Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an ...immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.
Peripartum cardiomyopathy (PPCM) is a potentially life‐threatening condition typically presenting as heart failure with reduced ejection fraction (HFrEF) in the last month of pregnancy or in the ...months following delivery in women without another known cause of heart failure. This updated position statement summarizes the knowledge about pathophysiological mechanisms, risk factors, clinical presentation, diagnosis and management of PPCM. As shortness of breath, fatigue and leg oedema are common in the peripartum period, a high index of suspicion is required to not miss the diagnosis. Measurement of natriuretic peptides, electrocardiography and echocardiography are recommended to promptly diagnose or exclude heart failure/PPCM. Important differential diagnoses include pulmonary embolism, myocardial infarction, hypertensive heart disease during pregnancy, and pre‐existing heart disease. A genetic contribution is present in up to 20% of PPCM, in particular titin truncating variant. PPCM is associated with high morbidity and mortality, but also with a high probability of partial and often full recovery. Use of guideline‐directed pharmacological therapy for HFrEF is recommended in all patients respecting contraindications during pregnancy/lactation. The oxidative stress‐mediated cleavage of the hormone prolactin into a cardiotoxic fragment has been identified as a driver of PPCM pathophysiology. Pharmacological blockade of prolactin release using bromocriptine as a disease‐specific therapy in addition to standard therapy for heart failure treatment has shown promising results in two clinical trials. Thresholds for devices (implantable cardioverter‐defibrillators, cardiac resynchronization therapy and implanted long‐term ventricular assist devices) are higher in PPCM than in other conditions because of the high rate of recovery. The important role of education and counselling around contraception and future pregnancies is emphasised.
Driven by enormous clinical need, myocardial tissue engineering has become a prime focus of research within the field of tissue engineering. Myocardial tissue engineering combines isolated functional ...cardiomyocytes and a biodegradable or nondegradable biomaterial to repair diseased heart muscle. The challenges in heart muscle engineering include cell related issues (such as scale up in a short timeframe, efficiency of cell seeding or cell survival rate, and immune rejection), the design and fabrication of myocardial tissue engineering substrates, and the engineering of tissue constructs
in vitro and
in vivo. Several approaches have been put forward, and a number of models combining various polymeric biomaterials, cell sources and bioreactors have been developed in the last 10 years for myocardial tissue engineering. This review provides a comprehensive update on the biomaterials, as well as cells and biomimetic systems, used in the engineering of the cardiac muscle. The article is organized as follows. A historic perspective of the evolution of cardiac medicine and emergence of cardiac tissue engineering is presented in the first section. Following a review on the cells used in myocardial tissue engineering (second section), the third section presents a review on biomaterials used in myocardial tissue engineering. This section starts with an overview of the development of tissue engineering substrates and goes on to discuss the selection of biomaterials and design of solid and porous substrates. Then the applications of a variety of biomaterials used in different approaches of myocardial tissue engineering are reviewed in great detail, and related issues and topics that remain challenges for the future progress of the field are identified at the end of each subsection. This is followed by a brief review on the development of bioreactors (fourth section), which is an important achievement in the field of myocardial tissue engineering, and which is also related to the biomaterials developed. At the end of this article, the major achievements and remaining challenges are summarized, and the most promising paradigm for the future of heart muscle tissue engineering is proposed (fifth section).
Advances in cancer therapy have resulted in significant improvement in long-term survival for many types of cancer but have also resulted in untoward side effects associated with treatment. One such ...complication that has become increasingly recognized is the development of cardiomyopathy and heart failure. Whether a previously healthy person from a cardiovascular perspective develops cancer therapy-related cardiac dysfunction or a high-risk cardiovascular patient requires cancer therapy, the team of oncologists and cardiologists must be better equipped with an evidence-based approach to care for these patients across the spectrum. Although the toxicities associated with various cancer therapies are well recognized, limitations to our understanding of the appropriate course of action remain. In this first of a 2-part review, we discuss the epidemiologic, pathophysiologic, risk factors, and imaging aspects of cancer therapy-related cardiac dysfunction and heart failure. In a subsequent second part, we discuss the prevention and treatment aspects, concluding with a section on evidence gap and future directions. We focus on adult patients in all stages of cancer therapy from pretreatment surveillance, to ongoing therapy, and long-term follow-up.
T-tubular invaginations of the sarcolemma of ventricular cardiomyocytes contain junctional structures functionally coupling L-type calcium channels to the sarcoplasmic reticulum calciumrelease ...channels (the ryanodine receptors), and therefore their configuration controls the gain of calcium-induced calcium release (CICR). Studies primarily in rodent myocardium have shown the importance of T-tubular structures for calcium transient kinetics and have linked T-tubule disruption to delayed CICR. However, there is disagreement as to the nature of T-tubule changes in human heart failure. We studied isolated ventricular myocytes from patients with ischemic heart disease, idiopathic dilated cardiomyopathy, and hypertrophic obstructive cardiomyopathy and determined T-tubule structure with either the fluorescent membrane dye di-8-ANNEPs or the scanning ion conductance microscope (SICM). The SICM uses a scanning pipette to produce a topographic representation of the surface of the live cell by a non-optical method. We have also compared ventricular myocytes from a rat model of chronic heart failure after myocardial infarction. T-tubule loss, shown by both ANNEPs staining and SICM imaging, was pronounced in human myocytes from all etiologies of disease. SICM imaging showed additional changes in surface structure, with flattening and loss of Z-groove definition common to all etiologies. Rat myocytes from the chronic heart failure model also showed both T-tubule and Z-groove loss, as well as increased spark frequency and greater spark amplitude. This study confirms the loss of T-tubules as part of the phenotypic change in the failing human myocyte, but it also shows that this is part of a wider spectrum of alterations in surface morphology.
IMPORTANCE Risk stratification of patients with nonischemic dilated cardiomyopathy is primarily based on left ventricular ejection fraction (LVEF). Superior prognostic factors may improve patient ...selection for implantable cardioverter-defibrillators (ICDs) and other management decisions. OBJECTIVE To determine whether myocardial fibrosis (detected by late gadolinium enhancement cardiovascular magnetic resonance LGE-CMR imaging) is an independent and incremental predictor of mortality and sudden cardiac death (SCD) in dilated cardiomyopathy. DESIGN, SETTING, AND PATIENTS Prospective, longitudinal study of 472 patients with dilated cardiomyopathy referred to a UK center for CMR imaging between November 2000 and December 2008 after presence and extent of midwall replacement fibrosis were determined. Patients were followed up through December 2011. MAIN OUTCOME MEASURES Primary end point was all-cause mortality. Secondary end points included cardiovascular mortality or cardiac transplantation; an arrhythmic composite of SCD or aborted SCD (appropriate ICD shock, nonfatal ventricular fibrillation, or sustained ventricular tachycardia); and a composite of HF death, HF hospitalization, or cardiac transplantation. RESULTS Among the 142 patients with midwall fibrosis, there were 38 deaths (26.8%) vs 35 deaths (10.6%) among the 330 patients without fibrosis (hazard ratio HR, 2.96 95% CI, 1.87-4.69; absolute risk difference, 16.2% 95% CI, 8.2%-24.2%; P < .001) during a median follow-up of 5.3 years (2557 patient-years of follow-up). The arrhythmic composite was reached by 42 patients with fibrosis (29.6%) and 23 patients without fibrosis (7.0%) (HR, 5.24 95% CI, 3.15-8.72; absolute risk difference, 22.6% 95% CI, 14.6%-30.6%; P < .001). After adjustment for LVEF and other conventional prognostic factors, both the presence of fibrosis (HR, 2.43 95% CI, 1.50-3.92; P < .001) and the extent (HR, 1.11 95% CI, 1.06-1.16; P < .001) were independently and incrementally associated with all-cause mortality. Fibrosis was also independently associated with cardiovascular mortality or cardiac transplantation (by fibrosis presence: HR, 3.22 95% CI, 1.95-5.31, P < .001; and by fibrosis extent: HR, 1.15 95% CI, 1.10-1.20, P < .001), SCD or aborted SCD (by fibrosis presence: HR, 4.61 95% CI, 2.75-7.74, P < .001; and by fibrosis extent: HR, 1.10 95% CI, 1.05-1.16, P < .001), and the HF composite (by fibrosis presence: HR, 1.62 95% CI, 1.00-2.61, P = .049; and by fibrosis extent: HR, 1.08 95% CI, 1.04-1.13, P < .001). Addition of fibrosis to LVEF significantly improved risk reclassification for all-cause mortality and the SCD composite (net reclassification improvement: 0.26 95% CI, 0.11-0.41; P = .001 and 0.29 95% CI, 0.11-0.48; P = .002, respectively). CONCLUSIONS AND RELEVANCE Assessment of midwall fibrosis with LGE-CMR imaging provided independent prognostic information beyond LVEF in patients with nonischemic dilated cardiomyopathy. The role of LGE-CMR in the risk stratification of dilated cardiomyopathy requires further investigation.
Aims
Cardio‐oncology clinics optimise the cardiovascular status of cancer patients but there is a limited description of their structure, case mix, activity and results. The purpose of this paper is ...to describe the activity and outcomes of a cardio‐oncology service, particularly with respect to supporting optimal cancer treatment and survival.
Methods and results
We prospectively studied patients referred to our service from February 2011 to February 2016. New York Heart Association (NYHA) class and parameters of cardiac function were measured at baseline and after optimisation by our service. Up‐titration of cardiac treatment, continuation of cancer therapy and mortality were used as outcome measures. Of the 535 patients (55.8% females) referred, rates of cardiotoxicity for anthracyclines, anti‐HER2 agents and tyrosine kinase inhibitors were 75.8%, 69.8% and 62.1%, respectively. Patients with left ventricular systolic dysfunction (LVSD) (n =128) were younger, had higher rates of hypertension and previous exposure to chemotherapy/radiotherapy (P < 0.001). At a median follow‐up of 360 days, 93.8% of the patients with LVSD showed improvement in left ventricular ejection fraction (45% pre vs. 53% post; P < 0.001) and NYHA class (NYHA III–IV in 22% pre vs. 10% post; P = 0.01). All patients with normal left ventricular ejection fraction and biochemical or functional myocardial toxicity and 88% of patients with LVSD were deemed fit for continuation of cancer therapy after cardiovascular optimisation.
Conclusions
Through the establishment of a cardio‐oncology service, it is feasible to achieve high rates of cardiac optimisation and cancer treatment continuation.
Echocardiography is frequently the initial noninvasive imaging modality used to assess patients with takotsubo cardiomyopathy (TTC). Standard transthoracic echocardiography can provide, even in the ...acute care setting, useful information about left ventricular (LV) morphology as well as regional and global systolic or diastolic function. It allows the differentiation of different LV morphologic patterns according to the localization of wall motion abnormalities. A "circumferential pattern" of LV myocardial dysfunction characterized by symmetric wall motion abnormalities involving the midventricular segments of the anterior, inferior, and lateral walls should be considered suggestive of TTC and included in the differential diagnosis of acute coronary syndromes. Moreover, advanced echocardiographic techniques, including speckle-tracking, myocardial contrast, and coronary flow studies, are providing mechanistic and pathophysiologic insights into this unique syndrome. Early identification of any potential complications (i.e., LV outflow tract obstruction, reversible moderate to severe mitral regurgitation, right ventricular involvement, thrombus formation, and cardiac rupture) are crucial for the management, risk stratification, and follow-up of patients with TTC. Because of the dynamic evolution of the syndrome, comprehensive serial echocardiographic examinations should be systematically performed. This review focuses on these aspects of imaging and the increasing understanding of the clinical and prognostic utility of echocardiography in TTC.
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