The structure and main findings of the current investigation are summarised in Fig 4.
The results of this study are important because:
They confirm that a substantial proportion of patients with TTS have known A/Ca, and demonstrate that breast cancer is the most common association.
They show that TTS in association with A/Ca more often presents as secondary TTS,with associate clinical impact includingsignificantly increased in-hospital MACE rates [17]. Indeed, Cammann et al. [8] have recently reported, within the InterTAK cohort, increased in-hospital death rates in patients with A/Ca and TTS.
They also show that patients with A/Ca have greater risks not only of late all-cause mortality, but somewhat surprisingly, a markedly increased risk of CVS death.
On multivariate analyses, factors predicting long-term mortality include male gender, extent of catecholamine release (normetanephrine concentrations), acute attack hemodynamic impact (presence of shock, early arrhythmias),and extent of inflammatory activation (hs-CRP concentrations).
Patients discharged on ACEi/ARB or on βBl had substantially lower mortality rates, and this apparent influence of discharge medication on survival was most marked among A/Ca patients who were prescribed ACEi/ARB.
Thus, findings (2) and (3) point strongly to some substantial and ongoing interaction between the presence of cancer and the probability of CVS complications (short- and long-term) of TTS. To the best of our knowledge, this is the first time that such an association has been reported.
The results also suggest that there are reciprocal long-term interactions between CVS outcomes and presence of A/Ca, in the sense that CVS death rates were substantially elevated in patients with A/Ca. Previously, it has been observed that patients with TTS have an increased risk of long-term cancer death relative to control populations. This was not strongly suggested by the current data, but no control population was used. The data regarding excess long-term CVS mortality in A/Ca patients, were statistically robust, but no complete explanation for the finding is currently available. One possible explanation would be related to patients’ age (older for A/Ca patients) and/or comorbidities. However, patients with A/Ca had similar CVS risk profiles (with the exception of age) to those without A/Ca, and patients’ age was not an independently significant predictor of mortality.
It could be also be argued that the “main” finding might have related to greater hemodynamic impact of the acute attack in patients with A/Ca, leading putatively to greater long-term myocardial fibrosis [18] and therefore greater risk of late cardiac failure and death. Indeed, the available data (see Table 1) suggest that hemodynamic impact might have been greater in A/Ca patients, but this was not studied in detail. A recent analysis from the InterTAK group [19] also demonstrated that clinical factors associated with haemodynamic impact of TTS attacks, including hypotension, tachycardia and reduced left ventricular ejection fraction, all function as adverse long-term prognostic markers. Other recent publications [20, 21] also documented that patients with A/Ca had poor in-hospital outcomes. As a number of neoplasms may be associated with increased catecholamine production, the associated neoplasms themselves may have contributed to severity of attacks, as schematized in Fig. 5. What is unlikely is that our observations were primarily related to the impact of heart failure induced by prior chemotherapy, as only a minority of patients had received chemotherapy and only 2 were receiving concurrent chemotherapy. Therefore, although precipitation of TTS is a well-recorded complication of cancer chemotherapy, direct contributions of chemotherapy per se to emergence of TTS are likely to be relevant only to a small proportion of TTS patients.
Discharge prescription of either ACEi/ARB or βBl predicted low mortality risk both on univariate (Fig. 3) and on multivariate analysis (Table 3). There are theoretical reasons why ACEi/ARB treatment might reduce risk of inflammation and therefore impact of TTS [22]. Furthermore, a previous meta-analysis [23] suggested that ACEi/ARB therapy reduces risk of TTS recurrence; in the current study, the observed annual rates of recurrence were 2.2 and 1.8% for patients with and without A/Ca, respectively (p = NS). The salutary effects of βBl therapy (Fig. 3b, Table 3) were a little surprising, given the relative β1-adrenoceptor selectivity of most currently used βBl and the implication from animal studies that the signal transduction pathway for catecholamine-induced precipitation of TTS is primarily or exclusively related to β2-adrenoceptor stimulation [4, 5]. Previous clinical studies [3, 10, 24] have failed to document any benefit associated with discharge therapy including βBl, but this issue now merits re-examination. Nevertheless, in a non-randomized data set, it remains possible that discharge prescription of βBl was biased towards “less ill” patients. Interestingly, the prognostic benefit of ACEi/ARB therapy seemed to be most marked in A/Ca patients.
The study, while representing the first of its type has a number of additional limitations.
It is possible that there may have been some inaccuracies in attribution of cause of death, and also that patient pharmacotherapies at discharge might not have been properly representative of long-term treatment.
No firm conclusions can be drawn about impact on recurrence rates, given the low number of diagnosed recurrences, the possibility that some recurrences were fatal, and the extensive use of ACEi/ARB, which may have reduced likelihood of recurrence [23].
On backwards stepwise multiple logistic regression, A/Ca per se was not a significant correlate of mortality risk. The most likely theoretical explanation for this finding was that A/Ca was an indirect factor predisposing to mortality, partially via increased severity of acute TTS episodes, as evidenced by the identification of acutely elevated plasma levels of normetanephrine and hs-CRP, presence of early arrhythmias and shock, and male gender as significant multivariate correlates of mortality. Plasma normetanephrine concentrations probably relate to severity of attacks both via intensity of initial catecholamine discharge and via its autonomic consequences of persistent sympathetic activation (for example in the face of hypotension). In the event, however, patients with A/Ca differed primarily on the basis of more intense early inflammation, as characterized via hs-CRP and NT-proBNP elevation (Table 1). Furthermore, there is a possibility that measurement of other parameters, such as liver/renal function tests and white blood cell count, may have shed additional insight on determinants of prognosis.
As regards mechanisms of association with CVS mortality risk, relevant data remain very limited, and no particular type of cancer predominated. While chronic inflammation may represent a risk factor for both carcinogenesis and development of ischemic heart disease [25], the current data add little beyond that.
How, then, might an association between A/Ca and long-term CVS mortality risk have operated? One possibility is that both index and recurrent attacks are more likely to occur in patients with cancer. In the current series, there were too few recurrent episodes to be certain about this possibility. Furthermore, it remains possible that some of the late CVS deaths might have reflected arrhythmias associated with recurrence.
A second possibility would be the induction of TTS as a complication of antineoplastic therapy [26] or because of prior cardiotoxicity induced by antineoplastic drugs. If this contributed to the current findings, it would probably have been a relatively minor factor, given that only 34.5% of patients with A/Ca had received chemo/immuno therapies.
A final possibility is of a “hormone-like” effect of some cancers inducing cardiotoxicity. There is evidence that many cancers may exhibit paracrine effects [27]. In general, such effects are potentially independent of the induction of TTS, or of the mechanisms, including Gi-protein biased post-receptor β2-adrenoceptor signalling and induction of nitrosative stress [7, 28], thought to underlie the pathogenesis of TTS. Figure 5, a schematic view of potential reciprocity between TTS and cancer both at the level of initiation and progression, represents an integrated view of our current mechanistic speculation in this regard.
However, it is also known that both ovarian and breast cancers may rely crucially on induction of activity of poly (ADPribose)polymerase-1 (PARP-1) [29], which appears to play a crucial role in myocardial energy impairment in a rat model of TTS [7]. To date, there is no suggested mechanism to explain multi-organ induction of PARP-1 activity, so this possibility remains to be tested.
In conclusion, A/Ca is a common finding among patients with TTS, and is associated with a more complicated in-hospital course, and a far higher long-term mortality risk, towards which ongoing cardiac events contribute substantially. While the mechanisms underlying this evidence of close ongoing association and probable reciprocity between TTS and cancer must remain somewhat speculative at this stage, at the very least the data would suggest that A/Ca be viewed as a high risk indexation factor among TTS patients.
The further finding that treatment with ACEi/ARB or βBl appears to be protective in long-term follow-up of TTS patients cannot be regarded as a substitute for randomized clinical trials, and indeed no such trials have yet been completed. However, coupled with the results of the previous meta-analysis [17], these data add to the argument for such a study to be undertaken.
