Pub Date : 2025-06-01DOI: 10.1016/j.jaccao.2025.03.007
Yasutomi Higashikuni MD, PhD , Colin Platt PhD , Margaret H. Hastings PhD , William C.W. Chen MD, PhD , Justin R.B. Guerra BS , Takeshi Tokuyama PhD , Fuad Gandhi Torizal DDS, PhD , Wenhao Liu MD , Takumi Obana , Abraham L. Bayer BS , Hannah Whipple BS , Alexandra Kuznetsov BA , Ashish Yeri PhD , Cole Turissini BS , Robert R. Kitchen PhD , Kota Shibayama , Takayoshi Matsumura MD, PhD , Norihiko Takeda MD, PhD , Hideki Uosaki MD, PhD , Aarti H. Asnani MD , Anthony Rosenzweig MD
Background
Cardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutics like doxorubicin, and contributes to heart failure development. There is a pressing need for cardiac-specific therapeutics that target cardiomyocyte loss, preventing chemotherapy complications without compromising chemotherapeutic efficacy.
Objectives
The authors employed massively parallel combinatorial genetic screening to find microRNA (miRNA) combinations that promote cardiomyocyte survival.
Methods
CombiGEM (combinatorial genetics en masse) screening in a cardiomyocyte cell line was followed by validation in the original cell type and screening in primary cardiomyocytes. The top combination was tested in mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing provided insight into possible mechanisms.
Results
Multiple miRNA combinations protected cardiomyocytes from doxorubicin in vitro. The most effective (miR-222+miR-455) appeared to act synergistically, and mitigated doxorubicin cardiotoxicity phenotypes in murine and zebrafish in vivo models. RNA sequencing revealed overlapping and synergistic regulation of relevant genes and biological processes in cardiomyocytes, including mitochondrial homeostasis, oxidative stress, muscle contraction, and others.
Conclusions
We identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. This study furthers our knowledge of the cardiac effects of miRNAs and their combinations and demonstrates the potential of CombiGEM for cardioprotective combinatorial therapeutic discovery.
{"title":"Mitigation of Doxorubicin Cardiotoxicity With Synergistic miRNA Combinations Identified Using Combinatorial Genetics en masse (CombiGEM)","authors":"Yasutomi Higashikuni MD, PhD , Colin Platt PhD , Margaret H. Hastings PhD , William C.W. Chen MD, PhD , Justin R.B. Guerra BS , Takeshi Tokuyama PhD , Fuad Gandhi Torizal DDS, PhD , Wenhao Liu MD , Takumi Obana , Abraham L. Bayer BS , Hannah Whipple BS , Alexandra Kuznetsov BA , Ashish Yeri PhD , Cole Turissini BS , Robert R. Kitchen PhD , Kota Shibayama , Takayoshi Matsumura MD, PhD , Norihiko Takeda MD, PhD , Hideki Uosaki MD, PhD , Aarti H. Asnani MD , Anthony Rosenzweig MD","doi":"10.1016/j.jaccao.2025.03.007","DOIUrl":"10.1016/j.jaccao.2025.03.007","url":null,"abstract":"<div><h3>Background</h3><div>Cardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutics like doxorubicin, and contributes to heart failure development. There is a pressing need for cardiac-specific therapeutics that target cardiomyocyte loss, preventing chemotherapy complications without compromising chemotherapeutic efficacy.</div></div><div><h3>Objectives</h3><div>The authors employed massively parallel combinatorial genetic screening to find microRNA (miRNA) combinations that promote cardiomyocyte survival.</div></div><div><h3>Methods</h3><div>CombiGEM (combinatorial genetics en masse) screening in a cardiomyocyte cell line was followed by validation in the original cell type and screening in primary cardiomyocytes. The top combination was tested in mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing provided insight into possible mechanisms.</div></div><div><h3>Results</h3><div>Multiple miRNA combinations protected cardiomyocytes from doxorubicin in vitro. The most effective (miR-222+miR-455) appeared to act synergistically, and mitigated doxorubicin cardiotoxicity phenotypes in murine and zebrafish in vivo models. RNA sequencing revealed overlapping and synergistic regulation of relevant genes and biological processes in cardiomyocytes, including mitochondrial homeostasis, oxidative stress, muscle contraction, and others.</div></div><div><h3>Conclusions</h3><div>We identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. This study furthers our knowledge of the cardiac effects of miRNAs and their combinations and demonstrates the potential of CombiGEM for cardioprotective combinatorial therapeutic discovery.</div></div>","PeriodicalId":48499,"journal":{"name":"Jacc: Cardiooncology","volume":"7 4","pages":"Pages 396-410"},"PeriodicalIF":12.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.jaccao.2025.03.008
Frits I. Mulder MD , Erzsébet Horváth-Puhó PhD , Nick van Es MD , Lars Pedersen PhD , Harry R. Büller PhD , Deirdre Cronin-Fenton PhD , Christian F. Christiansen MD, PhD , Hans Erik Bøtker MD, PhD , Krishnan Bhaskaran PhD , Henrik T. Sørensen MD, PhD
Background
Patients face an increased risk of cardiovascular disease shortly after a cancer diagnosis, but evidence on long-term risk among cancer survivors remains limited.
Objectives
In this study the authors sought to estimate the risk of cardiovascular disease in cancer survivors previously treated with systemic cancer therapy.
Methods
Using Danish population-based registries, we identified individuals who had received systemic cancer treatment and were free of both cancer and treatment 3 years after diagnosis (index date). For each cancer survivor, 5 cancer-free individuals from the general population were randomly selected, matched by birth year, sex, and calendar year. Participants were followed from the index date for up to 5 years. HRs were estimated using Cox regression, adjusted for potential confounders.
Results
Compared with 457,035 matched individuals, the 91,407 cancer survivors had an increased risk of heart failure or cardiomyopathy (HR: 1.08; 95% CI: 1.02-1.15), venous thromboembolism (HR: 1.50; 95% CI: 1.41-1.61), pericarditis, endocarditis, or myocarditis (HR: 1.30; 95% CI: 1.11-1.52), and kidney failure (HR: 1.17; 95% CI: 1.10-1.25), but not of ischemic heart disease, stroke, or atrial fibrillation. Estimates varied substantially by cancer type and treatment agent. For example, venous thromboembolism risk was consistently increased across nearly all cancer types, whereas hypertension risk was elevated for none. Ischemic heart disease risk was increased only among lung cancer survivors. Stroke was associated with platinum compounds but not with other systemic treatments.
Conclusions
Several cardiovascular disease risks were elevated among cancer survivors, with substantial variation by cancer type and treatment.
{"title":"Risk of Cardiovascular Disease in Cancer Survivors after Systemic Treatment","authors":"Frits I. Mulder MD , Erzsébet Horváth-Puhó PhD , Nick van Es MD , Lars Pedersen PhD , Harry R. Büller PhD , Deirdre Cronin-Fenton PhD , Christian F. Christiansen MD, PhD , Hans Erik Bøtker MD, PhD , Krishnan Bhaskaran PhD , Henrik T. Sørensen MD, PhD","doi":"10.1016/j.jaccao.2025.03.008","DOIUrl":"10.1016/j.jaccao.2025.03.008","url":null,"abstract":"<div><h3>Background</h3><div>Patients face an increased risk of cardiovascular disease shortly after a cancer diagnosis, but evidence on long-term risk among cancer survivors remains limited.</div></div><div><h3>Objectives</h3><div>In this study the authors sought to estimate the risk of cardiovascular disease in cancer survivors previously treated with systemic cancer therapy.</div></div><div><h3>Methods</h3><div>Using Danish population-based registries, we identified individuals who had received systemic cancer treatment and were free of both cancer and treatment 3 years after diagnosis (index date). For each cancer survivor, 5 cancer-free individuals from the general population were randomly selected, matched by birth year, sex, and calendar year. Participants were followed from the index date for up to 5 years. HRs were estimated using Cox regression, adjusted for potential confounders.</div></div><div><h3>Results</h3><div>Compared with 457,035 matched individuals, the 91,407 cancer survivors had an increased risk of heart failure or cardiomyopathy (HR: 1.08; 95% CI: 1.02-1.15), venous thromboembolism (HR: 1.50; 95% CI: 1.41-1.61), pericarditis, endocarditis, or myocarditis (HR: 1.30; 95% CI: 1.11-1.52), and kidney failure (HR: 1.17; 95% CI: 1.10-1.25), but not of ischemic heart disease, stroke, or atrial fibrillation. Estimates varied substantially by cancer type and treatment agent. For example, venous thromboembolism risk was consistently increased across nearly all cancer types, whereas hypertension risk was elevated for none. Ischemic heart disease risk was increased only among lung cancer survivors. Stroke was associated with platinum compounds but not with other systemic treatments.</div></div><div><h3>Conclusions</h3><div>Several cardiovascular disease risks were elevated among cancer survivors, with substantial variation by cancer type and treatment.</div></div>","PeriodicalId":48499,"journal":{"name":"Jacc: Cardiooncology","volume":"7 4","pages":"Pages 360-378"},"PeriodicalIF":12.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.jaccao.2025.05.002
Georgia K. Thomas MD, PhD , Josh West MS , Michele Golino MD, PhD , Emily Kontos BS , Emily Federmann MS , William Clark MD , John McCarty MD , Thomas Chelimsky MD , Benjamin VanTassell PharmD , Maria Toumpourleka MD , Pietro E. Lazzerini MD , Stavros Stavrakis MD, PhD , Antonio Abbate MD, PhD
Background
Postural orthostatic tachycardia (POTS) and orthostatic hypotension (OH) commonly occur after hematopoietic stem cell transplantation (HSCT).
Objectives
This study sought to determine the prevalence of POTS and OH before HSCT and the incidence of new cases after HSCT.
Methods
In this single-center, prospective study, patients were evaluated 30 days before and 30 and 100 days after HSCT. Blood pressure, heart rate, and plasma norepinephrine levels were measured in the supine position and after a 10-minute active stand test to assess for POTS or OH. After HSCT, adrenergic receptor (AR)–modulating autoantibody activity was measured in 8 subjects with POTS and 8 without.
Results
Among 46 patients, 40 (87.0%) underwent autologous and 6 (13.0%) allogeneic HSCT. Multiple myeloma was the most common indication (67.4%). Before HSCT, the prevalence of both POTS and OH was 4.3%. At 30 days after HSCT, POTS was present in 10 (25.6%) of 39 patients, including 9 (23.1%) new cases, and OH in 6 (15.4%), including 5 (12.8%) new cases. Patients with POTS at 30 days showed a significantly greater increase in norepinephrine levels upon standing (median 231% [Q1-Q3: 179%-343%]) compared with before HSCT (median 100% [Q1-Q3: 62%-183%]) (P = 0.005), which positively correlated with heart rate changes. AR-modulating autoantibody activity was also higher in patients with POTS vs those without and directly correlated with heart rate changes.
Conclusions
Approximately 1 in 4 patients developed POTS after HSCT, characterized by exaggerated increases in norepinephrine upon standing and elevated AR-modulating autoantibody activity.
{"title":"Postural Orthostatic Tachycardia Syndrome and Orthostatic Hypotension Following Hematopoietic Stem Cell Transplantation","authors":"Georgia K. Thomas MD, PhD , Josh West MS , Michele Golino MD, PhD , Emily Kontos BS , Emily Federmann MS , William Clark MD , John McCarty MD , Thomas Chelimsky MD , Benjamin VanTassell PharmD , Maria Toumpourleka MD , Pietro E. Lazzerini MD , Stavros Stavrakis MD, PhD , Antonio Abbate MD, PhD","doi":"10.1016/j.jaccao.2025.05.002","DOIUrl":"10.1016/j.jaccao.2025.05.002","url":null,"abstract":"<div><h3>Background</h3><div>Postural orthostatic tachycardia (POTS) and orthostatic hypotension (OH) commonly occur after hematopoietic stem cell transplantation (HSCT).</div></div><div><h3>Objectives</h3><div>This study sought to determine the prevalence of POTS and OH before HSCT and the incidence of new cases after HSCT.</div></div><div><h3>Methods</h3><div>In this single-center, prospective study, patients were evaluated 30 days before and 30 and 100 days after HSCT. Blood pressure, heart rate, and plasma norepinephrine levels were measured in the supine position and after a 10-minute active stand test to assess for POTS or OH. After HSCT, adrenergic receptor (AR)–modulating autoantibody activity was measured in 8 subjects with POTS and 8 without.</div></div><div><h3>Results</h3><div>Among 46 patients, 40 (87.0%) underwent autologous and 6 (13.0%) allogeneic HSCT. Multiple myeloma was the most common indication (67.4%). Before HSCT, the prevalence of both POTS and OH was 4.3%. At 30 days after HSCT, POTS was present in 10 (25.6%) of 39 patients, including 9 (23.1%) new cases, and OH in 6 (15.4%), including 5 (12.8%) new cases. Patients with POTS at 30 days showed a significantly greater increase in norepinephrine levels upon standing (median 231% [Q1-Q3: 179%-343%]) compared with before HSCT (median 100% [Q1-Q3: 62%-183%]) (<em>P</em> = 0.005), which positively correlated with heart rate changes. AR-modulating autoantibody activity was also higher in patients with POTS vs those without and directly correlated with heart rate changes.</div></div><div><h3>Conclusions</h3><div>Approximately 1 in 4 patients developed POTS after HSCT, characterized by exaggerated increases in norepinephrine upon standing and elevated AR-modulating autoantibody activity.</div></div>","PeriodicalId":48499,"journal":{"name":"Jacc: Cardiooncology","volume":"7 4","pages":"Pages 382-392"},"PeriodicalIF":12.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144308058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.jaccao.2025.01.019
Aderonke T. Abiodun MBChB , Chengsheng Ju MPharm, PhD , Catherine A. Welch BSc, MSc, PhD , Jennifer Lai MPH, PhD , Freya Tyrer BSc, MSc, PhD , Pinkie Chambers MPharm, PhD , Lizz Paley MSc , Sally Vernon MMath , John Deanfield BA , Mark de Belder MA, MD , Mark J. Rutherford BSc, MSc, PhD , Paul C. Lambert MSc, PhD , Sarah Slater MD , Kai-Keen Shiu MSc, PhD , Li Wei MPH, PhD , Michael D. Peake MD
Background
Fluoropyrimidine chemotherapy is administered first-line for many gastrointestinal cancers. However, patients with cardiovascular disease commonly receive alternative treatment due to cardiotoxicity concerns.
Objectives
This study sought to assess the risks of all-cause mortality and acute cardiovascular events with fluoropyrimidine treatment.
Methods
We conducted an observational cohort study applying a target trial emulation framework to linked national cancer, cardiac, and hospitalization registry data from the Virtual Cardio-Oncology Research Initiative. Adults diagnosed with tumors eligible for fluoropyrimidine-based chemotherapy as first-line therapy were included. All-cause mortality and a composite of hospitalization for acute cardiovascular events (acute coronary syndrome, heart failure, cardiac arrhythmia, cardiac intervention, cardiac arrest, and cardiac death) were compared in patients treated with fluoropyrimidine-based chemotherapy vs alternative management. Adjusted, weighted pooled logistic regression models were used to estimate the 1-year risk difference (RD).
Results
Among 103,110 patients (mean age 69.7 years, 59% male), the absolute risk of death at 1 year was significantly lower in fluoropyrimidine-treated patients (RD: −7.7%; 95% CI: −8.7% to −6.7%) with a small increased risk of acute cardiovascular events (RD: 0.9%; 95% CI: 0.0% to 1.9%). This was primarily due to arrhythmias (RD: 0.8%; 95% CI: 0.1% to 1.6%) and cardiac arrest (RD: 0.3%; 95% CI: 0.1% to 0.5%), with no increased risk of acute coronary syndromes including in the subgroup of patients with pre-existing coronary artery disease.
Conclusions
The markedly improved overall survival with fluoropyrimidines in patients with gastrointestinal cancer significantly outweighs the small risk of cardiac arrhythmia and arrest. Oncologists should take this into consideration for decision making to avoid undue clinical conservatism, particularly in patients with cardiovascular disease.
{"title":"Fluoropyrimidine Chemotherapy and the Risk of Death and Cardiovascular Events in Patients With Gastrointestinal Cancer","authors":"Aderonke T. Abiodun MBChB , Chengsheng Ju MPharm, PhD , Catherine A. Welch BSc, MSc, PhD , Jennifer Lai MPH, PhD , Freya Tyrer BSc, MSc, PhD , Pinkie Chambers MPharm, PhD , Lizz Paley MSc , Sally Vernon MMath , John Deanfield BA , Mark de Belder MA, MD , Mark J. Rutherford BSc, MSc, PhD , Paul C. Lambert MSc, PhD , Sarah Slater MD , Kai-Keen Shiu MSc, PhD , Li Wei MPH, PhD , Michael D. Peake MD","doi":"10.1016/j.jaccao.2025.01.019","DOIUrl":"10.1016/j.jaccao.2025.01.019","url":null,"abstract":"<div><h3>Background</h3><div>Fluoropyrimidine chemotherapy is administered first-line for many gastrointestinal cancers. However, patients with cardiovascular disease commonly receive alternative treatment due to cardiotoxicity concerns.</div></div><div><h3>Objectives</h3><div>This study sought to assess the risks of all-cause mortality and acute cardiovascular events with fluoropyrimidine treatment.</div></div><div><h3>Methods</h3><div>We conducted an observational cohort study applying a target trial emulation framework to linked national cancer, cardiac, and hospitalization registry data from the Virtual Cardio-Oncology Research Initiative. Adults diagnosed with tumors eligible for fluoropyrimidine-based chemotherapy as first-line therapy were included. All-cause mortality and a composite of hospitalization for acute cardiovascular events (acute coronary syndrome, heart failure, cardiac arrhythmia, cardiac intervention, cardiac arrest, and cardiac death) were compared in patients treated with fluoropyrimidine-based chemotherapy vs alternative management. Adjusted, weighted pooled logistic regression models were used to estimate the 1-year risk difference (RD).</div></div><div><h3>Results</h3><div>Among 103,110 patients (mean age 69.7 years, 59% male), the absolute risk of death at 1 year was significantly lower in fluoropyrimidine-treated patients (RD: −7.7%; 95% CI: −8.7% to −6.7%) with a small increased risk of acute cardiovascular events (RD: 0.9%; 95% CI: 0.0% to 1.9%). This was primarily due to arrhythmias (RD: 0.8%; 95% CI: 0.1% to 1.6%) and cardiac arrest (RD: 0.3%; 95% CI: 0.1% to 0.5%), with no increased risk of acute coronary syndromes including in the subgroup of patients with pre-existing coronary artery disease.</div></div><div><h3>Conclusions</h3><div>The markedly improved overall survival with fluoropyrimidines in patients with gastrointestinal cancer significantly outweighs the small risk of cardiac arrhythmia and arrest. Oncologists should take this into consideration for decision making to avoid undue clinical conservatism, particularly in patients with cardiovascular disease.</div></div>","PeriodicalId":48499,"journal":{"name":"Jacc: Cardiooncology","volume":"7 4","pages":"Pages 345-356"},"PeriodicalIF":12.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号