Publications by authors named "Alexander R Lyon"

171 Publications

Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure.

Cardiovasc Res 2021 Jun 22. Epub 2021 Jun 22.

National Heart and Lung Institute, Imperial College London, UK.

Aims: Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and absence of coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS.

Methods And Results: miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal) cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4) and G-protein subunit Gβ (GNB1) as underlying these effects.

Conclusion: miR-16 and miR-26a sensitise the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future.

Translational Perspective: TTS-associated miRs have the potential to be active players predisposing to TTS. Feasibly, their measurement in recovered TTS patients during subsequent periods of stress could be used to predict likelihood of recurrence, a significant risk in this population, and allow preventative action. Since they have been reported as raised in anxiety and depression, they could be part of a priming mechanism where chronic stress predisposes to an acute episode. Understanding the mechanistic basis for the sensitisation may also allow design of other prophylactic pharmacological therapies, including the pre/anti-miR constructs which are now starting to reach the clinic.
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http://dx.doi.org/10.1093/cvr/cvab210DOI Listing
June 2021

British Society for Echocardiography and British Cardio-Oncology Society guideline for transthoracic echocardiographic assessment of adult cancer patients receiving anthracyclines and/or trastuzumab.

Echo Res Pract 2021 03 31;8(1):G1-G18. Epub 2021 Mar 31.

Department of Cardiology, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK

The subspecialty of cardio-oncology aims to reduce cardiovascular morbidity and mortality in patients with cancer or following cancer treatment. Cancer therapy can lead to a variety of cardiovascular complications, including left ventricular systolic dysfunction, pericardial disease, and valvular heart disease. Echocardiography is a key diagnostic imaging tool in the diagnosis and surveillance for many of these complications. The baseline assessment and subsequent surveillance of patients undergoing treatment with anthracyclines and/or human epidermal growth factor (EGF) receptor (HER) 2-positive targeted treatment (e.g. trastuzumab and pertuzumab) form a significant proportion of cardio-oncology patients undergoing echocardiography. This guideline from the British Society of Echocardiography and British Cardio-Oncology Society outlines a protocol for baseline and surveillance echocardiography of patients undergoing treatment with anthracyclines and/or trastuzumab. The methodology for acquisition of images and the advantages and disadvantages of techniques are discussed. Echocardiographic definitions for considering cancer therapeutics-related cardiac dysfunction are also presented.
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http://dx.doi.org/10.1530/ERP-21-0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052569PMC
March 2021

Heart Failure Association, Heart Failure Society of America, and Japanese Heart Failure Society Position Statement on Endomyocardial Biopsy.

J Card Fail 2021 Jul 19;27(7):727-743. Epub 2021 May 19.

Cleveland Clinic, Cleveland Ohio.

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB.
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http://dx.doi.org/10.1016/j.cardfail.2021.04.010DOI Listing
July 2021

Heart Failure Association of the ESC, Heart Failure Society of America and Japanese Heart Failure Society Position statement on endomyocardial biopsy.

Eur J Heart Fail 2021 Jun 19;23(6):854-871. Epub 2021 May 19.

Cleveland Clinic, Cleveland, OH, USA.

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples have significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (i) an overview of the practical approach to EMB, (ii) an update on indications for EMB, (iii) a revised plan for HTx rejection surveillance, (iv) the impact of multimodality imaging on EMB, and (v) the current clinical practice in the worldwide use of EMB.
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http://dx.doi.org/10.1002/ejhf.2190DOI Listing
June 2021

Rotigaptide Infusion for the First 7 Days After Myocardial Infarction-Reperfusion Reduced Late Complexity of Myocardial Architecture of the Healing Border-Zone and Arrhythmia Inducibility.

J Am Heart Assoc 2021 May 17;10(9):e020006. Epub 2021 Apr 17.

National Heart & Lung Institute and ElectroCardioMaths Programme of the Imperial Centre for Cardiac EngineeringImperial College London London United Kingdom.

Background Survivors of myocardial infarction are at increased risk of late ventricular arrhythmias, with infarct size and scar heterogeneity being key determinants of arrhythmic risk. Gap junctions facilitate the passage of small ions and morphogenic cell signaling between myocytes. We hypothesized that gap junctions enhancement during infarction-reperfusion modulates structural and electrophysiological remodeling and reduces late arrhythmogenesis. Methods and Results Infarction-reperfusion surgery was carried out in male Sprague-Dawley rats followed by 7 days of rotigaptide or saline administration. The in vivo and ex vivo arrhythmogenicity was characterized by programmed electrical stimulation 3 weeks later, followed by diffusion-weighted magnetic resonance imaging and Masson's trichrome histology. Three weeks after 7-day postinfarction administration of rotigaptide, ventricular tachycardia/ventricular fibrillation was induced on programmed electrical stimulation in 20% and 53% of rats, respectively (rotigaptide versus control), resulting in reduction of arrhythmia score (3.2 versus 1.4, =0.018), associated with the reduced magnetic resonance imaging parameters fractional anisotropy (fractional anisotropy: -5% versus -15%; =0.062) and mean diffusivity (mean diffusivity: 2% versus 6%, =0.042), and remodeling of the 3-dimensional laminar structure of the infarct border zone with reduction of the mean (16° versus 19°, =0.013) and the dispersion (9° versus 12°, =0.015) of the myofiber transverse angle. There was no change in ECG features, spontaneous arrhythmias, or mortality. Conclusions Enhancement of gap junctions function by rotigaptide administered during the early healing phase in reperfused infarction reduces later complexity of infarct scar morphology and programmed electrical stimulation-induced arrhythmias, and merits further exploration as a feasible and practicable intervention in the acute myocardial infarction management to reduce late arrhythmic risk.
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http://dx.doi.org/10.1161/JAHA.120.020006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200720PMC
May 2021

The Evolving Immunotherapy Landscape and the Epidemiology, Diagnosis, and Management of Cardiotoxicity: Primer.

JACC CardioOncol 2021 Mar 12;3(1):35-47. Epub 2021 Jan 12.

Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Immune checkpoint inhibitors (ICIs) are newer therapies being applied to an increasing number of patients with cancer. Data suggest that up to 36% of cancer patients may be eligible for immunotherapy and, in late 2019, there were more than 3,362 clinical trials initiated to evaluate the effectiveness of immunotherapy, either as single agents or in combination with other immunotherapy, targeted therapies, or traditional cytotoxic or radiation therapy. With the combination of both immune and non-immune treatment approaches, the complexity in making the diagnosis of cardiotoxicity related to an ICI will increase substantially. Here, we summarize the published data on the epidemiology, diagnosis, and management of cardiotoxicity of ICIs. This is a rapidly evolving field, and as our understanding continues to evolve, previously considered hypotheses may not prove to be entirely correct. Research and continued collaborations are urgently needed to provide evidence-based cardiovascular care for this rapidly expanding and vulnerable cohort of patients. (J Am Coll Cardiol CardioOnc 2021;3:35-47) © 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1016/j.jaccao.2020.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034586PMC
March 2021

Incidence of cardiotoxicity and validation of the Heart Failure Association-International Cardio-Oncology Society risk stratification tool in patients treated with trastuzumab for HER2-positive early breast cancer.

Breast Cancer Res Treat 2021 Jul 5;188(1):149-163. Epub 2021 Apr 5.

Breast Unit, Department of Medicine, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, SM2 5PT, Surrey, UK.

Purpose: Trastuzumab improves survival in patients with HER2+ early breast cancer. However, cardiotoxicity remains a concern, particularly in the curative setting, and there are limited data on its incidence outside of clinical trials. We retrospectively evaluated the cardiotoxicity rates [left ventricular ejection fraction (LVEF) decline, congestive heart failure (CHF), cardiac death or trastuzumab discontinuation] and assessed the performance of a proposed model to predict cardiotoxicity in routine clinical practice.

Methods: Patients receiving curative trastuzumab between 2011 and 2018 were identified. Demographics, treatments, assessments and toxicities were recorded. Fisher's exact test, Chi-squared and logistic regression were used.

Results: 931 patients were included in the analysis. Median age was 54 years (range 24-83) and Charlson comorbidity index 0 (0-6), with 195 patients (20.9%) aged 65 or older. 228 (24.5%) were smokers. Anthracyclines were given in 608 (65.3%). Median number of trastuzumab doses was 18 (1-18). The HFA-ICOS cardiovascular risk was low in 401 patients (43.1%), medium in 454 (48.8%), high in 70 (7.5%) and very high in 6 (0.6%). Overall, 155 (16.6%) patients experienced cardiotoxicity: LVEF decline ≥ 10% in 141 (15.1%), falling below 50% in 55 (5.9%), CHF NYHA class II in 42 (4.5%) and class III-IV in 5 (0.5%) and discontinuation due to cardiac reasons in 35 (3.8%). No deaths were observed. Cardiotoxicity rates increased with HFA-ICOS score (14.0% low, 16.7% medium, 30.3% high/very high; p = 0.002).

Conclusions: Cardiotoxicity was relatively common (16.6%), but symptomatic heart failure on trastuzumab was rare in our cohort. The HFA-ICOS score identifies patients at high risk of cardiotoxicity.
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http://dx.doi.org/10.1007/s10549-021-06192-wDOI Listing
July 2021

Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor-Associated Myocarditis.

J Am Coll Cardiol 2021 Mar;77(12):1503-1516

Cardio-Oncology Program, Department of Cardiology, Clínica Universidad de Navarra, Pamplona and Madrid, Spain.

Background: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited.

Objectives: This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis.

Methods: In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block.

Results: Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE.

Conclusions: The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis.
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http://dx.doi.org/10.1016/j.jacc.2021.01.050DOI Listing
March 2021

Device closure for patent foramen ovale in patients with cryptogenic stroke: which patients should get it?

Eur Heart J Suppl 2020 Nov 6;22(Suppl M):M43-M50. Epub 2020 Dec 6.

LARC (Laboratorio Analisi e Ricerca Clinica) C.so Venezia 10-Turin - Italy and School of Medicine-, Insubria University, Varese, Italy.

Patent foramen ovale (PFO) and cryptogenic stroke (CS) both have a high prevalence. The optimal treatment to reduce stroke recurrence after CS remains controversial. Results from clinical trials, meta-analyses, and position papers, support percutaneous PFO device closure and medical therapy compared to medical therapy alone. However, the procedure may be associated with cardiac complications including an increased incidence of new atrial fibrillation. The benefit/risk balance should be determined on a case-by-case basis with the greatest benefit of PFO closure in patients with atrial septal aneurysm and PFO with large shunts. Future studies should address unsolved questions such as the choice of medical therapy in patients not undergoing closure, the duration of antiplatelet therapy, and the role of PFO closure in patients over 60 years old.
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http://dx.doi.org/10.1093/eurheartj/suaa163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916420PMC
November 2020

Electrocardiographic features of immune checkpoint inhibitor associated myocarditis.

J Immunother Cancer 2021 Mar;9(3)

Department of Dermatology and Allergy, LMU Klinikum, Munich, Germany.

Background: Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis.

Methods: From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested.

Results: Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39).

Conclusions: The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.
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http://dx.doi.org/10.1136/jitc-2020-002007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929895PMC
March 2021

Anticoagulation in patients with atrial fibrillation and active cancer: an international survey on patient management.

Eur J Prev Cardiol 2021 May;28(6):611-621

School of Medicine, University of Insubria, Via Ravasi, 2, 21100 Varese, Italy.

Background: In patients with active cancer and atrial fibrillation (AF) anticoagulation, thrombotic and bleeding risk still entail uncertainty.

Aim: We explored the results of an international survey examining the knowledge and behaviours of a large group of physicians.

Methods And Results: A web-based survey was completed by 960 physicians (82.4% cardiologists, 75.5% from Europe). Among the currently available anticoagulants for stroke prevention in patients with active cancer, direct oral anticoagulants (DOACs) were preferred by 62.6%, with lower values for low molecular weight heparin (LMWH) (24.1%) and for warfarin (only 7.3%). About 46% of respondents considered that DOACs should be used in all types of cancers except in non-operable gastrointestinal cancers. The lack of controlled studies on bleeding risk (33.5% of respondents) and the risk of drug interactions (31.5%) were perceived as problematic issues associated with use of anticoagulants in cancer. The decision on anticoagulation involved a cardiologist in 27.8% of cases, a cardiologist and an oncologist in 41.1%, and a team approach in 21.6%. The patient also was involved in decision-making, according to ∼60% of the respondents. For risk stratification, use of CHA2DS2-VASc and HAS-BLED scores was considered appropriate, although not specifically validated in cancer patients, by 66.7% and 56.4%, respectively.

Conclusion: This survey highlights that management of anticoagulation in patients with AF and active cancer is challenging, with substantial heterogeneity in therapeutic choices. Direct oral anticoagulants seems having an emerging role but still the use of LMWH remains substantial, despite the absence of long-term data on thromboprophylaxis in AF.
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http://dx.doi.org/10.1093/eurjpc/zwaa054DOI Listing
May 2021

Risk stratification and management of women with cardiomyopathy/heart failure planning pregnancy or presenting during/after pregnancy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy.

Eur J Heart Fail 2021 04 17;23(4):527-540. Epub 2021 Mar 17.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

This position paper focusses on the pathophysiology, diagnosis and management of women diagnosed with a cardiomyopathy, or at risk of heart failure (HF), who are planning to conceive or present with (de novo or previously unknown) HF during or after pregnancy. This includes the heterogeneous group of heart muscle diseases such as hypertrophic, dilated, arrhythmogenic right ventricular and non-classified cardiomyopathies, left ventricular non-compaction, peripartum cardiomyopathy, Takotsubo syndrome, adult congenital heart disease with HF, and patients with right HF. Also, patients with a history of chemo-/radiotherapy for cancer or haematological malignancies need specific pre-, during and post-pregnancy assessment and counselling. We summarize the current knowledge about pathophysiological mechanisms, including gene mutations, clinical presentation, diagnosis, and medical and device management, as well as risk stratification. Women with a known diagnosis of a cardiomyopathy will often require continuation of drug therapy, which has the potential to exert negative effects on the foetus. This position paper assists in balancing benefits and detrimental effects.
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http://dx.doi.org/10.1002/ejhf.2133DOI Listing
April 2021

Cardio-oncology: rationale, aims and future directions.

Curr Opin Support Palliat Care 2021 Jun;15(2):134-140

Cardio-Oncology Service, Royal Brompton Hospital, London, UK.

Purpose Of Review: Cardiovascular comorbidity among cancer patients is a growing clinical problem with the dramatic improvements in cancer survival. Cardio-oncology has developed as a new medical field dedicated to addressing the complex issues faced by patients who have both cancer and cardiovascular disease. This article explains to the reader what cardio-oncology services provide and the nature of cardiovascular problems caused by the growing array of modern cancer therapies.

Recent Findings: The list of potentially cardiotoxic cancer therapeutic agents is ever growing and dedicated cardio-oncology experts are required to tackle cardiovascular complications with minimal delay to necessary cancer therapy. Cardio-oncology services originated in academic centres but are now being set up around the world in all hospitals and clinics that provide care to cancer patients. Cardio-oncology plays an increasingly active role at every stage of cancer therapy including baseline risk assessment pretreatment, surveillance and prevention during treatment, response to acute complications and assessment in survivors post cardiotoxic treatments. New treatment strategies exist to optimize cancer treatment so it can be completed safely.

Summary: In the present review, we explore the rationale, aims and roles of cardio-oncology, as well as future directions, which will certainly require multidisciplinary international collaboration.
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http://dx.doi.org/10.1097/SPC.0000000000000544DOI Listing
June 2021

Pathophysiology of Takotsubo Syndrome: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 Feb;77(7):902-921

Department of Molecular and Clinical Medicine/Cardiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: https://twitter.com/ElmirOmerovic2.

Takotsubo syndrome (TTS) has been a recognized clinical entity for 31 years, since its first description in 1990. TTS is now routinely diagnosed in patients who present with acute chest pain, electrocardiographic changes, troponin elevation, unobstructed coronary arteries, and a typical pattern of circumferential left ventricular wall motion abnormalities that usually involve the apical and midventricular myocardium. Increasing understanding of this intriguing syndrome stems from wider recognition, possible increasing frequency, and a rising number of publications focused on the pathophysiology in clinical and laboratory studies. A comprehensive understanding of TTS pathophysiology and evidence-based treatments are lacking, and specific and effective treatments are urgently required. This paper reviews the pathophysiology of this fascinating syndrome; what is known from both clinical and preclinical studies, including review of the evidence for microvascular dysfunction, myocardial beta-adrenergic signaling, inflammation, and electrophysiology; and where focused research needs to fill gaps in understanding TTS.
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http://dx.doi.org/10.1016/j.jacc.2020.10.060DOI Listing
February 2021

CMR unveiling the cause of post CoVid-19 infection chest pain.

Int J Cardiovasc Imaging 2021 Jun 28;37(6):2025-2026. Epub 2021 Jan 28.

Royal Brompton Hospital, London, UK.

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http://dx.doi.org/10.1007/s10554-021-02161-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841042PMC
June 2021

Risk of Cardiovascular Diseases Among Older Breast Cancer Survivors in the United States: A Matched Cohort Study.

J Natl Compr Canc Netw 2021 01 5:1-10. Epub 2021 Jan 5.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: It has been suggested that cardiovascular risks are increased in breast cancer survivors, but few studies have quantified the risks of a range of specific clinically important cardiovascular outcomes in detail.

Patients And Methods: Women aged >65 years with incident breast cancer from 2004 to 2013 in the SEER-Medicare linked database were matched with 5 cancer-free female counterparts (5:1 ratio). Prevalence of specific cardiovascular outcomes at baseline was measured, then Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals for the risk of individual cardiovascular outcomes during follow-up. Modification of the effect was investigated by time since diagnosis, race/ethnicity, prior cardiovascular disease (CVD), and age.

Results: In all, 91,473 women with breast cancer and 454,197 without breast cancer were included. Women with breast cancer had lower baseline prevalence of all CVDs. Compared with cancer-free controls, breast cancer survivors had substantially increased risks of deep vein thrombosis (adjusted HR, 1.67; 95% CI, 1.62-1.73; 386,484 person-years of follow-up) and pericarditis (HR, 1.43; 95% CI, 1.38-1.49; 390,776 person-years of follow-up); evidence of smaller increased risks of sudden cardiac arrest, arrhythmia, heart failure, and valvular heart disease (adjusted HRs ranging from 1.05-1.09, lower CI limits all ≥1); and evidence of lower risk of incident angina, myocardial infarction, revascularization, peripheral vascular disease, and stroke (adjusted HRs ranging from 0.89-0.98, upper CI limits all ≤1). Increased risks of arrhythmia, heart failure, pericarditis, and deep vein thrombosis persisted >5 years after cancer diagnosis.

Conclusions: Women with a history of breast cancer were at increased risk of several CVDs, persisting into survivorship. Monitoring and managing cardiovascular risk throughout the long-term follow-up of women diagnosed with breast cancer should be a priority.
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http://dx.doi.org/10.6004/jnccn.2020.7629DOI Listing
January 2021

Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

Eur J Heart Fail 2020 12 12;22(12):2272-2289. Epub 2020 Nov 12.

Medical University of Graz, University Heart Center - Division of Cardiology, Graz, Austria.

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.
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http://dx.doi.org/10.1002/ejhf.2029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894564PMC
December 2020

Heart Failure Association of the European Society of Cardiology update on sodium-glucose co-transporter 2 inhibitors in heart failure.

Eur J Heart Fail 2020 11 27;22(11):1984-1986. Epub 2020 Oct 27.

Centre for Heart Diseases, Faculty of Health Sciences, Wrocław Medical University, Wrocław, Poland.

The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) has recently issued a position paper on the role of sodium-glucose co-transporter 2 (SGLT2) inhibitors in heart failure (HF). The present document provides an update of the position paper, based of new clinical trial evidence. Accordingly, the following recommendations are given: • Canagliflozin, dapagliflozin empagliflozin, or ertugliflozin are recommended for the prevention of HF hospitalization in patients with type 2 diabetes mellitus and established cardiovascular disease or at high cardiovascular risk. • Dapagliflozin or empagliflozin are recommended to reduce the combined risk of HF hospitalization and cardiovascular death in symptomatic patients with HF and reduced ejection fraction already receiving guideline-directed medical therapy regardless of the presence of type 2 diabetes mellitus.
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http://dx.doi.org/10.1002/ejhf.2026DOI Listing
November 2020

Role of serum biomarkers in cancer patients receiving cardiotoxic cancer therapies: a position statement from the Cardio-Oncology Study Group of the Heart Failure Association and the Cardio-Oncology Council of the European Society of Cardiology.

Eur J Heart Fail 2020 11 20;22(11):1966-1983. Epub 2020 Oct 20.

Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands.

Serum biomarkers are an important tool in the baseline risk assessment and diagnosis of cardiovascular disease in cancer patients receiving cardiotoxic cancer treatments. Increases in cardiac biomarkers including cardiac troponin and natriuretic peptides can be used to guide initiation of cardioprotective treatments for cancer patients during treatment and to monitor the response to cardioprotective treatments, and they also offer prognostic value. This position statement examines the role of cardiac biomarkers in the management of cancer patients. The Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in collaboration with the Cardio-Oncology Council of the ESC have evaluated the current evidence for the role of cardiovascular biomarkers in cancer patients before, during and after cardiotoxic cancer therapies. The characteristics of the main two biomarkers troponin and natriuretic peptides are discussed, the link to the mechanisms of cardiovascular toxicity, and the evidence for their clinical use in surveillance during and after anthracycline chemotherapy, trastuzumab and HER2-targeted therapies, vascular endothelial growth factor inhibitors, proteasome inhibitors, immune checkpoint inhibitors, cyclophosphamide and radiotherapy. Novel surveillance clinical pathways integrating cardiac biomarkers for cancer patients receiving anthracycline chemotherapy or trastuzumab biomarkers are presented and future direction in cardio-oncology biomarker research is discussed.
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http://dx.doi.org/10.1002/ejhf.2017DOI Listing
November 2020

Prevention, Detection, and Management of Heart Failure in Patients Treated for Breast Cancer.

Curr Heart Fail Rep 2020 12 26;17(6):397-408. Epub 2020 Sep 26.

Department of Cardiology, Oslo University Hospital, Postbox 4950, Ullevål, Nydalen, 0424, Oslo, Norway.

Purpose Of Review: Long-term survival has increased significantly in breast cancer patients, and cardiovascular side effects are surpassing cancer-related mortality. We summarize risk factors, prevention strategies, detection, and management of cardiotoxicity, with focus on left ventricular dysfunction and heart failure, during breast cancer treatment.

Recent Findings: Baseline treatment of cardiovascular risk factors is recommended. Anthracycline and trastuzumab treatment constitute a substantial risk of developing cardiotoxicity. There is growing evidence that this can be treated with beta blockers and angiotensin antagonists. Early detection of cardiotoxicity with cardiac imaging and circulating cardiovascular biomarkers is currently evaluated in clinical trials. Chest wall irradiation accelerates atherosclerotic processes and induces fibrosis. Immune checkpoint inhibitors require consideration for surveillance due to a small risk of severe myocarditis. Cyclin-dependent kinases4/6 inhibitors, cyclophosphamide, taxanes, tyrosine kinase inhibitors, and endocrine therapy have a lower-risk profile for cardiotoxicity. Preventive and management strategies to counteract cancer treatment-related left ventricular dysfunction or heart failure in breast cancer patients should include a comprehensive cardiovascular risk assessment and individual clinical evaluation. This should include both patient and treatment-related factors. Further clinical trials especially on early detection, cardioprevention, and management are urgently needed.
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http://dx.doi.org/10.1007/s11897-020-00486-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683437PMC
December 2020

Reversible exercise-induced left ventricular dysfunction in symptomatic patients with previous Takotsubo syndrome: insights from stress echocardiography.

Eur Heart J Cardiovasc Imaging 2020 Sep 18. Epub 2020 Sep 18.

Department of Cardiology, Royal Brompton and Harefield NHS Trust, Sydney Street, London SW3 6NP, UK.

Aims : Takotsubo syndrome (TTS) is usually associated with rapid and spontaneous recovery of left ventricular (LV) function. However, a proportion of patients may have persistent symptoms. This study aimed to determine the haemodynamic and LV contractile responses to exercise in these patients.

Methods And Results: Thirty symptomatic TTS patients referred for exercise echocardiography, a median of 15 months following the index TTS episode, were matched with 30 controls with normal exercise echocardiography. Beta-blockers were withheld prior to the test. LV volumes, ejection fraction (EF) and wall motion score index (WMSI), were measured at rest and stress. The TTS cohort were Caucasian women with mean age of 64.6 ± 7.4 years and similar coronary risk factor profile and EF to controls. Resting systolic blood pressure (SBP), LV end-diastolic volume, wall stress, and right ventricular fractional area change were higher in TTS patients compared with controls. Stress echo data showed similar exercise time, peak heart rate, and peak SBP in TTS patients vs. controls, but TTS patients had higher LV volumes, lower exercise LVEF (70 ± 10% vs. 78 ± 7%; P = 0.001), ΔLVEF (4 ± 8% vs. 12 ± 5%; P < 0.001), and WMSI (1.4 ± 0.4 vs. 1 ± 0; P < 0.001) compared with controls. Twenty TTS patients had clear exercise-induced wall motion abnormalities, mainly involving the apex or more globally, with a mean ΔLVEF of 1% compared with 12% in controls. Among the other 10 TTS patients, the ΔLVEF was 10%.

Conclusion: Symptomatic patients with previous TTS have a blunted contractile response to exercise. The therapeutic and prognostic implications of these findings need further investigation.
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http://dx.doi.org/10.1093/ehjci/jeaa237DOI Listing
September 2020

Cardio-oncology care in the era of the coronavirus disease 2019 (COVID-19) pandemic: An International Cardio-Oncology Society (ICOS) statement.

CA Cancer J Clin 2020 11 10;70(6):480-504. Epub 2020 Sep 10.

Department of Cardiovascular Disease, Mayo Clinic, Rochester, Minnesota.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID-19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID-19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio-oncology and outlines key modifications in the approach to this ever-increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS-CoV-2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.
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http://dx.doi.org/10.3322/caac.21635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934086PMC
November 2020

Exercise-Induced Reversible Apical Ballooning in a Patient With Previous Takotsubo Syndrome and Ongoing Symptoms.

Circ Cardiovasc Imaging 2020 09 2;13(9):e010237. Epub 2020 Sep 2.

Royal Brompton and Harefield NHS Trust, Sydney Street, London, United Kingdom (H.Y.Y., K.W., A.J.B., A.R.L., R.S.K.).

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http://dx.doi.org/10.1161/CIRCIMAGING.119.010237DOI Listing
September 2020

Cardiovascular changes during peanut-induced allergic reactions in human subjects.

J Allergy Clin Immunol 2021 Feb 21;147(2):633-642. Epub 2020 Jul 21.

Section of Inflammation, Repair and Development, National Heart & Lung Institute, Imperial College London, London, United Kingdom.

Background: Food allergy is the most common cause of anaphylaxis. Changes in posture during acute reactions can trigger fatal outcomes, but the impact of allergic reactions on the cardiovascular system in nonfatal reactions remains poorly understood.

Objective: Our aim was to systematically evaluate changes in cardiovascular function during acute allergic reactions to peanut.

Methods: Participants underwent double-blind placebo-controlled food challenge to peanut as part of a clinical trial. Changes in hemodynamic parameters (heart rate, stroke volume, blood pressure, and peripheral blood flow) and electrocardiogram findings during food challenges were assessed using noninvasive continuous monitoring.

Results: A total of 57 adults (median age 24 years [interquartile range = 20-29]), 53% of whom were female, participated; 22 (39%) had anaphylaxis. Acute reactions were associated with significant changes in stroke volume (mean decrease of 4.2% [95% CI = 0.8-7.6; P = .03]), heart rate (mean increase 11.6% [95% CI = 8.4-14.8; P < .0001]), and peripheral blood flow (mean increase 19.7% [95% CI = 10.8-28.6; P < .0001]), irrespective of reaction severity. These changes were reproduced at a subsequent repeat peanut challenge in 26 participants, and could be reversed with administration of intravenous fluids which resulted in faster resolution of abdominal symptoms.

Conclusions: In this first detailed human study of cardiovascular changes during food-induced allergic reactions, we found evidence for significant fluid redistribution, independent of reaction severity. This provides a sound rationale for optimizing venous return during significant allergic reactions to food. Finally, these data provide a new paradigm for understanding severity in anaphylaxis, in which poor outcomes may occur as a result of a failure in compensatory mechanisms.
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http://dx.doi.org/10.1016/j.jaci.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858218PMC
February 2021

Cardiac dysfunction in cancer patients: beyond direct cardiomyocyte damage of anticancer drugs: novel cardio-oncology insights from the joint 2019 meeting of the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart.

Cardiovasc Res 2020 09;116(11):1820-1834

Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

In western countries, cardiovascular (CV) disease and cancer are the leading causes of death in the ageing population. Recent epidemiological data suggest that cancer is more frequent in patients with prevalent or incident CV disease, in particular, heart failure (HF). Indeed, there is a tight link in terms of shared risk factors and mechanisms between HF and cancer. HF induced by anticancer therapies has been extensively studied, primarily focusing on the toxic effects that anti-tumour treatments exert on cardiomyocytes. In this Cardio-Oncology update, members of the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart discuss novel evidence interconnecting cardiac dysfunction and cancer via pathways in which cardiomyocytes may be involved but are not central. In particular, the multiple roles of cardiac stromal cells (endothelial cells and fibroblasts) and inflammatory cells are highlighted. Also, the gut microbiota is depicted as a new player at the crossroads between HF and cancer. Finally, the role of non-coding RNAs in Cardio-Oncology is also addressed. All these insights are expected to fuel additional research efforts in the field of Cardio-Oncology.
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http://dx.doi.org/10.1093/cvr/cvaa222DOI Listing
September 2020

The Role of Biomarkers in Cardio-Oncology.

J Cardiovasc Transl Res 2020 06 8;13(3):431-450. Epub 2020 Jul 8.

Cardio-Oncology Service, Royal Brompton Hospital, Sydney St, Chelsea, London, SW3 6NP, UK.

In the field of cardio-oncology, it is well recognised that despite the benefits of chemotherapy in treating and possibly curing cancer, it can cause catastrophic damage to bystander tissues resulting in a range of potentially of life-threatening cardiovascular toxicities, and leading to a number of damaging side effects including heart failure and myocardial infarction. Cardiotoxicity is responsible for significant morbidity and mortality in the long-term in oncology patients, specifically due to left ventricular dysfunction. There is increasing emphasis on the early use of biomarkers in order to detect the cardiotoxicity at a stage before it becomes irreversible. The most important markers of cardiac injury are cardiac troponin and natriuretic peptides, whilst markers of inflammation such as interleukin-6, C-reactive protein, myeloperoxidase, Galectin-3, growth differentiation factor-15 are under investigation for their use in detecting cardiotoxicity early. In addition, microRNAs, genome-wide association studies and proteomics are being studied as novel markers of cardiovascular injury or inflammation. The aim of this literature review is to discuss the evidence base behind the use of these biomarkers for the detection of cardiotoxicity.
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http://dx.doi.org/10.1007/s12265-020-10042-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360533PMC
June 2020

Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC).

Eur J Heart Fail 2020 09 21;22(9):1504-1524. Epub 2020 Aug 21.

Department of Cardiology, Leiden University Medical Centre, Leiden, The Netherlands.

Cardiovascular (CV) imaging is an important tool in baseline risk assessment and detection of CV disease in oncology patients receiving cardiotoxic cancer therapies. This position statement examines the role of echocardiography, cardiac magnetic resonance, nuclear cardiac imaging and computed tomography in the management of cancer patients. The Imaging and Cardio-Oncology Study Groups of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in collaboration with the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the ESC have evaluated the current evidence for the value of modern CV imaging in the cardio-oncology field. The most relevant echocardiographic parameters, including global longitudinal strain and three-dimensional ejection fraction, are proposed. The protocol for baseline pre-treatment evaluation and specific surveillance algorithms or pathways for anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor tyrosine kinase inhibitors, BCr-Abl tyrosine kinase inhibitors, proteasome inhibitors and immune checkpoint inhibitors are presented. The indications for CV imaging after completion of oncology treatment are considered. The typical consequences of radiation therapy and the possibility of their identification in the long term are also summarized. Special populations are discussed including female survivors planning pregnancy, patients with carcinoid disease, patients with cardiac tumours and patients with right heart failure. Future directions and ongoing CV imaging research in cardio-oncology are discussed.
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http://dx.doi.org/10.1002/ejhf.1957DOI Listing
September 2020

Sodium-glucose co-transporter 2 inhibitors in heart failure: beyond glycaemic control. A position paper of the Heart Failure Association of the European Society of Cardiology.

Eur J Heart Fail 2020 09 5;22(9):1495-1503. Epub 2020 Aug 5.

Department of Internal Medicine, and Department of Research and Education, General Hospital Murska Sobota, Murska Sobota, Slovenia.

Heart failure (HF) is common and associated with a poor prognosis, despite advances in treatment. Over the last decade cardiovascular outcome trials with sodium-glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus have demonstrated beneficial effects for three SGLT2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) in reducing hospitalisations for HF. More recently, dapagliflozin reduced the risk of worsening HF or death from cardiovascular causes in patients with chronic HF with reduced left ventricular ejection fraction, with or without type 2 diabetes mellitus. A number of additional trials in HF patients with reduced and/or preserved left ventricular ejection fraction are ongoing and/or about to be reported. The present position paper summarises recent clinical trial evidence and discusses the role of SGLT2 inhibitors in the treatment of HF, pending the results of ongoing trials in different populations of patients with HF.
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http://dx.doi.org/10.1002/ejhf.1954DOI Listing
September 2020

Cancer and cardiovascular disease - Authors' reply.

Lancet 2020 06;395(10241):1904-1905

Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(20)30232-4DOI Listing
June 2020
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