Stress cardiomyopathy in patients with central nervous system disease

Overview

Stress cardiomyopathy stands for a clinical syndrome characterized by the onset of myocardial dysfunction caused by stressful event. A common trigger is neurological disease, most commonly non-traumatic subarachnoid hemorrhage and ischemic stroke. The development of stress cardiomyopathy may cause arterial hypotension, arrhythmias, or acute heart failure in these patients. Despite the reversibility of the disease, its secondary form is particularly dangerous because of the risk of developing serious complications. Causal treatment focuses on eliminating the cause; further therapy is symptomatic, guided by echocardiographic findings. The aim of this review article is to summarize the current knowledge regarding stress cardiomyopathy focusing on up -⁠ -to-date diagnostics and treatment and highlight their differences in patients with neurological disease.

Keywords:

acute coronary syndrome – ischemic stroke – stress cardiomyopathy – subarachnoid hemorrhage – takotsubo

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

Introduction

Stress cardiomyopathy (SCMP), also known as takotsubo cardiomyopathy, neurogenic cardiomyopathy, adrenergic cardiomyopathy or broken heart syndrome, was first described in Japan in 1990 [1]. SCMP is defined as a clinical syndrome in which there is an acute development of systolic and diastolic dysfunction of the ventricle lasting less than 21 days, developing immediately or several days apart in response to psychological or physical stress [2]. Due to the pathophysiology of the disease, the development of SCMP is often encountered in patients with neurological brain damage. There is no unified nomenclature for this etiology of SKMP in the literature; the disease is also commonly referred to as neurogenic stunned myocardium, neurogenic stress cardiomyopathy or takotsubo syndrome [3].

The current incidence of SCMP is 15-30 cases per 100,000 population per year [2]. Initially, SCMP was considered a rare disease, but its incidence has been increasing in recent years. This may be due to the increasing life expectancy of the population and the associated increase in the number of patients with risk factors, as well as the increasing awareness of this diagnosis among health professionals and, last but not least, the improvement in the quality of diagnosis and access to care [4,5].

 

Pathophysiology

The pathophysiology of SKMP in neurological diseases is not precisely known, but it is related to the pathological consequences of neuro-cardiac interaction via the autonomic nervous system. Using neuroimaging methods, the presence of functional and structural changes in the limbic system has been demonstrated in patients with SKMP. These changes could also have a role in the prediction of persons at risk [6,7]. During stress, there is central sympathetic stimulation and an exaggerated release of adrenaline, noradrenaline and cortisol [6,8]. This causes direct damage and necrosis of cardiomyocytes, possibly also the development of multiple spasms of epicardial arteries, and the development of myocardial stunning. Excessive vasoconstriction causing impaired microcirculation appears to be another possible mechanism [2]. A finding that supports the theory of cardiomyocyte damage by sympathetic activity is the distribution of sympathetic beta receptors on the ventricular walls, which corresponds to the typical morphological impairment in SCMP [1,6,7]. A review of recent articles dealing with the pathophysiology of SKMP in neurological diseases is shown in Table 1 [3,6-9].

 

Risk factors

SCMP occurs most frequently in postmenopausal women (up to 90% of cases) [1,3]. Increased sympathetic tone, higher oxidative stress, more frequent anxiety, depression and sleep disturbances have been cited as reasons. Patients with preexisting psychiatric or neurological disease, patients with bronchial asthma, diabetics and substance abusers are also at risk for developing SCMP. This is probably due to a disorder of the autonomic nervous system and neural regulation of cardiac activity. Genetic predisposition, including adrenergic gene polymorphisms, is also likely to play a role in the development of SCMP [1,3,5,10].

 

Forms and etiology

Stress cardiomyopathy can be divided into primary and secondary. The primary form is caused by emotional stress [11] and tends to be the primary reason for hospital admission [2]. It is more commonly encountered in older women and may be triggered by, for example, the death of a loved one, an act of violence or anxiety. However, it can also be an extremely happy moment (happy heart syndrome) [12].

The secondary form is called SCMP developing as a consequence of a serious illness, often developing during hospitalization. The trigger may be e.g. severe trauma, surgery, sepsis or pain. The secondary type is more commonly seen in younger patients, both men and women [2,10,13]. We should think about the possible development of secondary type of SCMP in critically ill patients in intensive care units, where it can cause arrhythmias, arterial hypotension or heart failure. The secondary form also has a worse prognosis [11].

A very common trigger of secondary SCMP is neurological disease. Typically, non-traumatic subarachnoid haemorrhage (SAC) is involved, with an incidence of SCMP of 0.8-4.4%, where the location of SAC in the posterior cranial fossa and Hunt-Hess and Fisher scores of 3 and 4 are associated with a higher risk of developing SCMP [3]. However, recent studies have reported the occurrence of SKMP in up to 28% of patients with SAK, and the reasons given for underdiagnosis do not differ from those mentioned above for SKMP in general [14]. Another trigger may be ischemic CMP (iCMP), where the incidence is estimated to be around 0.5% and the development of SKMP is often associated with insular cortex damage [8]. The notion that SKMP should precede the development of iCMP and be a possible cause of it is still unresolved. There are also many case reports in the literature where SKMP developed in patients with craniocerebral trauma, spinal cord injury or after epileptic seizure, as well as in patients after intracranial or spondylo-surgical procedures [8,10,15].

In approximately 30% of cases, the aetiology of SKMP is unknown.

 

Morphological division

According to the affected area, SKMP can be divided into five types (Table 2). The typical and generally most common form is the finding of akinesia of the apical segment of the left ventricle (LV) with its balloon dilatation and basal hyperkinesis. However, in patients with neurological impairment, atypical forms are more likely to be encountered, namely the midventricular or inverted (basal) form [1,3,8,14]. A more rarely described form is damage to the right ventricle or to both ventricles simultaneously [13], but the likely reason seems to be the neglect of its examination. Thus, the true prevalence of right ventricular involvement is unknown, but according to some authors it is estimated to be up to one third of cases [1]. Rarely, SCMP may manifest as focal kinetic impairment.

 

Examination

Stress cardiomyopathy has no specific clinical manifestation. The clinical picture can be varied, probably from an asymptomatic form to physical weakness to cardiogenic shock. SCMP typically presents with anginal chest pain (>75%), dyspnoea (50%) or syncope with arterial hypotension (5-10%). Other severe symptoms such as pulmonary oedema, arrhythmias, heart failure or cardiogenic shock with tachycardia, arterial hypotension and the presence of cold acres may be present. A systolic murmur may be present [2].

Differential diagnosis of circulatory instability in sedated and ventilated patients in neurointensive care (e.g., post-SAC patients) with high circulatory support with noradrenaline is difficult. Sedation, administration of nimodipine for prevention of vasospasm, hypovolaemia (absolute and relative), sepsis, increased intrathoracic pressure during artificial pulmonary ventilation, obstructive shock or other cardiac causes such as myocardial infarction with or without ST elevation, and last but not least the inflammatory response of the body after SAK itself [17] and surgery, etc., may contribute to arterial hypotension. It is important to think carefully about the cause of arterial hypotension and, last but not least, to perform at least an orientation echocardiographic examination and, if a cardiac aetiology of circulatory instability is suspected, to complete an expert examination by a cardiologist. The possibility of the development of SCMP should always be considered in the differential diagnosis of new-onset circulatory instability or arrhythmias [1,18].

 

Finding on ECG

Pathological findings on ECG are present in up to 95% of SCMP cases [2]. The typical finding is ST segment elevation (44%) or inverted T waves (41%), which are more common findings in SKMP in neurological disease. Conversely, ST segment depression is not typical for SKMP. QT interval prolongation is a frequent finding, which usually develops within 48 h after stroke and may be the cause of the development of ventricular arrhythmias [1,7]. Differentiating SKMP from acute coronary syndrome (ACS) by ECG findings is difficult. In SKMP, the distribution of ST and T wave elevations is usually different from that of ACS, with findings extending beyond the involvement of a single coronary artery. Typically, ST elevations are found in leads II, aVR and V 2-6, while contralateral ST depression and Q waves are absent. The ECG changes over time in both entities and the findings may overlap. For this reason, coronary angiography to rule out ACS is unavoidable in most cases.

 

Laboratory signs of myocardial damage and echocardiography findings

Troponin levels are elevated in more than 90% of patients with SCMP. Baseline values may be similar to those in ACS, but peak values are lower [19]. Myocardial creatine kinase isoenzyme (CK-MB) is only slightly elevated. Typically, there is a difference between small elevations in values compared with extensive ventricular wall kinetics abnormalities. Brain natriuretic peptide (BNP) and NT-proBNP tend to be elevated several fold with peak values at 24-48 h, values tend to be higher than in ACS [2].

In the group of patients with neurological disease, the diagnosis by cardiomarkers is more difficult due to the fact that their rise is a common phenomenon and may reflect the neurological damage itself. The rise of CK-MB is described in patients with extensive hemispheric iCMP and is usually of non-cardiac origin. NT-proBNP elevation is described in up to 65% of patients with iCMP and in 59% of patients with hemorrhagic CMP (hCMP) incl. However, NT-proBNP levels are up to 10-fold higher in the presence of hCMP. Troponin T or I elevation is described in 5-8% of patients with iCMP, 22% of patients with hCMP and up to 38% of patients with SAK. The American Stroke Association recommends routine testing of basal troponin levels in patients with acute stroke [9]. The evolution of cardiac marker values over time is important for further diagnosis [14].

A typical finding on echocardiographic examination is that of circumferential akinesia or dyskinesia, which does not correspond to vascular supply from a single coronary artery. Nevertheless, echocardiographic examination is not sufficiently reliable to distinguish between ACS and SCMP. The findings in the apical form of SKMP are similar to those of anteroapical myocardial infarction, and right ventricular SKMP may have echocardiographic findings similar to those of acute cor pulmonale in pulmonary embolism [1].

 

Diagnostic criteria and differential diagnosis

The diagnostic criteria are based on the presence of a transient regional disturbance of ventricular kinetics beyond the area of one coronary artery, history of stress, presence of risk factors, ECG changes and elevation of cardiac markers. The reversibility of the disease at baseline is of course unknown, but may help to retrospectively establish an accurate diagnosis. There are several diagnostic criteria developed, but there is no uniform consensus on their use worldwide. These include the International Takotsubo Diagnostic Criteria (InterTAK diagnostic score), the Revised Mayo Clinic Criteria, or the Heart Failure Association-European Society of Cardiology Criteria [1].

The diagnosis of SCMP is not simple, it is necessary to consider all the data in a clinical context. The main point is to exclude ACS, for which the InterTAK diagnostic score can be used (Table 3). However, in most patients the finding is not clear-cut, and therefore it is important to consider coronary angiography. However, even the presence of a positive finding on coronary angiography does not exclude SCMP. Up to 15% of patients with SKMP also have coexisting coronary artery disease; ACS alone may be a trigger for SKMP [8]. In contrast, 1-2% of patients with suspected STEMI (5-6% in women) have SKMP [2]. Ventriculography may help to distinguish the morphological type of SKMP. Myocarditis or pheochromocytoma should be considered in the differential diagnosis. If available, cardiac MRI should be added because of its higher sensitivity compared to echocardiography alone [2,19].

The diagnostic procedure for patients with suspected SKMP in neurological disease is primarily the same. However, in patients with intracranial haemorrhage, it must be adapted at some stage to the patient's condition and risks based on their primary disease.

Diagnostic ventriculography and/or coronary angiography can be performed without heparin and other antiplatelet agents, i.e. without the underlying disease being affected by increased bleeding. In contrast, percutaneous intervention is associated with the need for heparin and, if a stent is placed, antiplatelet therapy, which is contraindicated in patients with intracranial bleeding. In these patients, coronary angiography should rather not be performed in the initial phase. However, in the case of a persistent troponin rise, persistent kinetics disturbance corresponding to a single coronary artery region, male patient, low-grade SAC, and known coronary artery disease or diagnostic doubt, it is appropriate to complete coronary angiography several days apart, or in the case of SAC, after treatment of the source [3,14,18]. A possible option is to perform MRI or CTA of the coronary arteries; however, its results correlate with the findings of invasive coronary angiography in about 80% and it is therefore necessary to know its limitations [14].

 

Complications

Stress cardiomyopathy was originally considered a benign disease due to the reversibility of myocardial dysfunction. However, particularly secondary forms of SCMP are dangerous because of the risk of developing serious complications. These occur in approximately 20% of patients in the acute phase. The presence of acute neurological disease is one of the risk factors for the development of severe complications. Other factors are acute psychiatric illness, an initial reduced LV ejection fraction below 45% and an initial troponin level elevated 10-fold above normal. The most common complications are summarized in Table 4 [19].

 

Therapies

Causal therapy focuses only on the elimination of the cause of SCMP, other therapies are mainly symptomatic, aimed at the treatment of complications. To date, there is no randomized trial or recommended approach for the treatment of SKMP [2,20]. SKMP has been excluded from the recommended cardiomyopathy therapies because of its specific course and reversibility [21]. In patients with SKMP, continuous ECG monitoring including QT interval for at least 48-72 h is important. In these patients, euvolemia and normal values of calcemia and magnesemia should be maintained. There are no clear recommendations for the initiation of anticoagulation and possibly antiplatelet therapy; their indication should be considered in each patient individually according to his/her associated diseases. In patients with findings of extensive myocardial akinesis and a reduction of LV ejection fraction below 30%, the initiation of anticoagulation therapy is indicated due to the risk of intracardiac thrombosis [2,22], however, in patients with intracardiac haemorrhage or at high risk of intracardiac haemorrhage, therapy should be delayed [2,3,8].

Based on the pathophysiology of the disease, the use of beta-blockers to reduce basal hypercontractility seems to be an appropriate choice [1,19]. However, these are contraindicated in bradycardia, prolonged QT interval, hypotension and shock. In these cases, the use of short-acting betablockers (esmolol, landiolol) may be considered [23,24] and their dose titrated under echocardiographic control. The use of angiotensin-converting hormone inhibitors is also appropriate in the absence of contraindications [8,19].

In the setting of heart failure, it is important to evaluate the presence of left ventricular outflow tract obstruction (LVOTO) and associated mitral insufficiency during systolic anterior motion (SAM). In patients without LVOTO, in the absence of arterial hypotension, we administer beta-blockers, and titrate diuretics and venodilators to reduce venous return and filling pressures when there are signs of congestion in the small circulation. In hypotensive patients without LVOTO, administration of inotropics is indicated and, if necessary, titration of vasopressors at the lowest possible dose [2]. Given the etiology of the disease, the use of non-catecholamine agents is to be considered, but their role in the therapy of SCMP is still unclear [13]. The selective alpha 1 agonist phenylephrine or vasopressin appears to be a suitable vasopressor compared to mixed alpha and beta agonists [2,20,22]. Levosimendan appears to be a safe inodilator option [25]. In patients with LVOTO findings, we titrate short-term beta-blockers and, if necessary, vasopressors to maintain perfusion pressure; administration of inotropics and vasodilators is contraindicated [2,20]. Therapy should be guided by expert echocardiography, each intervention individually evaluated and adjusted according to the result. The use of invasive hemodynamic measurements to optimize cardiac output, such as PiCCO, should be considered [14]. If shock progression persists, one of the mechanical circulatory supports should be considered, e.g. left-sided cardiac support, intraaortic balloon counterpulsation or extracorporeal membrane oxygenation [2,19,20].

Recommendations for the setting of long-term therapy in patients after SCMP are not supported by sufficient studies. The use of angiotensin-converting enzyme inhibitors or sartans is recommended to prevent recurrence of SCMP. Some studies have reported estrogen administration to postmenopausal patients as beneficial [19,22]. The protective effect of long-term administration of beta-blockers has not been demonstrated [8]. In patients with SCMP in SAC, it was hypothesized that the administration of betablockers could contribute to improved neurological outcome due to the reduction of cerebral metabolism. Studies have failed to clearly demonstrate this, and the Neurocritical Care Society does not recommend routine administration of betablockers in these patients [3].

A summary of the therapy is shown in Figure 1 [16].

 

Forecast

In most patients, spontaneous restoration of ventricular function usually occurs within 1-2 weeks (range 2 days to 6 weeks). Up to 20 % of patients after undergoing SCMP experience recurrence of the disease, with an average recurrence rate of 2-4 % per year. Women are more often involved [2,10,19]. In some patients, symptoms such as fatigue, dyspnoea or chest pain may persist despite normalisation of ventricular function [19]. Mortality rates of around 5% have been reported in hospitalized patients with secondary SCMP and are higher in men [2,3,8]. Mortality rates of up to 20% have been reported in patients with SCMP requiring vasopressor administration. Predictors of adverse outcome are physical trigger, acute neurological or psychiatric illness, admission troponin 10 times higher than normal and admission LV ejection fraction below 45% [18]. In patients with SAK or iCMP, cardiac complications tend to be the second most common cause of death after neurological damage alone [3,9].

 

Discussion

Despite the growing awareness of SCMP in patients with neurological disease and the increasing frequency of its occurrence, there are no specific recommendations for its diagnosis and treatment; current approaches are based on expert opinions [3,8,10,14].

Stress cardiomyopathy, regardless of the presence or absence of neurological disease, has a similar pathophysiology, clinical course and therapy [3]. SCMP associated with neurological damage is a variant of the secondary form of SCMP, its development is most often described in patients with severe SAK and in patients with iCMP with extensive hemispheric damage and involvement of the insular cortex; however, due to the pathophysiology, it is also possible to develop it in other neurological diseases [8,9]. SKMP develops most commonly within 48 h after a neurological insult [3]. Postmenopausal women are the highest risk group for the development of SKMP [1,8,9]. In terms of clinical findings, in contrast to classic SCMP, it is more often manifested by dyspnoea when heart failure develops than by chest pain [14]. In contrast to classic SMKP, for which the findings of ST elevation and echocardiographic findings are typical of the apical form, in SMKP in neurological diseases, the ECG findings are characterized by the presence of inverted T waves, and on echocardiographic examination we find rather one of the atypical forms -⁠ basal, midventricular or focal form [1,3,8,14]. However, it is important to emphasize that there is no clear boundary between the symptoms of SCMP and neurogenic SCMP, and it is not uncommon for a patient with neurological disease to present with clinical findings more typical of classic SCMP [3]. Laboratory findings do not differ between classic and neurogenic SKMP, but it is important to keep in mind that elevations of cardioenzymes are also associated with neurological damage itself without the presence of myocardial damage [9], and thus it is necessary to monitor their dynamics over time [14]. The above diagnostic procedure must be modified and personalized according to the condition and disease of each patient. It is always a matter of comparing the benefits versus the risks of the performed examination. Although the performance of coronary angiography is essential to exclude ACS and to definitively diagnose SCMP, it is an invasive procedure with the need for anticoagulation therapy and, if intervention is performed, dual antiplatelet therapy. These medications are contraindicated in patients with intracranial bleeding and could complicate other interventions that might be needed in the following days (insertion of ventricular drainage, etc.); on the other hand, their non-administration increases the risk of thrombosis of the inserted stent [3,14,18]. Performing coronary angiography should not delay definitive treatment of the aneurysm in the case of SAC. Therefore, coronarography should be performed only after definitive treatment of the aneurysm, and only in patients in whom clinical and laboratory suspicion of ACS persists (see above) [14].

The spectrum of complications of SCMP and the overall treatment of patients with SCMP are the same for the group of patients with and without neurological disease. In the absence of specific recommendations for antiplatelet and anticoagulant therapy, individualization of the deployment of this therapy according to the associated diseases of the patient is necessary [2,22]. In the therapy of SCMP in patients with neurological disease, particular emphasis should be placed on optimizing cardiac output in order to maintain adequate cerebral perfusion [14].

The prognosis of patients with SCMP in non-traumatic SAC and iCMP is difficult to assess, as these patients often die related to their primary neurological disease, not from cardiac complications [3]. Several studies have found worse neurological outcome, a higher incidence of vasospasm, and significantly higher mortality in patients with aneurysmal SAK compared with the group without SMKP [3]. Inadequate cerebral perfusion in heart failure has been proposed as one of the causes.

 

Conclusion

Stress cardiomyopathy, regardless of its etiology, is an underdiagnosed disease whose pathophysiology is not precisely known. As part of the differential diagnosis of angina pectoris, arterial hypotension, and arrhythmias, not only in patients with neurological disease, we should routinely use at least a landmark echocardiographic examination. SCMP is not a benign disease; patients should be thoroughly examined and monitored. Therapy is predominantly symptomatic, aimed at treating complications.

 

List of abbreviations

ACS -⁠ acute coronary syndrome

BNP -⁠ brain natriuretic peptide

CK-MB -⁠ myocardial creatine kinase isoenzyme

ECG -⁠ electrocardiogram

iCMP -⁠ ischemic CMP

InterTAK Diagnostic Criteria -⁠ International Takotsubo Diagnostic Criteria

LK -⁠ left ventricle

LVOTO -⁠ left ventricular outflow tract obstruction

NT-proBNP -⁠ N-terminal fragment for brain natriuretic peptide

PiCCO -⁠ Pulse Contour Cardiac Output

SAK -⁠ subarachnoid haemorrhage

SAM -⁠ systolic anterior motion mitral valve

SKMP -⁠ stress cardiomyopathy

STEMI -⁠ ST elevation myocardial infarction

 

Financial support

Supported by the Internal Grant Support Project of Krajská zdravotní, a. s., registration number: IGA-KZ-2021-1-12.

 

Conflict of interest

The authors declare that they have no conflict of interest in relation to the subject of the study.

 

Table 1. Recent publications dealing with the pathophysiology of stress cardiomyopathy in patients with neurological disease. 

Author	Year	Title of study	Type	Study Objective	Content
Brazdil V et al [6].	2022	The role of central autonomic nervous system dysfunction in Takotsubo syndrome: a systematic review [6]	Review	A summary of the evidence regarding NKO	Neuroimaging methods show that in SKMP, brain: 1. Changes in perfusion, metabolism, structure and function of brain tissues belonging to NKO; 2. 2. structural and functional changes in the pathways connecting NKO.
Baker C et al [3].	2021	Takotsubo syndrome in neurologic disease	Review	Differentiation between SKMP in general and Takotsubo syndrome	The authors distinguish the TS unit for SKMP in neurological disease and discuss its specific features and differences from SKMP in general. For the differences, see Table 2.
Sposato LA et al [8].	2020	Post-stroke cardiovascular complications and neurogenic cardiac injury: a JACC state-of-the-art review	review	Description and pathophysiology of neurocardiogenic syndromes	The authors describe SCMP as one of the neurocardiogenic syndromes, i.e. myocardial damage resulting from damage to the neuro-cardiac axis
Chen Z et al [9].	2017	Brain-heart interaction: cardiac complications after stroke	Review	Description of the pathophysiology at NKO	Pathologies at the level of the NKO significantly affect mortality and morbidity of patients.
Klein C et al [7].	2017	Takotsubo syndrome -⁠ predictable from brain imaging data	original work	Assessment of brain MRI findings typical of SCMP	Patients with SKMP show homogeneous anatomical and neurophysiological features that could be used to identify patients at risk for developing SKMP.

NKO, neurocardiac axis; SKMP, stress cardiomyopathy; TS, Takotsubo syndrome

 

 

Table 2. Morphological types of stress cardiomyopathy [1,2,16].

Type of stress cardiomyopathy	Prevalence	Diagram*
Apical (typical form)	75-80 %	Fig. A
midventricular	10-20 %	fig. B
basal (inverted)	5 %	Fig. C
focal	rare	Fig. D
right-sided or bilateral	33 %**	Fig. E

* grey part shows the dysfunctional part of the ventricle, ** explained in the text

LK -⁠ left ventricle, PK -⁠ right ventricle

 

 

Table 3. International Takotsubo Diagnostic Criteria (InterTAK diagnostic score) [19].

Female sex	25 points		Score	Probability of SCMP
Emotional stress	24 points		< 30	1 %
Physical stress	13 points		= 50	18 %
Absence of ST depression	12 points		> 70	90 %
Psychiatric illness	11 points
Neurological disease	9 points
Prolonged QTc interval	6 points

SKMP -⁠ stress cardiomyopathy.

 

 

Table 4. Complications of stress cardiomyopathy [19].

Common	acute heart failure (12-45%) LV outflow tract obstruction (LVOTO) (10-25%) Mitral insufficiency (14-25%) Cardiogenic shock (6-20%)
Less common	Atrial fibrillation (5-15%) Left ventricular thrombus (2-8%) AV block (5%) cardiac arrest (4-6%)
Rare	tachyarrhythmias, bradyarrhythmias (2-5 %) Torsades de Pointes (2-5 %) Death (1-4.5%) Ventricular arrhythmias (3%) Acute ventricular septal defect (<1%)

AV, atrioventricular; LV, left ventricular; LVOTO, left ventricular outflow tract obstruction