validation cohort. RESULTS: From 2003 to 2015, 25 451 PNs were performed. The overall rate of major complications was 4.9%. The final risk score consisted of 10 predictors: age, sex, congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, chronic kidney disease, diabetes, hypertension, obesity, and smoking. In the training cohort, the area under the receiver operating characteristic curve (AUC) was 0.75 (95% confidence interval [CI] 0.73-0.78), while the AUC for the validation cohort was 0.73 (95% CI 0.70-0.75). The predicted probabilities of major complication in the low- (≤10 points), intermediate- (11-20 points), high- (21-30 points), and very high-risk (>30 points) categories were 3% (95% CI 2.6-3.2), 8% (95% CI 7.2-9.2), 24% (95% CI 20.5-27.8), and 41% (95% CI 34.5-47.8), respectively. CONCLUSIONS: We developed and validated the PREP score to predict the risk of complications after PN based on patient characteristics. Calculation of the PREP score can help providers select treatment options for patients with a cT1a renal mass and enhance the informed consent process for patients planning to undergo PN.

SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy.

Centronuclear myopathies (CNMs) are characterized by muscle weakness and increased numbers of central nuclei within myofibers. X-linked myotubular myopathy, the most common severe form of CNM, is caused by mutations in MTM1, encoding myotubularin (MTM1), a lipid phosphatase. To increase our understanding of MTM1 function, we conducted a yeast two-hybrid screen to identify MTM1-interacting proteins. Striated muscle preferentially expressed protein kinase (SPEG), the product of SPEG complex locus (SPEG), was identified as an MTM1-interacting protein, confirmed by immunoprecipitation and immunofluorescence studies. SPEG knockout has been previously associated with severe dilated cardiomyopathy in a mouse model. Using whole-exome sequencing, we identified three unrelated CNM-affected probands, including two with documented dilated cardiomyopathy, carrying homozygous or compound-heterozygous SPEG mutations. SPEG was markedly reduced or absent in two individuals whose muscle was available for immunofluorescence and immunoblot studies. Examination of muscle samples from Speg-knockout mice revealed an increased frequency of central nuclei, as seen in human subjects. SPEG localizes in a double line, flanking desmin over the Z lines, and is apparently in alignment with the terminal cisternae of the sarcoplasmic reticulum. Examination of human and murine MTM1-deficient muscles revealed similar abnormalities in staining patterns for both desmin and SPEG. Our results suggest that mutations in SPEG, encoding SPEG, cause a CNM phenotype as a result of its interaction with MTM1. SPEG is present in cardiac muscle, where it plays a critical role; therefore, individuals with SPEG mutations additionally present with dilated cardiomyopathy.

The Role of PhD Faculty in Advancing Research in Departments of Surgery.

OBJECTIVE: To determine the academic contribution as measured by number of publications, citations, and National Institutes of Health (NIH) funding from PhD scientists in US departments of surgery. SUMMARY BACKGROUND DATA: The number of PhD faculty working in US medical school clinical departments now exceeds the number working in basic science departments. The academic impact of PhDs in surgery has not been previously evaluated. METHODS: Academic metrics for 3850 faculties at the top 55 NIH-funded university and hospital-based departments of surgery were collected using NIH RePORTER, Scopus, and departmental websites. RESULTS: MD/PhDs and PhDs had significantly higher numbers of publications and citations than MDs, regardless of academic or institutional rank. PhDs had the greatest proportion of NIH funding compared to both MDs and MD/PhDs. Across all academic ranks, 50.2% of PhDs had received NIH funding compared with 15.2% of MDs and 33.9% of MD/PhDs (P < 0.001). The proportion of PhDs with NIH funding in the top 10 departments did not differ from those working in departments ranked 11 to 50 (P = 0.456). A greater percentage of departmental PhD faculty was associated with increased rates of MD funding. CONCLUSIONS: The presence of dedicated research faculty with PhDs supports the academic mission of surgery departments by increasing both NIH funding and scholarly productivity. In contrast to MDs and MD/PhDs, PhDs seem to have similar levels of academic output and funding independent of the overall NIH funding environment of their department. This suggests that research programs in departments with limited resources may be enhanced by the recruitment of PhD faculty.

The positive association of Association for Academic Surgery membership with academic productivity.

BACKGROUND: To evaluate the academic productivity and National Institutes of Health (NIH) funding of members of the Association for Academic Surgery (AAS). METHODS: Academic metrics including, numbers of publications, citations, and NIH funding history were determined for 4015 surgical faculty at the top 55 NIH-funded departments of surgery, using Scopus, NIH RePORT, and the Grantome online databases. RESULTS: AAS membership included 20.5% (824) of all 4015 surgical faculty in this database. For members of the AAS, publications (P) ± standard deviation and citations (C) ± SD were P: 54 ± 96 and C: 985 ± 3321, compared with P: 31 ± 92, C: 528 ± 3001 for nonmembers, P < 0.001. Higher academic productivity among AAS members was observed across all subspecialty types and was especially pronounced for assistant and associate professors. AAS membership was also associated with increased rates of NIH funding and better productivity for equally funded surgical faculty compared with nonmembers. Analysis of AAS membership by subspecialty revealed that AAS members were most commonly general surgery faculty (57.8%); however, only 7.4% of the faculty was affiliated with cardiothoracic surgery. There was also a lack of dedicated science and/or research faculty (0.6% versus 3.4%) among the members of the AAS. CONCLUSIONS: AAS membership appears to be correlated with greater academic performance among junior and midlevel surgical faculty. This improvement is observed regardless of subspecialty. Increased participation of faculty within subspecialties such as cardiothoracic surgery and, a greater focus on increasing the numbers of dedicated research faculty within the AAS may help increase the scientific impact and productivity among members of the society.

Normal myofibrillar development followed by progressive sarcomeric disruption with actin accumulations in a mouse Cfl2 knockout demonstrates requirement of cofilin-2 for muscle maintenance.

Cofilin-2, a small actin-binding protein and member of the AC protein family that includes cofilin-1 and destrin, is predominantly expressed at sarcomeres in skeletal and cardiac muscles. The role of cofilin-2 in muscle development and function is unclear. In humans, recessive cofilin-2 mutations have been associated with nemaline myopathy with minicores. To investigate the functional role of cofilin-2 in vivo, we generated constitutive and muscle-specific cofilin-2-deficient mice using a cre-loxP strategy. Cofilin-2-deficient mice were similar to their wild-type (WT) littermates at birth, but died by day 8. They were significantly smaller, severely weak and had very little milk in their stomachs. The sarcomeric structure was intact at birth, but by Day 7, skeletal muscles showed severe sarcomeric disruptions starting at the Z-line, along with filamentous actin accumulations consistent with a lack of actin depolymerization activity. Cofilin-2-deficient muscles contained elevated numbers of slow fibers and exhibited upregulation of slow fiber-specific genes. Increased amounts of other sarcomeric proteins including α-actinin-2, α-sarcomeric actin and tropomyosin were also present. While destrin was not expressed in either WT or cofilin-2-deficient muscles, cofilin-1 was similarly expressed in developing myofibers of both genotypes. There was no evidence for compensatory changes in expression of either family member in cofilin-2-deficient tissues. The onset of pathology and weakness in cofilin-2-deficient muscles correlated with normal developmental loss of cofilin-1 expression within myofibers, suggesting that cofilin-1 serves as an early developmental sarcomeric isoform. Overall, cofilin-2, although not critical for muscle development, is essential for muscle maintenance.

"Covering provider": an effort to streamline clinical communication chaos.

Objective: This report describes a root cause analysis of incorrect provider assignments and a standardized workflow developed to improve the clarity and accuracy of provider assignments. Materials and Methods: A multidisciplinary working group involving housestaff was assembled. Key drivers were identified using value stream mapping and fishbone analysis. A report was developed to allow for the analysis of correct provider assignments. A standardized workflow was created and piloted with a single service line. Pre- and post-pilot surveys were administered to nursing staff and participating housestaff on the unit. Results: Four key drivers were identified. A standardized workflow was created with an exclusive treatment team role in Epic held by a single provider at any given time, with a corresponding patient list column displaying provider information for each patient. Pre- and post-survey responses report decreased confusion, decreased provider identification errors, and increased user satisfaction among RNs and residents with sustained uptake over time. Conclusion: This work demonstrates structured root cause analysis, notably engaging housestaff, to develop a standardized workflow for an understudied and growing problem. The development of tools and strategies to address the widespread burdens resulting from clinical communication failures is needed.

Whole genome sequencing identifies SCN2A mutation in monozygotic twins with Ohtahara syndrome and unique neuropathologic findings.

Mutations in SCN2A gene cause a variety of epilepsy syndromes. We report a novel SCN2A-associated epilepsy phenotype in monozygotic twins with tonic seizures soon after birth and a suppression-burst electroencephalography (EEG) pattern. We reviewed the medical records, EEG tracings, magnetic resonance imaging (MRI), and neuropathologic findings, and performed whole genome sequencing (WGS) on Twin B's DNA and Sanger sequencing (SS) on candidate gene mutations. Extensive neurometabolic evaluation and early neuroimaging studies were normal. Twin A died of an iatrogenic cause at 2 weeks of life. His neuropathologic examination was remarkable for dentate-olivary dysplasia and granule cell dispersion of the dentate gyrus. Twin B became seizure free at 8 months and was off antiepileptic drugs by 2 years. His brain MRI, normal at 2 months, revealed evolving brainstem and basal ganglia abnormalities at 8 and 15 months that resolved by 20 months. At 2.5 years, Twin B demonstrated significant developmental delay. Twin B's WGS revealed a heterozygous variant c.788C>T predicted to cause p.Ala263Val change in SCN2A and confirmed to be de novo in both twins by SS. In conclusion, we have identified a de novo SCN2A mutation as the etiology for Ohtahara syndrome in monozygotic twins associated with a unique dentate-olivary dysplasia in the deceased twin.

Association of clinical prediction scores with hospital mortality in an adult medical and surgical intensive care unit in Kenya.

Importance: Mortality prediction among critically ill patients in resource limited settings is difficult. Identifying the best mortality prediction tool is important for counseling patients and families, benchmarking quality improvement efforts, and defining severity of illness for clinical research studies. Objective: Compare predictive capacity of the Modified Early Warning Score (MEWS), Universal Vital Assessment (UVA), Tropical Intensive Care Score (TropICS), Rwanda Mortality Probability Model (R-MPM), and quick Sequential Organ Failure Assessment (qSOFA) for hospital mortality among adults admitted to a medical-surgical intensive care unit (ICU) in rural Kenya. We performed a pre-planned subgroup analysis among ICU patients with suspected infection. Design setting and participants: Prospective single-center cohort study at a tertiary care, academic hospital in Kenya. All adults 18 years and older admitted to the ICU January 2018-June 2019 were included. Main outcomes and measures: The primary outcome was association of clinical prediction tool score with hospital mortality, as defined by area under the receiver operating characteristic curve (AUROC). Demographic, physiologic, laboratory, therapeutic, and mortality data were collected. 338 patients were included, none were excluded. Median age was 42 years (IQR 33-62) and 61% (n = 207) were male. Fifty-nine percent (n = 199) required mechanical ventilation and 35% (n = 118) received vasopressors upon ICU admission. Overall hospital mortality was 31% (n = 104). 323 patients had all component variables recorded for R-MPM, 261 for MEWS, and 253 for UVA. The AUROC was highest for MEWS (0.76), followed by R-MPM (0.75), qSOFA (0.70), and UVA (0.69) (p < 0.001). Predictive capacity was similar among patients with suspected infection. Conclusion and relevance: All tools had acceptable predictive capacity for hospital mortality, with variable observed availability of the component data. R-MPM and MEWS had high rates of variable availability as well as good AUROC, suggesting these tools may prove useful in low resource ICUs.

Implementation approaches and barriers for rule-based and machine learning-based sepsis risk prediction tools: a qualitative study.

Objective: Many options are currently available for sepsis surveillance clinical decision support (CDS) from electronic medical record (EMR) vendors, third party, and homegrown models drawing on rule-based (RB) and machine learning (ML) algorithms. This study explores sepsis CDS implementation from the perspective of implementation leads by describing the motivations, tool choices, and implementation experiences of a diverse group of implementers. Materials and Methods: Semi-structured interviews were conducted with and a questionnaire was administered to 21 hospital leaders overseeing CDS implementation at 15 US medical centers. Participants were recruited via convenience sampling. Responses were coded by 2 coders with consensus approach and inductively analyzed for themes. Results: Use of sepsis CDS is motivated in part by quality metrics for sepsis patients. Choice of tool is driven by ease of integration, customization capability, and perceived predictive potential. Implementation processes for these CDS tools are complex, time-consuming, interdisciplinary undertakings resulting in heterogeneous choice of tools and workflow integration. To improve clinician acceptance, implementers addressed both optimization of the alerts as well as clinician understanding and buy in. More distrust and confusion was reported for ML models, as compared to RB models. Respondents described a variety of approaches to overcome implementation barriers; these approaches related to alert firing, content, integration, and buy-in. Discussion: While there are shared socio-technical challenges of implementing CDS for both RB and ML models, attention to user education, support, expectation management, and dissemination of effective practices may improve feasibility and effectiveness of ML models in quality improvement efforts. Conclusion: Further implementation science research is needed to determine real world efficacy of these tools. Clinician acceptance is a significant barrier to sepsis CDS implementation. Successful implementation of less clinically intuitive ML models may require additional attention to user confusion and distrust.

Training Internal Medicine Residents in Difficult Diagnosis: A Novel Diagnostic Second Opinion Clinic Experience.

Background: In primary care clinics, time constraints and lack of exposure to highly complex cases may limit the breadth and depth of learning for internal medicine residents. To address these issues, we piloted a novel experience for residents to evaluate patients with puzzling symptoms referred by another clinician. Objective: To increase internal medicine residents' exposure to patients with perplexing presentations and foster a team-based approach to solving diagnostically challenging cases. Methods: During the academic year 2020-2021, residents participating in their 2-week primary care "block" rotation were given protected time to evaluate 1-2 patients from the Stanford Consultative Medicine clinic, an internist-led diagnostic second opinion service, and present their patients at the case conference. We assessed the educational value of the program with resident surveys including 5-point Lickert scale and open-ended questions. Results: 21 residents participated in the pilot with a survey response rate of 66.6% (14/21). Both the educational value and overall quality of the experience were rated as 4.8 out of 5 (SD 0.4, range 4-5; 1:"very poor"; 5:"excellent"). Residents learned about new diagnostic tools as well as how to approach complex presentations and diagnostic dilemmas. Residents valued the increased time devoted to patient care, the team-based approach to tackling difficult cases, and the intellectual challenge of these cases. Barriers to implementation include patient case volume, time, and faculty engagement. Conclusions: Evaluation of diagnostically challenging cases in a structured format is a highly valuable experience that offers a framework to enhance outpatient training in internal medicine.

The impact of members of the Society of University Surgeons on the scholarship of American surgery.

BACKGROUND: A core objective of the Society of University Surgeons (SUS) is research focused: to "advance the art and science of surgery through original investigation." This study sought to determine the current impact of the SUS on academic surgical productivity. METHODS: Individual faculty data for numbers of publications, citations, and National Institute of Health (NIH) funding history were collected for 4,015 surgical faculty at the top 55 NIH-funded departments of surgery using SCOPUS and the NIH Research Portfolio Online Reporting Tools. SUS membership was determined from membership registry data. RESULTS: Overall, 502 surgical faculty (12.5%) were SUS members with 92.7% holding positions of associate or full professor (versus 59% of nonmembers). Median publications (P) and citations (C) among SUS members were P: 112, C: 2,460 versus P: 29, C: 467 for nonmembers (P < .001). Academic productivity was considerably higher by rank for SUS members than for nonmembers: associate professors (P: 61 vs 36, C: 1,199 vs 591, P < .001) and full professors (P: 141 vs 81, C: 3,537 vs 1,856, P < .001). Among full professors, SUS members had much higher rates of NIH funding than did nonmembers (52.6% vs 26%, P < .05) and specifically for R01, P01, and U01 awards (37% vs 17.7%, P < .01). SUS members were 2 times more likely to serve in divisional leadership or chair positions (23.5% vs 10.2%, P < .05). CONCLUSION: SUS society members are a highly productive academic group. These data support the premise that the SUS is meeting its research mission and identify its members as very academically productive contributors to research and scholarship in American surgery and medicine.

Development of Soft Tissue Sarcomas in Ribosomal Proteins L5 and S24 Heterozygous Mice.

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome associated with ribosomal protein (RP) gene mutations. Recent studies have also demonstrated an increased risk of cancer predisposition among DBA patients. In this study, we report the formation of soft tissue sarcoma in the Rpl5 and Rps24 heterozygous mice. Our observation suggests that even though one wild-type allele of the Rpl5 or Rps24 gene prevents anemia in these mice, it still predisposes them to cancer development.

Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease.

We describe a large Lebanese family with two affected members, a young female proband and her male cousin, who had multisystem involvement including profound global developmental delay, severe hypotonia and weakness, respiratory insufficiency, blindness, and lactic acidemia-findings consistent with an underlying mitochondrial disorder. Whole-exome sequencing was performed on DNA from the proband and both parents. The proband and her cousin carried compound heterozygous mutations in the PMPCA gene that encodes for α-mitochondrial processing peptidase (α-MPP), a protein likely involved in the processing of mitochondrial proteins. The variants were located close to and postulated to affect the substrate binding glycine-rich loop of the α-MPP protein. Functional assays including immunofluorescence and western blot analysis on patient's fibroblasts revealed that these variants reduced α-MPP levels and impaired frataxin production and processing. We further determined that those defects could be rescued through the expression of exogenous wild-type PMPCA cDNA. Our findings link defective α-MPP protein to a severe mitochondrial disease.

Skeletal muscle microRNA and messenger RNA profiling in cofilin-2 deficient mice reveals cell cycle dysregulation hindering muscle regeneration.

Congenital myopathies are rare skeletal muscle diseases presenting in early age with hypotonia and weakness often linked to a genetic defect. Mutations in the gene for cofilin-2 (CFL2) have been identified in several families as a cause of congenital myopathy with nemaline bodies and cores. Here we explore the global messenger and microRNA expression patterns in quadriceps muscle samples from cofillin-2-null mice and compare them with sibling-matched wild-type mice to determine the molecular pathways and mechanisms involved. Cell cycle processes are markedly dysregulated, with altered expression of genes involved in mitotic spindle formation, and evidence of loss of cell cycle checkpoint regulation. Importantly, alterations in cell cycle, apoptosis and proliferation pathways are present in both mRNA and miRNA expression patterns. Specifically, p21 transcript levels were increased, and the expression of p21 targets, such as cyclin D and cyclin E, was decreased. We therefore hypothesize that deficiency of cofilin-2 is associated with interruption of the cell cycle at several checkpoints, hindering muscle regeneration. Identification of these pathways is an important step towards developing appropriate therapies against various congenital myopathies.

Determining the Drivers of Academic Success in Surgery: An Analysis of 3,850 Faculty.

OBJECTIVE: Determine drivers of academic productivity within U.S. departments of surgery. METHODS: Eighty academic metrics for 3,850 faculty at the top 50 NIH-funded university- and 5 outstanding hospital-based surgical departments were collected using websites, Scopus, and NIH RePORTER. RESULTS: Mean faculty size was 76. Overall, there were 35.3% assistant, 27.8% associate, and 36.9% full professors. Women comprised 21.8%; 4.9% were MD-PhDs and 6.1% PhDs. By faculty-rank, median publications/citations were: assistant, 14/175, associate, 39/649 and full-professor, 97/2250. General surgery divisions contributed the most publications and citations. Highest performing sub-specialties per faculty member were: research (58/1683), transplantation (51/1067), oncology (41/777), and cardiothoracic surgery (48/860). Overall, 23.5% of faculty were principal investigators for a current or former NIH grant, 9.5% for a current or former R01/U01/P01. The 10 most cited faculty (MCF) within each department contributed to 42% of all publications and 55% of all citations. MCF were most commonly general (25%), oncology (19%), or transplant surgeons (15%). Fifty-one-percent of MCF had current/former NIH funding, compared with 20% of the rest (p<0.05); funding rates for R01/U01/P01 grants was 25.1% vs. 6.8% (p<0.05). Rate of current-NIH MCF funding correlated with higher total departmental NIH rank (p < 0.05). CONCLUSIONS: Departmental academic productivity as defined by citations and NIH funding is highly driven by sections or divisions of research, general and transplantation surgery. MCF, regardless of subspecialty, contribute disproportionally to major grants and publications. Approaches that attract, develop, and retain funded MCF may be associated with dramatic increases in total departmental citations and NIH-funding.

Cofilin-2 phosphorylation and sequestration in myocardial aggregates: novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy.

BACKGROUND: Recently, tangles and plaque-like aggregates have been identified in certain cases of dilated cardiomyopathy (DCM), traditionally labeled idiopathic (iDCM), where there is no specific diagnostic test or targeted therapy. This suggests a potential underlying cause for some of the iDCM cases. [Corrected] OBJECTIVES: This study sought to identify the make-up of myocardial aggregates to understand the molecular mechanisms of these cases of DCM; this strategy has been central to understanding Alzheimer's disease. METHODS: Aggregates were extracted from human iDCM samples with high congophilic reactivity (an indication of plaque presence), and the findings were validated in a larger cohort of samples. We tested the expression, distribution, and activity of cofilin in human tissue and generated a cardiac-specific knockout mouse model to investigate the functional impact of the human findings. We also modeled cofilin inactivity in vitro by using pharmacological and genetic gain- and loss-of-function approaches. RESULTS: Aggregates in human myocardium were enriched for cofilin-2, an actin-depolymerizing protein known to participate in neurodegenerative diseases and nemaline myopathy. Cofilin-2 was predominantly phosphorylated, rendering it inactive. Cardiac-specific haploinsufficiency of cofilin-2 in mice recapitulated the human disease's morphological, functional, and structural phenotype. Pharmacological stimulation of cofilin-2 phosphorylation and genetic overexpression of the phosphomimetic protein promoted the accumulation of "stress-like" fibers and severely impaired cardiomyocyte contractility. CONCLUSIONS: Our study provides the first biochemical characterization of prefibrillar myocardial aggregates in humans and the first report to link cofilin-2 to cardiomyopathy. The findings suggest a common pathogenetic mechanism connecting certain iDCMs and other chronic degenerative diseases, laying the groundwork for new therapeutic strategies.