Why Predominantly Women?

↳ This is a section part of Moment: Takotsubo Cardiomyopathy

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Summary

Natural History and Prognosis

While TTC has a good prognosis, it is by no means a benign disease. In the majority of cases, the LV wall motion abnormalities resolve in days to weeks. Systolic function can take longer to normalise and on average resolves over 4–10 weeks.4,10,40 One study that followed patients with TTC demonstrates that the rate of recurrence is 2.9 % per year within the first 4 years, and 1.3 % per year subsequently.40

In-hospital mortality from TTC in the acute phase is generally around 1 % though it can be as high as 9 %.4,10,41,42 Independent predictors for mortality in TTC include the presence of certain comorbid conditions and male gender.41 A study by Brinjikji et al. using the NIS from 2008 to 2009 demonstrated that in-hospital mortality was significantly higher in males than in females: 8.4 versus 3.6 % respectively.41 Males also had a higher incidence of developing life-threatening complications including cardiogenic shock and cardiac arrest as well as dying from these complications, whereas females were more likely to develop acute CHF. However, out of the patients who experienced in-hospital mortality, over 80 % consisted of those with concomitant critical illnesses, such as sepsis, acute renal failure, stroke and respiratiory insufficiency.41 Since men had more underlying critical illnesses than women, this could explain their higher mortality rate and higher rates of developing and dying from acute complications.41 Furthermore, significantly more males present initially with cardiogenic shock or out-of-hospital cardiac arrest.43

Cardiogenic shock occurs in 4–20 % of patients with TTC,41,44 as a result of ventricular failure or LVOT obstruction. If LVOT obstruction is responsible for cardiogenic shock, it is usually accompanied by systolic anterior motion (SAM) of the mitral valve. Mortality from cardiogenic shock with TTC is reported to be as high as 16 % in some cases.41 Ventricular arrhythmias occur in 4–9 % of TTC patients in the acute phase. Of those that develop ventricular fibrillation or cardiac arrest, mortality is reported to range from 1 % to as high as 27 %.41

Interestingly, causes of long-term mortality differ in patients with a history of TTC compared with patients with ACS: a majority of TTC patients die of non-cardiac causes in the long term. Sharkey et al. reported that during an average follow-up period of 1.3 years, 17 out of the 133 TTC survivors died, with none being from a cardiac cause.10 In another study by Song et al., with a mean follow up of 42 months, mortality from non-cardiac causes was significantly higher than that from cardiac causes: 21 versus 2 %, respectively.42 Non-cardiac diseases, such as malignancy and stroke, were found to be an independent risk factor for long-term mortality.42 This is different from ACS patients in whom long-term mortality is usually from cardiac causes.45

Increasing evidence for an association between malignancy and TTC exists. One study shows TTC patients to have a significantly higher incidence of any malignancy compared with population-matched MI and orthopaedic patients.6 Another study demonstrated that 18 % of TTC patients versus 3 % of MI patients have a history of malignancy at the time of the event.45 Subsequently, seven patients in the TTC group versus zero patients in the MI group went on to develop cancer at the follow-up time of about 1.6 years.45 Additionally, in the COUNTS study, 10 % of patients have a malignancy.7 The association of malignancy with TTC brings up the possibility that TTC may be a manifestation of a paraneoplastic syndrome,7,43,45 which may imply that TTC is neither as benign as previously believed, nor does it have as favourable a long-term prognosis.

Why Predominantly Women?

TTC affects a disproportionately greater number of post-menopausal women compared with pre-menopausal women and age-matched men.5 There are several mechanisms proposed to explain this sex difference. It has been reported that catecholamine stress induces upregulation of immediate early genes (IEGs), certain proto-oncogenes and heat shock proteins that are not shown to be activated during reperfusion after an ischaemic episode.13 Oestrogen minimises the catecholamine-induced upregulation of IEGs, genes that are transiently activated to rapidly adapt to a stressor.13 Supplementation with oestradiol decreased the stress-induced upregulation of IEGs in rat models. Oestradiol-supplemented ovariectomised rats did not show any significant reduction in LV contraction whereas ovariectomised rats without supplementation with oestradiol showed a significant reduction in LV contraction.46 Therefore, oestrogen counteracts the cardiac effects of the SNS by decreasing the production of IEGs.8

Oestrogen has also been implicated in maintaining appropriate glucose uptake for cardiac energy. A recent report indicates that the female heart depends on glucose as its energy source more than the male heart.47 The female heart most efficiently utilises glucose between ages 51–70 and after age 70, glucose uptake is reduced.47 The relative lack of oestrogen as women age, therefore, may potentiate this attenuated glucose uptake thus predisposing post- menopausal females to TTC. Males are not predisposed to TTC despite their relative lack of oestrogen because they are not as dependent on glucose as their preferential cardiac energy substrate.47

Oestrogen may also play a role in enhancing the β-adrenoreceptor sensitivity and in promoting vasodilation. Post-menopausal women have a decreased β-adrenoreceptor responsiveness to catecholamine stimulation than younger females.48 However, their α-adrenoreceptor vasoconstriction response to catecholamines remains the same.48 As a result, there is more β-adrenoreceptor stimulation in relation to β-adrenoreceptor responsiveness thus leading to more vasoconstriction, which in the setting of endothelial dysfunction may trigger TTC. Additionally, oestrogen indirectly increases the production of nitric oxide thus promoting vasodilation.8 This nitric oxide-induced vasodilation helps minimise the effect of catehcholamines, especially in the microvasculature.8

Stollberger et al.49 discuss two opposing speculations related to the sex difference in TTC: 1) males are better protected biologically against stress and 2) males are biologically less resistant than females against stress. Historically, men were exposed to more physical stressors than women and therefore may be better protected biologically than women.49 Additionally, males have a higher density of adrenergic receptors compared with women and can thus protect themselves from catecholamine excess better than females.5 On the other hand, males have a higher rate of sudden cardiac death and therefore possibly die more frequently from the acute LV dysfunction and thus die before they are diagnosed with TTC.49

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