A Change of Heart: Multi-modal Strategies Investigating Cardiovascular Development, Disease and Regeneration

Neil Chi, MD, PhD

Univesity of California, San Diego

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Full abstract coming soon! 

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Presence of donor DQ2/DQA1*05 and/or DQ7/DQA1*05 Risk Heterodimer Mismatch and Development of de novo Donor Specific Antibodies after Heart Transplantation

Mary Jane Farr, MD, MSC

University of Texas, Southwestern Medical Center

 

Purpose

De novo donor-specific antibodies (dnDSA) after heart transplant (HT) portend a poor prognosis. HLA epitope mismatch between donor and recipient may report on the risk for rejection and development of dnDSA, specifically in the case of DQ2/DQA1*05 or DQ7/DQA1*05 risk heterodimer mismatches (RHM). We sought to determine the prevalence of HM in a recent cohort of HT recipients who made DQ dnDSA < 3 years after HT and assessed their impact on post-HT outcomes.

 

Methods

This is a single-center retrospective study of all HT recipients between 1/2018 – 9/2023 who developed DQ dnDSA. All patients had a negative T and B flow crossmatch at the time of HT, and all patients received standard induction and triple immunosuppression (IS).  Patients and donors in our cohort were HLA typed by LabType SSO, and patients who received an organ from a DQ2/DQA1*05 and/or DQ7/DQA1*05 donor while not expressing those heterodimers met the criteria for RHM. Our sub-cohort was further evaluated for rates of antibody-mediated rejection (AMR), development of coronary artery vasculopathy (CAV), allograft dysfunction (LVEF < 50%), and survival. 

 

Results

A total of 273 patients were identified, of whom 32 made DQ dnDSA after HT, with 10 RHM+ and 22 RHM-. The median time to dnDSA development was 226 days (IQR 81, 1256) in RHM+ vs. 484 (IQR 206, 1141) in RHM-, p=0.6. Within 3 years after HT, 9/10 patients with RHM+ had at least one episode of AMR1-2, 6 patients experienced allograft dysfunction, and 2 died (CAV3-cardiac arrest and fulminant AMR-cardiogenic shock). Of the 8 survivors in RHM+, 6 patients have persistent dnDSA despite augmented IS therapies, and none have developed CAV. There were no deaths in the RHM- group. 

 

Conclusion

Risk heterodimer mismatch portends a higher risk trajectory after HT, but it is unclear whether the presence of RHM+ should warrant the augmentation of IS therapies. 

For patients with clinical manifestations of dnDSA and RMH+, novel immunosuppressive therapies might be considered to suppress dnDSA to avoid or mitigate AMR events.

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Co-authors: L Truby, H Beaini, M de Oliveira Valdo Giugni, N Hendren, C Wrobel, N Tapaskar, K Burns, M Peltz and C Lacelle

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Deficiency of lncRNA MERRICAL abrogates macrophage chemotaxis and diabetes-associated atherosclerosis

Mark W. Feinberg, MD

Brigham and Women's Hospital, Harvard Medical School

 

Despite current therapies and prevention measures, individuals with diabetes experience a disproportionately higher risk of cardiovascular events in part due to accelerated atherosclerotic burden and impaired angiogenic activity in the heart and limb. Diabetes-associated atherosclerosis involves excessive immune cell recruitment and plaque formation. However, the mechanisms remain poorly understood. Transcriptomic analysis of the aortic intima in Ldlr-/- mice on a high-fat, high-sucrose-containing (HFSC) diet identified a macrophage-enriched nuclear long noncoding

RNA (lncRNA), MERRICAL (macrophage-enriched lncRNA regulates inflammation, chemotaxis, and atherosclerosis). MERRICAL expression is localized to the nucleus of M1-macrophages and increases by 249% in intimal lesions during progression. lncRNA-mRNA pair genomic mapping revealed that MERRICAL positively correlates with the chemokines Ccl3 and Ccl4. MERRICAL-deficient macrophages exhibit lower Ccl3 and Ccl4 expression, chemotaxis, and inflammatory responses. Mechanistically, MERRICAL guides the WDR5-MLL1 complex to activate CCL3 and CCL4 transcription via H3K4me3 modification. MERRICAL deficiency in HFSC diet-fed Ldlr-/- mice reduces lesion formation by 74% in the aortic sinus and 86% in the descending aorta by inhibiting leukocyte recruitment into the aortic wall and pro-inflammatory responses. These findings unveil a regulatory mechanism whereby targeting a macrophage-enriched lncRNA potently inhibits chemotactic responses, alleviating lesion progression in diabetes.

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The Future of Cardiovascular Innovation

Paul Johnson Wang MD

Stanford University

 

Why think about future directions in cardiovascular innovation? 

What are the key questions we can ask?  

How can we increase the rate of cardiovascular discovery?

Can we use innovation strategies to help inform scientific discovery?

Can we bring experts from various fields, such as artificial intelligence, engineering, material science, chemistry, etc., into the academic cardiovascular research tent, including the AHA?

Can we find ways to foster scientific interaction and collaboration more effectively at our international scientific meetings?  

Can we find ways to increase scientific interaction between these meetings?  

How can we encourage team science? 

What are the most effective ways to share new knowledge? How can we increase the pace of sharing knowledge? How can we more effectively share scientific and clinical data?

How can we create a public domain database of electronic health records, e.g., using a federated model?

How can we create and fund additional clinical research networks? 

How can we invigorate the clinician-scientist pipeline? How do we attract the best and the brightest to cardiovascular research?

How can we increase the diversity of clinician-scientists?

How can we bring together industry and academia to collaborate on solving intractable problems?

Are targeted competitive “moon shot” awards an effective funding mechanism?

How can academia and industry work together to solve intractable medical problems?

How can we reduce costs and decrease the time to bring innovative technologies to patients?

How can we develop new grant funding mechanisms to increase innovation?

How can we re-imagine the grant review process to increase innovation?

How can we create innovation training programs across the country?

Can we recognize innovation in academic promotion?

How can we educate the public better about the needs for cardiovascular discovery? 

How can we use AI and data science to accelerate innovation?

Together, we can answer these questions and accelerate cardiovascular innovation.

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Advancing Actionable Science in Cardio-Oncology: From Longitudinal Cohort Studies to Clinical Trials

Bonnie Ky, MD, MSCE

University of Pennsylvania

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Cancer and cardiovascular disease are two of the largest contributors to morbidity and mortality globally. Despite this tremendous public health burden, there are fundamental gaps in our understanding of disease mechanisms and in the application of evidence-based strategies for the clinical care of patients living with and beyond cancer. The fundamental goals of our research program are to gain insight into the underlying mechanisms and predictors of cancer therapy cardiotoxicity, and to translate this understanding to the clinical care of patients. We leverage new knowledge derived from detailed phenotypic characterization of individual patient clinical characteristics, the social determinants of health, biologic markers, and echocardiography-derived measures of myocardial mechanics and function. We use this knowledge to inform cardioprotective intervention studies to define new strategies to mitigate cardiovascular disease in the growing population of patients living with and beyond cancer.

Deep Phenotyping Pulmonary Hypertension: Moving Beyond Traditional WSPH Groups

Jane Leopold MD FACC, FAHA, FSCAI

Brigham and Women's Hospital, Harvard Medical Center​

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Patients with pulmonary hypertension are assigned to one of 5 World Symposium of Pulmonary Hypertension (WSPH) groups based on their underlying disease pathophysiology (precapillary pulmonary arterial hypertension, left heart disease, lung disease or hypoxia, chronic thromboembolic disease, or other diseases). Assignment to a WSPH group has implications for disease prognostication and therapeutic interventions. It has become apparent that there is significant clinical and biological heterogeneity among patients in each WSPH group and that pulmonary hypertension endophenotypes may be resolved through a precision medicine approach. The NHLBI Pulmonary Vascular Disease Phenomics (PVDOMICS) study enrolled patients with pulmonary hypertension, at-risk disease comparators, and healthy controls with the aim of defining new classifications of pulmonary hypertension based on deep clinical and multiomics phenotyping. The study enrolled 750 patients with pulmonary hypertension across all WSPH groups, 347 disease comparators, and 96 healthy controls from 7 clinical sites across the United States. Patients and disease comparators underwent protocolized cardiac, pulmonary, hemodynamic, exercise, sleep and multimodality imaging studies; multiomics profiling was performed using peripheral venous, mixed venous, pulmonary capillary wedge, and arterial blood specimens. To date, there have been several novel findings that explain some of the heterogeneity among patients in each WSPH group. These findings have implications for patient treatment, therapeutics, and prognosis. 

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​Novel mechanistic insights into DMD-associated cardiomyopathy

Pradeep MA Mammen, MD, FACC, FAHA, FHFSA

University of Kansas School of Medicine

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Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder involving mutations in the DMD gene, resulting in progressive wasting of skeletal muscle and heart failure. The lack of dystrophin within the cardiomyocytes leads to increased oxidative stress, inflammation, and cardiac fibrosis, which collectively leads to advanced cardiomyopathy, the major contributor to mortality in DMD patients. Although significant strides have been made in treating maladaptive cardiac remodeling in non-DMD heart failure (CHF) patients, there are no definitive therapies to effectively induce long term reverse cardiac remodeling and improve overall cardiac function within DMD patients. Recently, our group completed a cardiac MRI study in DMD patients and the data demonstrates adult DMD patients have very low left ventricular (LV) mass and low LV concentricity as compared to age-, sex-, and weight-matched patients with non-ischemic cardiomyopathy (NICM) as well as normal, healthy patients enrolled in the Dallas Heart Study. This observation is novel and raises the question as to whether or not the development of pathological cardiac hypertrophy is truly the primary mechanism underlying DMD-associated cardiomyopathy as it is in other forms of NICM. In fact, data from our laboratory indicates that mdx mice, a murine model of DMD, also have low cardiac mass due to a decrease in nuclear Yap in neonatal cardiomyocytes resulting in defects in proliferative gene expression during the first week of life. Thus, lower LV mass index, lower LV concentricity and higher LVEDV index of DMD hearts, suggest that DMD patients develop a unique form of eccentric, dilated non-hypertrophic cardiomyopathy that is distinct from that of standard NICM patients and may therefore present unique therapeutic challenges and opportunities.

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NADPH Oxidase 4 Contributes to the Development of Heart Failure with Preserved Ejection Fraction​

Francis J. Miller, MD, FAHA

University of Kansas School of Medicine

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Cellular generation of reactive oxygen species is essential for maintaining cardiovascular homeostasis; however, an imbalance between oxidants and antioxidants is a hallmark of disease. The NADPH oxidases (Nox) are a major source of redox-dependent signaling in cells. We have previously shown that Nox1 NADPH oxidase is proinflammatory, promigratory, and contributes to atherosclerosis lesion formation. The role of Nox4 NADPH oxidase is less well understood but has been implicated in fibrosis and metabolism. Therefore, we investigated the role of Nox4 in the pathogenesis of heart failure with preserved ejection fraction (HFpEF), a condition affecting over half of heart failure patients. We employed a mouse model that combined metabolic stress (high-fat diet) and endothelial dysfunction (nitric oxide inhibition) to induce HFpEF progression in wild-type and global Nox4 knockout mice. After 12 weeks, wild-type HFpEF mice exhibited increased wall thickness, elevated heart weight, higher brain natriuretic peptide (BNP) and interleukin-1β levels, reduced exercise tolerance, and cardiac fibrosis.  In contrast, Nox4-deficient mice demonstrated substantial protection from many of these changes, maintaining normal exercise capacity and minimal cardiac remodeling. Mechanistic investigations revealed that Nox4 mediates inflammation, fibrosis, and cellular metabolism. Metabolomic analysis showed the accumulation of long-chain acylcarnitine in wild-type HFpEF animals, suggesting metabolic disruption. RNA sequencing further highlighted gene expression changes associated with compromised ATP production, a critical mechanism linking mitochondrial dysfunction to heart failure. Unlike Nox1, Nox4 activity is primarily regulated by its expression levels.  We identified two conserved miR-9 binding sites in the 3' untranslated region of Nox4 mRNA. Experiments with human cells showed that miR-9 overexpression dramatically reduced Nox4 expression by approximately 70%. Luciferase assays confirmed direct miR-9 binding to Nox4 mRNA. Our findings suggest that inhibition of Nox4 could be a promising therapeutic approach for HFpEF, potentially reducing cardiac fibrosis, decreasing inflammation, and maintaining metabolic function. Identifying miR-9 as a key Nox4 regulator offers an additional potential intervention strategy. These findings provide insights into the molecular mechanisms of HFpEF and the potential for developing targeted treatments for a condition currently lacking therapeutic options.

Power of Zero: Shaping Past, Present and Future of Primary CVD Risk Assessment & Management

Khurram Nasir, MD, MPH, MSc, FACC, FAHA, FASPC, FSSCT

Houston Methodist DeBakey Heart and Vascular Center

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The cornerstone of preventive cardiology lies in accurately identifying individuals at risk of cardiovascular disease (CVD). Traditional risk prediction models, such as the Framingham Risk Score and Pooled Cohort Equations (PCE), have long guided treatment decisions, offering valuable population-level insights. However, their imprecision at the individual level often leads to risk misclassification, resulting in the overtreatment of low-risk individuals and the undertreatment of those at higher risk.

Coronary artery calcium (CAC) testing has transformed this landscape by directly assessing subclinical atherosclerosis, the primary driver of CVD events. At the heart of this transformation is the "Power of Zero"—the observation that a CAC score of zero reliably identifies individuals with remarkably low intermediate- and long-term cardiovascular risk. Validated across diverse populations, age groups, and risk profiles, the absence of CAC among intermediate risk individuals enables clinicians to possibly de-escalate interventions where appropriate, emphasizing lifestyle strategies over pharmacologic therapies. Conversely, the presence of CAC pinpoints individuals who are most likely to benefit from more intensive preventive interventions.

Emerging evidence extends the Power of Zero’s utility to traditionally high-risk populations, including individuals with diabetes mellitus, familial hypercholesterolemia, and elevated lipoprotein(a). Among these groups, the absence of CAC reflects a striking resilience to future cardiovascular events, offering a nuanced perspective on treatment intensity and resource allocation. This insight is reshaping the management of high-risk patients, allowing for more tailored approaches to preventive care.

Looking to the future, the interplay between CAC testing and advanced imaging modalities like coronary computed tomography angiography (CCTA) offers exciting possibilities. While CCTA provides detailed assessments of plaque morphology and high-risk features, current evidence underscores that the predictive power of CAC zero remains unmatched, even in the presence of exclusive non-calcified plaques. At the same time, CCTA holds promise in advancing our understanding of coronary artery disease biology, progression, and the impact of both current and emerging therapies.

The Power of Zero represents a paradigm shift in cardiovascular prevention, simplifying risk assessment, promoting cost-effective care, and empowering shared decision-making. It embodies the transition from imprecise, risk-based estimates to evidence-driven, disease-focused care. By integrating CAC testing into clinical practice, the Power of Zero not only enhances treatment decisions but also redefines the future of cardiovascular risk assessment and management, inspiring precision and fostering transformative patient outcomes.

Improving the safety of PCI: Tribulations, Trials, and Transfusions

Sunil V. Rao, MD, FACC, FSCAI

NYU Grossman School of Medicine, NYU Langone Health System

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Percutaneous coronary intervention (PCI) is the most common cardiovascular procedure. As a minimally invasive treatment for coronary artery disease, PCI in appropriate patients reduces anginal symptoms, may prevent future myocardial infarction, and in patients with either non-ST-segment or ST-segment elevation myocardial infarction, reduces short and long-term major adverse cardiovascular events. Performed on a background of potent antithrombotic therapy, the most common complication of PCI is bleeding at the vascular access site. Our group was among the first to describe the incidence and predictors of bleeding post-PCI, and to define the association between periprocedural bleeding and short- and long-term outcomes. We found that up to 10% of patients undergoing PCI have a bleeding complication and that these events are associated with an increased risk for subsequent myocardial infarction, stent thrombosis, and death. We then embarked on a series of studies examining strategies to reduce bleeding risk, which included the use of radial artery access rather than femoral artery access. The SAFE-PCI for Women trial, which we conducted within the American College of Cardiology’s CathPCI Registry, was among several that demonstrated the superiority of radial access over femoral access for PCI. Trials conducted in STEMI patients showed that radial approach reduces mortality. These studies led to a Class I recommendation for transradial PCI in clinical practice guidelines. As the implementation of radial approach increased in the United States from 1% in 2007 to 75% in 2024, there was an opportunity to expedite patient recovery from the procedure. We used data from the CathPCI registry to demonstrate the same-day discharge after elective PCI was as safe as overnight observation. As the reimbursement landscape changed, same-day discharge after elective PCI has now become the standard of care across the country. We are continuing to work on increasing the efficiency and safety of the patient experience and have recently launched a novel milestone-based discharge pathway that has decreased post-PCI length of stay by 38% without an increase in complications or readmission.

Myocardial Infarction with No Obstructive Coronary Arteries

Harmony R. Reynolds, MD

NYU Grossman School of Medicine

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Full abstract coming soon! 

Global Burden and Future Trends for Cardiovascular Diseases

Gregory Roth, MD, MPH

University of Washington

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Cardiovascular diseases (CVD) are the leading cause of premature mortality globally. Our group applies advanced quantitative methods to examine disease burden, disparities and health economics globally and in the United States. We lead the CVD group for the multinational Global Burden of Disease (GBD) Study. Our Program in Cardiovascular Health Metrics (PCHM) works to improve the evidence base needed for high quality public health and health system decision-making, and to educate and train researchers in this field. 

The GBD study, supported by a network of over 12,000 collaborators around the world, measures 371 diseases and 88 risk factors for 204 countries and territories. Through a multidisciplinary approach, we integrate data from over 100,000 sources, employing statistical techniques to enhance accuracy and validity. 

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For the year 2021, we  estimated over 612 million (95%UI 570-650) prevalent cases and over 19.4 million (95%UI 17.8-20.1) deaths due to CVD. Taken together, these conditions were the leading cause of global disease burden, accounting for 14.9% (95%UI 13.6-16.1) of total global disability-adjusted life years (DALYs). Ischemic heart disease was the most prevalent of CVD (315 million cases) followed by peripheral arterial disease, ischemia stroke, rheumatic heart disease and atrial fibrillation. There were 55.5 million cases of heart failure globally in 2021. Since 1990, years of life lost prematurely due to CVD have increased for most regions of the world. Declines seen only in highly developed countries have stopped and CVD is now rising again. We estimate CVD deaths will rise to 27 million annually by 2050.

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Analysis of all available data on modifiable cardiovascular risk shows rising disease burden attributable to high body mass index and blood glucose, as well as systolic blood pressure, ambient air pollution, LDL cholesterol and alcohol use. Exposure to tobacco smoking has declined, and only high-income locations have seen decreases in air pollution and cholesterol. Particulate air pollution now ranks as the leading modifiable risk factor globally followed by high systolic blood pressure and smoking.

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Similar health metric methods can be employed to understand variation in CVD burden within countries. At the U.S. county-level, there is extensive geographic variation in death due to CVD. We estimate that total U.S. health spending for CVD would rise from $382 billion in 2025 to $538 billion in 2050. Ischemic heart disease and heart failure would account for the largest amount of spending in 2050, followed by atrial fibrillation, stroke and hypertension ($113, $109, $75, $65, and $59 billion respectively).

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These findings offer insights into the epidemiology of CVD and provide evidence for policy and practice. By continuously refining health metric methods and collaborating with global partners, PCHM aims to support the development of effective strategies to reduce the burden of CVD worldwide.

Facilitating international quality improvement initiatives in patients with heart disease. Insights of the first implementation program in Mexico in patients with acute coronary syndrome

Jorge Saucedo, MD

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Full abstract coming soon! 

Subclinical cardiac dysfunction in diverse populations to inform heart failure prevention

Amil Madhukar Shah, MD, MPH

University of Texas Southwestern Medical Center

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Progressive cardiac dysfunction precedes clinical heart failure and is an optimal target for heart failure prevention, but early impairments can be difficult to detect and confounded by aging. The overarching objective of our research program is to understand the burden of and mechanisms underlying cardiac dysfunction that antecedes clinical heart failure, especially heart failure with preserved ejection fraction, in higher risk populations. We integrate longitudinal cardiovascular imaging into diverse community-based cohorts and clinical trials to understand predictors of disease, and leverage high-dimensional -omics technologies (proteomics, metabolomics) to explore associated molecular markers relevant to heart failure development. We pursue these studies within the framework of the Social-Ecological model, evaluating the social patterning of ‘pre-heart failure’ and using these technologies to interrogate the biologic processes by which social determinants of health impact heart failure risk. These studies ultimately aim to improve the diagnosis of pre-clinical cardiac dysfunction and enable strategies to prevent heart failure development.

A Change of Heart: Multi-modal Strategies Investigating Cardiovascular Development, Disease and Regeneration

Nathan O. Stitziel MD, PhD

Washington University School of Medicine

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Coronary artery disease and its sequalae remain leading causes of morbidity and mortality worldwide despite effective LDL-lowering therapies, signaling a need for novel therapeutic targets causally related to disease. Unfortunately, despite decades of research focused on disease pathogenesis, we still lack a sufficient pharmacopeia for treating coronary artery disease, in part because the overwhelming majority of cardiovascular therapies entering Phase I clinical trials fail to obtain regulatory approval. Notably, the failure of these agents to reach the clinic is typically due to lack of efficacy, often reflecting inadequate models of human disease used in the process of target discovery. 

 

We and others believe that human genetic studies have distinct advantages for discovering drug targets that are likely to be effective. By rooting our work in the results of large-scale gene mapping studies, our laboratory uses genetic loci underlying the inherited basis of disease as genomic guideposts highlighting important regions of the human genome harboring potential therapeutic targets. Within those loci, we deploy genomic and computational approaches to nominate prioritized genes and pursue evidence of causal relationships to disease through animal models and Mendelian randomization. Finally, we use traditional molecular and cell biology approaches to clarify mechanisms and pursue therapeutic targeting. Among the novel genes and pathways we have discovered using this approach, we identified the extracellular matrix protein SVEP1 as a causal factor that promotes atherosclerosis and mapped PEAR1 as a novel SVEP1 receptor that appears to mediate its influence on disease. We are now employing this framework with advances in single-nucleus multimodal technologies and anticipate further acceleration toward the identification of additional causal genes and novel therapeutic targets.

Meeting The Underserved Halfway - Local Efforts to Reduce Disparities in Access to Cardiovascular Care

George A. "Rick" Stouffer MD

Washington University School of Medicine

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Inequities in access to cardiovascular care are widespread and novel approaches to improve access for disadvantaged patients are needed. To increase access of underserved patients, the University of North Carolina Division of Cardiology partnered with Piedmont Health Systems (PHS), a federally qualified health center (FQHC) to embed a free/low-cost cardiology clinic within PHS. This is a retrospective review of 636 consultations performed on 505 unique patients. The mean age was 49±15 years, 65% were female, 70% were an ethnic/racial minority, 68% were uninsured, and 79% had comorbid diagnoses. Patients seen at the PHS-Cardiology Clinic were younger and more likely to be members of a racial/ethnic minority group and uninsured than patients seen at an academic cardiology clinic. The primary reasons for referral were for chest pain (30%), evaluation of murmur (20%), shortness of breath (14%), abnormal heart rhythm (12%), palpitations (11%), and hypertension (10%). 130 (21%) patients were referred to a tertiary center for additional cardiac testing and 25 (5%) had a surgical or interventional procedure. Echocardiography was done in 291 unique patients, of which 133 (46%) were abnormal with 100 (34%) of these findings being new diagnoses. Important congenital, valvular or cardiomyopathic disease was present in 43 patients with at least one guideline directed intervention occurring in 35 (81.4%) of these patients. ‘Rarely appropriate’ echocardiograms as determined by Appropriate Use Criteria (AUC) guidelines had a lower rate of abnormal findings than ‘appropriate’ echocardiograms but 16% of patients with ‘rarely appropriate’ indications had clinically important findings with a majority of these being in patients with a murmur.

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Conclusions: Embedding a cardiology clinic within an FQHC was successful at reaching a disadvantaged, high risk population with 70% of patients being an ethnic/racial minority, 68% being uninsured, 79% having significant comorbidities and 46% having abnormal findings on echocardiography. The rates of undiagnosed echocardiographic abnormalities are high in underserved populations and AUC criteria, derived primarily from academic practices, may need to be modified for underserved population. In particular, AUC criteria for underserved patients with a murmur should be modified to take into account that some of these patients will not have access to echocardiography in the future.

Towards Personalized Prosthetc Graft Replacement for Genetically Triggered Thoracic Aortic Aneurysms

Jonathan W. Weinsaft, MD

Weill Cornell Medicine, New York Presbyterian Hospital

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For patients with thoracic aortic aneurysms (TAA), surgical replacement of the ascending aorta with current standard of care prosthetic grafts eliminates risk for dissection in graft-replaced regions and can thus be lifesaving. Nevertheless, accumulating evidence reveals that proximal aortic grafting can increase risk for downstream dissection, which is also life-threatening: Risk is greatest in patients with genetically triggered TAA, who undergo graft replacement at lower thresholds, higher frequency, and younger age - after which risk for dissection in graft-replaced regions is eliminated but possibility of distal regions complications increases. Clinical research by our group has shown that up to two thirds of dissections in genetic TAA patients occur in the distal (arch or descending) aorta. We have also shown that over half of distal dissections with genetic TAA occur after graft surgery; proximal grafting has been linked to >2-fold increase in risk for dissection independent of aortic size. For example, our work using the NIH GenTAC registry demonstrated risk for dissection in distal aortic regions to increase after TAA grafting, and highlighted limits of aortic size to predict events. In this cohort, antecedent imaging showed that while aortic size was slightly larger in patients with subsequent events (p=0.001), magnitude of difference was small (median Δ=0.8cm); only 14% of patients who developed dissection had marked aortic dilation and over half of such events (two-thirds in Marfan syndrome) occurred in patients with proximal grafts. Our clinical observations are consistent with experimental data: In imaging and computational modelling studies, graft-induced increments in proximal aortic stiffness have been shown to alter distal aortic hemodynamics: We have used an array of imaging tools - including cardiac magnetic resonance (CMR) 4D flow and echocardiography-derived strain - to demonstrate that proximal grafts alter biomechanics of the distal aorta, as evidenced by post-operative increments in flow velocity, wall shear stress, and vessel wall strain (all p<0.05). Aortic stiffness is increased with genetic TAA - it is also known that mechanical loading forces drive adverse aortic remodeling. There is thus a critical need to identify markers of distal aortic disease progression after proximal grafting, with focus on altered hemodynamic loading in relation to graft characteristics. A central hypothesis of our research is that loss of proximal aortic compliance due to stiff prosthetic grafts induces adverse distal aortic remodeling (driven by increased wall and shear stress) and predicts adverse prognosis. This is actively being tested through study of genetic TAA patients undergoing prosthetic graft replacement, via integrated Aims to test if graft implantation produces progressive increments in adverse remodeling, identify aortic features responsible for adverse remodeling, and explore if these are modifiable via a new class of tailored grafts and/or if widely generalizable surrogates of graft-induced remodeling predict clinical events. Cutting edge CMR technologies are being integrated with computational modeling of fluid structure interactions - informed by material property testing of resected aortic tissue and computational simulations of tailored grafts for which compliance can be paired to patient-specific aortic features. Results will yield insight into mechanisms of adverse remodeling and post-operative events, enhance risk stratification for current grafts, and inform personalized therapy by guiding design of new prototypes of tailored grafts - towards the shared goal of improving outcomes for TAA patients who benefit from proximal grafting but remain at risk for serious clinical events in the residual native aorta.