Is heart rate in post-hematopoietic stem cell transplant patients clinically relevant?

ABSTRACT

Patients with hematological malignancies undergoing hematopoietic stem cell transplantation (HSCT) have become a critical treatment option in the treatment of many hematological malignancies, myeloproliferative disorders, and some solid tumors.

Although HSCT has the potential of offering either a cure or minimizing disease burden while improving overall survival, HSCT is associated with some morbidity and mortality, particularly hypertension, diabetes, dyslipidemia, and renal disease with an increased cumulative incidence of cardiovascular (CVD) complications.

Aside from the usual heart failure and arrhythmias, a less described complication is sinus tachycardia. The latter was once considered an innocuous finding in post-HSCT patients and mostly attributed to dehydration, low counts, deconditioning, chemotherapy, and/or infection.

However, new data has shown that a number of these post-HSCT patients may harbor inappropriate sinus tachycardia, which can be associated with the eventual development of heart failure if not identified and treated.

We believe that discussion of this topic not only is needed to raise awareness of this condition as patients might no longer be under the care of their oncologists but, most importantly, could be seen at any age, and general health practitioners might otherwise not be aware of this literature.

KEYWORDS:

• Sinus tachycardia
• arrhythmia
• autonomic dysfunction
• hematologic malignancies
• bone marrow transplant
• oncology

Since the advent of hematopoietic stem cell transplantation (HSCT) [1], the intravenous infusion of hematopoietic stem and progenitor cells has become a critical therapeutic intervention in treatment to establish marrow and immune function in a wide array of patients afflicted with either acquired or inherited malignant as well as nonmalignant clinical entities [2].

Regardless of which HSCT (allogenic, autologous, or syngeneic) category is selected, this intervention, which is intrinsically dependent on donor availability, transplantation indication, and the overall medical condition of the recipient [1,2], offers the potential of a cure or minimizing disease burden while improving overall survival has been undeniable [3]. Unfortunately, follow-up data has shown the occurrence of late complications that increase morbidity and mortality [1,4].

Specifically, not only HSCT recipients are prone to develop hypertension, diabetes, dyslipidemia, and renal disease and late cardiovascular (CVD) complications compared to the general population, but also, HSCT recipients are more likely to die from CVD complications (3.6 per 1000 person-years [95% CI, 1.7–5.5]) [5].

These CVD complications can be either found during the acute post- HSCT or in long-term survivors [6]. Most of the acute-phase CVD events are arrhythmias that can occur either the first 100 days post HSCT or later [7]. Aside from except complications due to overwhelming infection, cases of rapidly progressive heart failure, cardiac tamponade, and ventricular arrhythmias were initially reported during the acute HSCT phase [8]. However, with improved protocols and timely pretransplant screening for cardiac risk factors, these complications have diminished significantly [6]. Unfortunately, patients surviving the initial 100 days post HSCT still remain at risk with a reported 10-year cumulative incidence of developing hypertension (37.7%), type 2 diabetes mellitus (18.1%), and dyslipidemia (46.7%) [9]. Moreover, direct exposure to cardiotoxic chemotherapy and in some cases radiation places patients at risk for late CVD complications, particularly in patients with a frail CVD reserve pretransplant.

Of particular importance to this writing is the development of arrhythmias [6]. The risk of developing arrhythmias post HSCT has been shown to increase with age, presence of obesity, grade 2–4 graft-versus-host reaction, and anthracyclines use [6]. Furthermore, the presence of a low ejection fraction, renal dysfunction, or supraventricular complexes during the pretransplant evaluation have all also been recognized as risk factors for the development of arrhythmias post HSCT [6].

Atrial fibrillation followed by atrial flutter and supraventricular arrhythmias have been the most common arrhythmias seen post HSCT, occurring between 9 and 27% of both autologous and allogenic HSCT cases [10]. Not only are these arrhythmias associated with longer hospital stays and admission costs but also with increased risk mortality [10].

A less commonly mentioned cardiac arrhythmia among HSCT recipients is sinus tachycardia (ST). Traditionally, ST has been attributed to one of several potential mechanisms including (a) an ectopic atrial focus in the sinus node region, (b) normal sinus node with increased sympathetic tone or failure to respond to vagal stimulation, or (c) by an intrinsic abnormality of the sinus node that is usually triggered by some underlying pathological entity clearly described elsewhere [11–13].

In contrast, inappropriate ST (IST) individuals suffer from an increased resting heart rate (HR). Although no specific HR best defines IST, the traditional criterion of diagnosis requires a resting daytime sinus rate of more than 100 beats/min with average 24-h HRs of more than 90 beats/min that could not be otherwise explained by any physiological, psychological, or substances and drugs known to increase HR [11,13]. In addition to HR, patients with IST often are afflicted with multiple, incapacitating or disabling symptoms including palpitations, dyspnea, dizziness, lightheadedness, and near syncope that might not be at all dependent on HR alone [11,13].

In fact, the critical difference between ST and IST is that the former generally is explainable while the cause of IST is not quite easily apparent and in most cases difficult to characterize. In fact, symptomatic IST patients may include a spectrum of disorders related to increased sinus node automaticity, disordered autonomic activation, or both [11,13].

It is our belief that lack of data regarding the occurrence of ST either immediately post transplant or months and years post HSCT is probably attributed to a previously preconceived notion of the inconsequential nature of ST in this setting. Likely ST was probably attributed to low counts, dehydration, poor nutrition, deconditioning, and fatigue once infection was excluded in these patients.

Proper documentation of HR in post-HSCT patients did not became clinically relevant until Deuring et al. published their results on cardiac autonomic function [14]. These investigators studied HR and respiratory sinus arrhythmia on 145 allo-HSCT patients and compared these data to that obtained from age- and gender-matched controls [14]. After a mean follow-up of 4.3 years post transplant, these investigators noted that not only post-HSCT patients had persistently higher mean HR values and greater degree of sinus arrhythmia than controls but also lower parasympathetic control [14]. More importantly, these results were translated into more complaints of fatigue with lower degrees of fitness scores among HSCT patients than the control group [14].

More importantly, data from Noor et al. studying a total of 282 cancer survivors, 7% of which had hematological disorders, not only found that 22 of these patients had some degree of autonomic impairment but also IST was identified in 20.8% of these cancer patients [15]. Even though this was a small and retrospective analysis with data coming from a single center, this is valuable information not only regarding the identification of autonomic dysfunction but also finding IST as one of the manifestations of autonomic impairment [15]. This data adds to the available information linking tachycardia that has been seen among breast cancer patients previously treated with anthracyclines as well as Hodgkin’s disease patients after radiation treatment [16,17].

These studies provide compelling evidence that cancer treatments might in fact be associated with alterations of the autonomic system that require better documentation. Clinically, simple assessments of resting HR and/or the presence of postural symptoms might identify a group of individuals in whom a more comprehensive evaluation might be required once the usual suspects of dehydration, anxiety, low counts, infection, and deconditioning have been properly excluded.

Even when managing IST by simply controlling symptoms and reducing HR, which might not be at all related but in fact challenging in cancer patients, the most important clinical aspect of recognizing an abnormal resting HR is identifying the trigger. Which physiological or psychological trigger(s) are involved in this abnormal response? [11,13] Although most of the IST patients are generally healthy [11,13], the occurrence of IST among cancer patients in general, particularly post HSCT, has not been characterized, and this remains as an area of uncertainty. Albeit IST rarely results in cardiomyopathy [11,13], persistent elevation of the resting HR or an inappropriate increase in HR with minimal physical activity is known to alter left ventricular systolic and diastolic function [18]. More specifically, excessive HR was shown to reduce upright cardiac output in young healthy controls aged 13–23 years [18], so we can only speculate what tachycardia might do in older patients, in those post HSCT, and those with coexisting cardiac conditions or those exposed to certain drugs [19]. Finally, it is also important to remember that it is not uncommon for tachycardia-induced cardiomyopathy to occur months to years after the initial onset of ST [16,17].

It is our belief that awareness of the potential occurrence of ST among post-HSCT patients and better documentation of HR both in the immediate and upon follow-up visits are needed if the clinical relevance of this arrhythmia could be more widely known. First, proper documentation of its prevalence is required. Even when the surrogate outcome of HR by itself might not be sufficient, availability of blood pressure readings and documentation of fatigue levels should be readily available among all HSCT recipients. Simple correlations can then be made with regards to well-being, exercise tolerance, and development of other CVD complications post HSCT and the potential development of autonomic dysfunction. The latter should be the task of general practitioners following patients’ long post HSCT, and if any symptoms of dysautonomia are concerning, then refer them back to the cardiooncologist to determine if these symptoms are truly a manifestation of the autonomic system, particularly when autonomic dysfunction has been known to be highly prevalent in cancer patients but also associated with disabling fatigue and reduced survival. Therefore, a simple documentation of resting HR or fatigue complaints associated with fast HR with minimal exertion should raise concern to the clinician and prompt diligent identification.

Relevant to the claim that HR is an important variable in the prognosis of cardiac patients comes data recently released from analysis done from Rush University Medical Center that included 622 patients with lung cancer, leukemia, lymphoma, and multiple myeloma (2008–2016) [20]. In this analysis, cancer patients with resting tachycardia had worse prognosis [20]. Specifically, of the cancer patients who experienced tachycardia, 62% died within 10 years of diagnosis that sharply contrasts to only 22.9% of the control group [20].

Certainly, recognition of ST as potential new cardiotoxic manifestation that could be either the result of certain cancers or secondary to the treatments utilized requires better documentation as another clinical marker to be utilized in the follow-up of cancer patients.

It is important, based on this data, to recognize the potential contribution of certain pre-HSCT cardiotoxic exposures as well as well-recognized preexisting CVD risk factors that could place patients at risk of ST or IST that could contribute to post-HSCT CVD morbidity [21]. Based on data we have reviewed, ST could be seen in certain patients that might have been exposed to factors such as prior total body radiation ablative therapy, use of multidrug conditioning regimen with different mechanisms, or development of clinically silent heart failure, myocarditis, pulmonary hypertension underlying, cardiac deconditioning, or unrecognized automimic dysfunction [21].

Surely, we need to continue with our due diligence to exclude common offenders such as dehydration, anxiety, fear, anemia, pain, and potential unrecognized infections in these immunocompromised patients as the most common causes of ST. However, when all other common triggers have been discarded, additional investigation should be now entertained, particularly in post-HSCT patients, and particularly when these patients complain of weakness, fatigue, dizziness, and postural symptoms that are further aggravated by minimal exertion. The latter might not be necessarily the result of their maintenance chemotherapy treatment or patient’s deconditioning but due to unrecognized autonomic dysfunction.

Based on the recent data of tachycardia as a potential marker of increased mortality [20], it should be sufficient to get HR as another variable to be recognized as a potential cardiotoxic side effect. Even when reduction in left ventricular systolic function has been a well-recognized red-flag, identification of IST, particularly when associated with postural symptoms, might raise concerns for possible autonomic dysfunction. IST should be further investigated with the intention of considering remote telemetry monitoring, echocardiographic examination, and treadmill stress testing.

Surely, a significant number of HSCT patients already being referred to cardiology might already have been preemptively started on ACE inhibitors/ARB II receptor blockers, beta-blockers, or a combination thereof by their oncologists. Certainly, this practice should be applauded. However, it is crucial to be reminded of the simple fact that treatment of IST with either beta-blockers or calcium channel blockers might not be either effective or well tolerated and treatment with ivabradine might be recognized as a much better alternative [22].

Certainly, there will be those who would argue that given the ongoing healthcare reform and building economic pressures, the mere suggestion of additional testing in a condition not so commonly known might simply be unreasonable. To what we simply must respond, until recently this was not even in our clinical radar. However, it appears more common as more data becomes available and patients continue to survive longer.

Even though we need more data to conclusively make any statements with regards to either ST or IST in post-HSCT patients, our primary goal is to raise awareness of the importance of HR documentation both in the pretransplant and post-HSCT patient follow-up. The data we have presented simply tells us that there is a group of these patients that would eventually be affected with fast HR that could be clinically relevant [5,8–10,21,23,24].

Everyone involved in the general care of post-HSCT recipients needs a better understanding of the HR in these patients to be able to identify IST and recognize its potential detrimental cardiac consequences if left undetected and untreated.

Therefore, with the possibility that HR could become an important clinical variable to identify patients at risk of developing CVD complications post HSCT, we then propose to include HR into the already available hematopoietic stem cell transplant comorbidity index (HCT-CI) [25]. This calculator comprises 17 different categories of organ dysfunction, and all positive findings are summated into a total score that provides information of the overall and nonrelapse mortality risk of patients post HSCT. Under cardiac arrhythmia, ST should be included to the already known variables that include atrial fibrillation and flutter, sick sinus syndrome, and ventricular arrhythmias.

Even when we might expect IST in older patients, it is important to be reminded that young patients post HSCT might be cured from their malignancy and otherwise be lost for follow-up IST might remain less noticeable for longer periods of time. We should remain vigilant. IST should not be ignored, as George R. R. Martin once said, ‘It’s the ones who look innocent I need to beware.’

Declaration of financial/other relationships

The authors declare they have no conflict of interest. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

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Additional information

Funding

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