What is the relationship between cardiorespiratory fitness (CRF) and the risk of atrial fibrillation (AF)?

The FIT project study group consisted of 64,561 adults (mean age, 55 years; 46% female; 64% whites) who underwent clinically indicated exercise treadmill testing (ETT).

There were 4,616 new cases of AF over a median follow-up period of 5.4 years. The unadjusted 5-year cumulative incidence of AF with respect to the level of CRF (< 6 METs, 6-9 METs, 10-11 METs, and >11 METs) was 19%, 10%, 5%, and 4%, respectively. Each additional MET achieved on stress testing was associated with a 7% lower risk of developing AF.

The inverse relationship between CRF and AF was stronger in obese patients. The authors concluded that there is an inverse relationship between performance on ETT and the incidence of AF. The mechanisms underlying the inverse relationship between fitness and AF risk remain unclear.

AF is perpetuated by structural remodelling of the atria, manifested by fibrosis, which not only affects the left atrium, but also other atrial regions, such as the sinus node. It is possible that some patients with poor CRF were unable to exercise further due to chronotropic incompetence, in addition to other causes, such as deconditioning and coexisting comorbidities.

Recent studies have also suggested that elite athletes may be more likely to develop AF. The above-described study cannot address this finding since such individuals would be very unlikely to have been referred for exercise testing.
Source:

Cardiorespiratory Fitness and Risk of Incident Atrial Fibrillation: Results From the Henry Ford Exercise Testing (FIT) Project. Circulation 2015;Apr 22.

Many of the chemotherapeutic agents in use today can have associated cardiovascular side effects, the most common of which are cardiomyopathy and heart failure (HF). Amongst the various medications, the anthracycline class of drugs (e.g., doxorubicin and epirubicin) and the human epidermal growth factor receptor type 2 (HER 2) monoclonal antibody, trastuzumab, have been most commonly implicated and best studied. A recent meta-analysis of 55 published randomized controlled trials showed that the use of anthracycline-based versus nonanthracycline-based regimens was associated with a significantly increased risk of both clinical and subclinical cardiotoxicity. Despite this toxicity, anthracyclines remain the cornerstone of treatment in many malignancies, including lymphomas, leukaemias, and sarcomas, and are still widely used in both advanced and early-stage breast cancer. Combined therapy generally increases the incidence of cardiotoxicity.

The mortality rate among patients with cancer has decreased over the past 20 to 30 years. However, cardiac toxicity (cardiotoxicity) from cancer therapy has become a leading cause of morbidity and mortality in survivors. In patients who develop heart failure (HF) from cancer therapy, the mortality rate is as high as 60% by 2 years. Therefore, contemporary management of patients with cancer should include careful consideration of potential cardiotoxicity during therapy, with a focus on early detection and intervention.

Two types of cardiomyopathy have been defined to distinguish anthracycline-induced myocardial damage (type I) from trastuzumab-induced myocardial dysfunction (type II). Type I cardiomyopathy is related to the cumulative dose, is largely irreversible, and results from free radical formation and mitochondrial dysfunction ultimately leading to myofibrillar disarray and necrosis. In contrast, type II cardiomyopathy is not dose-related, may be reversible, and results in no apparent ultrastructural changes. Several definitions of cardiotoxicity have been proposed. The most commonly used definition is a ≥ 5% reduction in symptomatic patients (or ≥10% reduction in asymptomatic patients) in the left ventricular ejection fraction (LVEF) from baseline to an LVEF < 55%. Early detection of cardiotoxicity has predominantly relied upon serial cardiac imaging to identify a reduction in left ventricular (LV) function without signs or symptoms of heart failure (stage B HF).

The PREDICT study is a prospective, community-based study of 597 cancer patients undergoing anthracycline-based chemotherapy in 24 community oncology programs. It is primarily a study of the effectiveness of using cardiac biomarkers to predict cardiotoxicity, along with an analysis of the results of various forms of treatment of the cardiotoxicity. During up to 12 months of follow-up, 11% of PREDICT participants experienced a cardiac event, most commonly symptomatic heart failure or a greater than 10% drop in left ventricular ejection fraction, which took a patient from normal range to below normal. Another impressive finding was the substantial burden of conventional cardiovascular risk factors present at baseline in patients scheduled for anthracycline-based chemotherapy. In a multivariate logistic regression analysis, the higher a cancer patient’s cardiovascular risk factor level, the greater the likelihood of chemotherapy-related cardiotoxicity.  A baseline B-type natriuretic peptide (BNP) level in excess of 100 pg/mL was a powerful predictor of a chemotherapy-related cardiac event, with an associated 2.1-fold increased risk. As a predictor of cardiotoxicity during the study period, baseline BNP had a sensitivity of 35%, a specificity of 85%, a positive predictive value of 22%, and – most importantly – a negative predictive value of 92%.

One predictor is the patient’s type of cancer. In PREDICT, patients with lymphoma had a twofold greater risk of developing treatment-related cardiotoxicity, compared with those with breast cancer. Moreover, those with a cancer diagnosis other than lymphoma or breast cancer had a fivefold greater risk than breast cancer patients.

Myocardial imaging as a tool for predicting which patients will develop cardiotoxicity during or after cancer therapy is another active area of investigation.

The use of LVEF has important limitations. First, the measurement of LVEF is subject to technique-related variability, which can be higher than the thresholds used to define cardiotoxicity. Second, the reduction in LVEF is often a late phenomenon, with failure to recover systolic function in up to 58% of patients despite intervention.

Other investigators have shown that myocardial deformation (strain imaging) with speckle tracking echocardiography (STE) holds considerable promise as a tool for predicting which patients will develop cardiotoxicity during or after cancer therapy. Reductions in echocardiographic measures of myocardial deformation parameters (strain and strain rate) are a sign of subclinical myocardial changes from cancer therapy and occur prior to any change in LVEF as assessed by conventional 2D echocardiography.

Importantly, early reduction in myocardial deformation appears to forecast the development of subsequent cardiotoxicity, with STE measured global longitudinal strain (GLS) being the most consistent parameter. The thresholds of change in GLS to predict cardiotoxicity have ranged from 10% to 15% using STE. An early fall in GLS by STE between 10% and 15% predicts subsequent cardiotoxicity (including both asymptomatic and symptomatic LV dysfunction).

Hence, there has been a growing interest in markers of early myocardial changes (i.e., changes with normal LVEF) that may predict the development of subsequent LVEF reduction or the progression to HF, so that preventive strategies with established cardioprotective medications such as beta-blockers, angiotensin-converting enzyme inhibitors, or dexrazoxane could be implemented.

When treatment with enalapril and carvedilol was initiated within the first couple of months following the end of chemotherapy, 64% of patients experienced complete recovery of their LVEF. When the heart failure medications were commenced 3-4 months after completing chemotherapy, the LVEF recovery rate dropped to 28%. No complete recovery of LVEF occurred in patients who began enalapril plus carvedilol after 6 months. Predictors of increased risk are helpful in identifying cancer therapy-related cardiotoxicity early in its course when aggressive treatment with standard heart failure medications such as beta-blockers and ACE inhibitors (ACEI) is most likely to be beneficial. Complete LVEF recovery and associated cardiac events reduction may be achieved when cardiac dysfunction is detected early and treatment with ACEI, possibly in combination with beta-blockers, is promptly initiated.

Source:

. Thavendiranathan P, et al. Use of Myocardial Strain Imaging by Echocardiography for the Early Detection of Cardiotoxicity in Patients During and After Cancer Chemotherapy: A Systematic Review. J Am Coll Cardiol. 2014;63(25_PA):2751-2768. doi:10.1016/j.jacc.2014.01.073

. Cardinale D, et al. Anthracycline-Induced Cardiomyopathy: Clinical Relevance and Response to Pharmacologic Therapy. J Am Coll Cardiol. 2010;55(3):213-220. doi:10.1016/j.jacc.2009.03.095

The mortality rate among patients with cancer has decreased over the past 20 to 30 years. However, cardiac toxicity (cardiotoxicity) from cancer therapy has become a leading cause of morbidity and mortality in survivors. In patients who develop heart failure (HF) from cancer therapy, the mortality rate is as high as 60% by 2 years. Therefore, contemporary management of patients with cancer should include careful consideration of potential cardiotoxicity during therapy, with a focus on early detection and intervention.

Several definitions of cardiotoxicity have been proposed. The most commonly used definition is a ≥ 5% reduction in symptomatic patients (or ≥10% reduction in asymptomatic patients) in the left ventricular ejection fraction (LVEF) from baseline to an LVEF < 55%. Early detection of cardiotoxicity has predominantly relied upon serial cardiac imaging to identify a reduction in left ventricular (LV) function without signs or symptoms of heart failure (stage B HF).

The use of LVEF has important limitations. First, the measurement of LVEF is subject to technique-related variability, which can be higher than the thresholds used to define cardiotoxicity. Second, the reduction in LVEF is often a late phenomenon, with failure to recover systolic function in up to 58% of patients despite intervention. Hence, there has been a growing interest in markers of early myocardial changes (i.e., changes with normal LVEF) that may predict the development of subsequent LVEF reduction or the progression to HF, so that preventive strategies with established cardioprotective medications such as beta-blockers, angiotensin-converting enzyme inhibitors, or dexrazoxane could be implemented.

All studies of early myocardial changes with chemotherapy demonstrate that alterations of myocardial deformation precede significant change in left ventricular ejection fraction (LVEF). Using tissue Doppler-based strain imaging, peak systolic longitudinal strain rate has most consistently detected early myocardial changes during therapy, whereas with speckle tracking echocardiography (STE), peak systolic global longitudinal strain (GLS) appears to be the best measure. A 10% to 15% early reduction in GLS by STE during therapy appears to be the most useful parameter for the prediction of cardiotoxicity, defined as a drop in LVEF or heart failure.

A systemic review published in July 2014 in the American Journal of Cardiology (JACC), by P. Thavendiranathan et al.,  confirms the value of echocardiographic myocardial deformation (strain imaging) parameters for the early detection of myocardial changes and prediction of cardiotoxicity in patients receiving cancer therapy.

These results can be summarized into the following key points:

1. Cardiotoxicity from cancer therapy is a leading cause of morbidity and mortality in cancer survivors, and is most typically defined as a decrease in left ventricular ejection fraction (LVEF) by ≥ 5% or ≥ 10% for symptomatic and asymptomatic patients, respectively. As early identification may alter management and attenuate cardiotoxicity, there is a need for early markers of cardiotoxicity before a significant change in EF occurs.
2. Echocardiographic assessment of LVEF or diastolic function does not appear to be able to identify cardiotoxicity at an early subclinical phase.
3. Existing studies consistently identify that changes in myocardial deformation happen earlier than changes in LVEF. Using two-dimensional strain imaging, global longitudinal strain is more reproducible than other measures of strain such as global radial strain or global circumferential strain. Using tissue Doppler-based imaging, longitudinal strain rate appears to be a consistent marker of changes in myocardial deformation, while other measures appear to be less reliable.
4. On a review of the literature examining the prognostic value of strain imaging in chemotherapy patients, an early decrease of 10-11% (95% confidence interval, 8-15%) in global longitudinal strain predicts cardiotoxicity. Other individual markers have not been predictive, although combined use of global longitudinal strain and LV twist may be a better predictor than the former variable alone.
5. Late cardiotoxicity can be observed several years after chemotherapy is completed. While there are multiple studies examining myocardial deformation during a longer-term follow-up after treatment, the relationship of abnormal findings and prognosis remains uncertain.
6. Radiotherapy may also be associated with early changes of the myocardium, and some literature has observed a change in myocardial deformation immediately following treatment, although separating the effects from radiotherapy and chemotherapy is difficult, as they are often used simultaneously.
7. Current recommendations for cardiac evaluation of patients prior to cancer treatment are variable and not specific. While multiple modalities can be used, echocardiography has advantages given its versatility, low cost, and excellent safety profile.
8. While normal ranges for global longitudinal strain from a recent meta-analysis suggest a normal cutoff of -19% to -22%, there is significant between-patient variability, suggesting that within-patient changes in strain may be more reliable than population-based thresholds.
9. While strain imaging is a promising method to identify early cardiotoxicity, further multicenter study is needed that includes cancers other than breast cancer, and compares management and outcomes between patients initiated on cardioprotective therapy on the basis of strain imaging versus traditional measures such as LVEF.

Source:

Thavendiranathan P, Poulin F, Lim KD, Plan JC, Woo A, Marwick TH. Use of Myocardial Strain Imaging by Echocardiography for the Early Detection of Cardiotoxicity in Patients During and After Cancer Chemotherapy – A Systematic Review J Am Coll Cardiol. 2014;63(25_PA):2751-2768. doi:10.1016/j.jacc.2014.01.073

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