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Chronic Takotsubo Syndrome with Acute Exacerbations May be the Villainin the Increase of Morbidity and Mortality in Patients with DecompensatedChronic Heart Failure

Shams Y-Hassan

PII: S0167-5273(14)00296-4DOI: doi: 10.1016/j.ijcard.2014.01.085Reference: IJCA 17622

To appear in: International Journal of Cardiology

Received date: 13 January 2014Accepted date: 18 January 2014

Please cite this article as: Y-Hassan Shams, Chronic Takotsubo Syndrome with AcuteExacerbations May be the Villain in the Increase of Morbidity and Mortality in Patientswith Decompensated Chronic Heart Failure, International Journal of Cardiology (2014),doi: 10.1016/j.ijcard.2014.01.085

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Chronic Takotsubo Syndrome with Acute Exacerbations May be the Villain in the

Increase of Morbidity and Mortality in Patients with Decompensated Chronic Heart

Failure

Author’s surname: Y-Hassan

Short title: Chronic Takotsubo with acute exacerbations

Key words: Takotsubo; heart failure; broken heart, neurogenic stunned myocardium,

sympathetic denervation

Author’s name: Shams Y-Hassan, MD

Karolinska Institute at Karolinska University Hospital

Department of Cardiology

Corresponding Author

Y-Hassan S, MD

Address: Karolinska University Hospital, Huddinge, Department of Cardiology, S- 141 86

Stockholm, Sweden

Tel number: +46 8 58582805

Fax number: +46 8 58586710

E-mail: shams.younis-hassan@karolinska.se

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Takotsubo syndrome (TS), is currently a well-recognized acute cardiac disease entity [1].

Chronic heart failure (CHF) is characterized by a continuous interaction between the state of

myocardial dysfunction and counteractions with the aim of preservation of cardiovascular

homeostasis [2]. The continuous exaggerated countermeasures have deleterious effects

resulting in episodes progressive heart failure, life-threatening arrhythmias, and sudden death.

Critical review of the clinical presentation and course, cardiac image study findings, cardiac

biomarkers, local cardiac sympathetic scintigraphic findings and therapeutic responses in TS

and decompensated CHF has been done. The same sequence of events and findings, which

take place acutely in TS, occur in a chronic form with acute exacerbation in decompensated

CHF. This novel hypothesis is presented in this manuscript.

First: In about 70% of patients with TS, the disease is preceded by an emotional or a physical

stress factor. Among the physical stress factors, which merit mentioning in this context is the

increased catecholamine levels in diseased conditions as in pheochromocytoma and

exogenous catecholamine administration in which the catechoalmines may act as an important

trigger factor for TS. In CHF, the countermeasures to the left ventricular dysfunction, which

initially aimed to preserve the cardiovascular homeostasis, are constituted of the

compensatory neurohumoral mechanisms, which include increase in catecholamines,

activation of renin-angiotensin-aldosterone system (RAAS) and the intense activation of the

sympathetic nervous system.. High levels of norepinephrine have been reported in patients

with CHF and has shown to be independently (p<0.002) related to subsequent risk of

mortality [3]. The RAAS is activated in heart failure and the degree of activation is correlated

to the prognosis [2]. Taken together, activation of all these systems lead to chronic

sympathetic nervous system activation including cardiac sympathetic nerve terminals in CHF

in a manner similar to the trigger factors inducing acute TS.

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Second: TS has a clinical presentation identical to that of acute coronary syndrome. The

condition may be complicated by heart failure, pulmonary oedema, cardiogenic shock,

arrhythmias, and sudden (albeit rarely) death. The patients develop mild to moderate elevation

of myocardial infarction biomarkers, and marked elevation of the brain natruretic peptide

(BNP) and the N-terminal pro-BNP [1]. In decompensated CHF, progressive heart failure,

life threatening arrhythmia, and sudden death are serious complications. Measurement of

myocardial biomarkers shows mild elevations of myocardial infarction biomarkers and

marked elevation of BNP, N-terminal pro-BNP. Using high sensitivity cardiac troponin

assays, measurable cardiac troponin concentrations may be present in nearly all patients with

CHF particularly in those with more severe heart failure [4].

Third: A characteristic feature of TS is the regional left ventricular wall motion abnormality

(LVWMA) with a peculiar circumferential pattern, extending beyond the coronary artery

supply region and resulting in a conspicuous “ballooning” of the left ventricle during systole.

If the patients survive the acute stage of the disease, the prognosis is favourable and the

LVWMA is “reversible” usually resolving within days to weeks. The left ventricular

dysfunction in decompensated CHF is usually described as depressed left ventricular ejection

fraction. The characteristics and the pattern of the LVWMA in decompensated CHF are not

well described. However, the left ventricular remodelling, which is a common process in

patients with worsening heart failure, results in changes of the left ventricular geometry with

an alteration of the left ventricular shape from more ellipsoid to more “spherical” [5]. The

term spherical and not ballooning has been used in CHF because the pattern of the regional

left ventricular ballooning is difficult to determine due to the confounding, pre-existing

advanced LVWMA. It has been reported that treatment of progressive heart failure with beta

blockers Carvedilol results in improvement of the left ventricular ejection fraction from

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25.4% to 37.3% and has been shown to improve in cardiac sympathetic Iodine 123 meta-

iodobenzylguanindine (123

I-MIBG) uptake [6]. This implies that the acute worsening of left

ventricular dysfunction in decompensated CHF is “reversible” if treated appropriately.

Fourth: Regarding the pathogenesis of TS, Convergent data coming mainly from

neurological literature support the hypothesis that local cardiac sympathetic disruption and

norepinephrine spillover causes TS [7]. In both induced and in spontaneous subarachnoid

hemorrhage, which a well-recognized trigger factor for TS, signs suggestive of increased

cardiac sympathetic over-activity have been documented. Surgical (spinal cord transection or

severing) or pharmacological (reserpine, propranolol) sympathectomy has shown to have

protective cardiac effects in both induced animal and spontaneous human subarachnoid

hemorrhage studies [7]. Signs of local cardiac sympathetic denervation evaluated by both 123

I-

MIBG scintigraphy [8] and 11

C hydroxyephedrine positron emissions tomography (PET)

imaging have been demonstrated in TS [9]. There are also substantial data supporting the

evidence of local cardiac sympathetic disruption evaluated by 123

I-MIBG scintigraphy in

decompensated CHF. It was first 1988, Schcofer et al [10] who described the potential role

for 123

I-MIBG imaging in CHF. Merlet et al [11] demonstrated in 1992 that the cardiac 123

I-

MIBG imaging was found to be a potent prognostic marker when compared to noninvasive

hemodynamic indices. The finding of cardiac sympathetic disruption evaluated with 123

I-

MIBG imaging; the prognostic utility of 123

I-MIBG uptake defect and its superiority over all

other traditional functional and biohumoral markers even when used in combination have

been confirmed in many other studies [2, 12-15]. The 123

I-MIBG scintigraphy has shown to

have prognostic value across a spectrum of left ventricular ejection fractions and appears to

improve risk discrimination beyond clinical and biomarker data regardless of left ventricular

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ejection fraction [16]. Noteworthy is that the cardiac sympathetic denervation in patients with

CHF is a reversible phenomenon as that of TS [15].

Fifth: In TS, surgical (spinal cord transection or severing) or pharmacological (reserpine,

propranolol) sympathectomy has shown to have protective cardiac effects in both induced

animal and spontaneous human subarachnoid hemorrhage studies [7]. Liang et al in one study

have shown that preadmission beta-blockers were associated with decreased incidence of

neurogenic stunned myocardium in aneurysmal subarachnoid hemorrhage [17]. In CHF,

numerous studies have shown that the cardiac 123

I-MIBG uptake and washout rate improve

after therapy with Beta-blockers [6], angiotensin converting enzyme inhibitors (ACE-I),

ACE-I and addition of valsartan, angiotensin receptor blockers (ARBs) candesartan [18],

spironolactone [19], device implantation, and cardiac resynchronization therapy (CRT) [20].

In conclusion, in both TS and decompensated CHF, there are substantial data supporting the

evidence of local cardiac sympathetic disruption and norepinephrine spillover triggered by an

emotional or physical stress factor in TS and by more than one trigger factors in

decompensated CHF. This sympathetic disruption causes a peculiar type of circumferential

LVWMA resulting in a conspicuous regional ballooning of the LV in TS; worsening of

LVWMA in CHF results in remodelling of the LV and changing the LV geometry from

ellipsoid to spherical in shape. The LVWMA is usually completely reversible in TS. The

worsening of the LVWMA in CHF is also reversible if treated appropriately. Both conditions

are characterized by mild elevation of the cardiac troponins and marked elevation of NT-pro-

BNP. The only difference between the two conditions is that the abovementioned sequence of

events occurs acutely in TS and chronically with acute exacerbation in chronic heart failure.

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Consequently, chronic TS with acute exacerbation may be the main pathogenesis for the

increased morbidity and mortality in patients with decompensated CHF

Acknowledgments

The authors of this manuscript have certified that they comply with the Principles of Ethical

Publishing in the international Journal of Cardiology [21]

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