&

Role of Positive Emotions in

Takotsubo Cardiomyopathy
Syeda S. Sultana, MBBSa, Sibtain Nisar, MBBSb,
FNU Manoj Kumar, MBBSc, Haysum Khan, MBBSd,
Hamayle Saeed, MBBSe, Gulfam Ahmed, MBBSf, and
Jahanzeb Malik, MBBSg*
From the a Department of Medicine, Southern Medical College, Chittagong, Bangladesh, b Depart-
ment of Medicine, Lady Reading Hospital, Peshawar, Pakistan, c Department of Medicine, Jinnah
Sindh Medical University, Karachi, Pakistan, d Department of Medicine, Shifa College of Medicine,
Islamabad, Pakistan, e Department of Medicine, Fatima Memorial Hospital, Lahore, Pakistan,
f
Department of Medicine, Muhammad Hospital, Lahore, Pakistan and g Department of Cardiovascu-
lar Medicine, Cardiovascular Analytics Group, Islamabad, Pakistan.

Abstract: Takotsubo Cardiomyopathy, also known as

“broken heart syndrome,” is a transient cardiac condi-
tion characterized by sudden left ventricular dysfunc-
tion, often triggered by emotional stress or significant
life events. While research has predominantly focused
on the impact of negative emotions and emotional stres-
sors, there is a growing interest in understanding the
role of positive emotions in this unique cardiac syn-
drome. This narrative review explores the emerging
research on positive emotions and Takotsubo Cardiomy-
opathy. It provides an overview of studies investigating
the relationship between positive emotions and the con-
dition, highlighting key findings and observations. Posi-
tive emotions, such as joy, happiness, gratitude, and
optimism, have been associated with improved emo-
tional well-being, better-coping mechanisms, and poten-
tial cardiovascular protection. Some studies suggest that
individuals experiencing higher levels of positive emo-
tions may have a reduced risk of developing Takotsubo
Cardiomyopathy. However, the research in this area is

*Corresponding author: Jahanzeb Malik, Department of Cardiovascular Medicine, Cardiovascular Analytics

Group, Islamabad, Pakistan. E-mail: heartdoc86@gmail.com
Curr Probl Cardiol 2023;48:101997
0146-2806/$ see front matter
https://doi.org/10.1016/j.cpcardiol.2023.101997

Curr Probl Cardiol, December 2023 1

 still limited, with small sample sizes and challenges in
quantifying positive emotions. Additionally, the inter-
play between positive and negative emotions requires
further exploration to fully understand their impact on
cardiovascular health. Despite these limitations, har-
nessing positive emotions in cardiac care holds promise
for enhancing patient outcomes and emotional well-
being. Integrating positive psychology into clinical prac-
tice and cardiac rehabilitation may lead to more holistic
and patient-centered approaches to cardiovascular care.
Further longitudinal studies, interventional trials, and
mechanistic investigations are needed to strengthen the
evidence base and identify potential therapeutic per-
spectives. As research progresses, addressing these gaps
will provide valuable insights into the complex relation-
ship between emotions and cardiovascular health,
benefiting patients affected by Takotsubo Cardiomyopa-
thy and other cardiovascular conditions. (Curr Probl
Cardiol 2023;48:101997.)

Introduction

&
T
akotsubo cardiomyopathy, commonly known as “broken heart
syndrome,” is a unique and intriguing cardiac disorder that
has gained significant attention in recent years.1 First
described in Japan in the early 1990s, it is characterized by sudden
and severe left ventricular dysfunction, often triggered by intense
emotional stress or significant life events.2 Unlike typical myocardial
infarction resulting from obstructed coronary arteries, takotsubo car-
diomyopathy presents without evidence of significant blockages, mak-
ing it a distinct and puzzling condition.3 While the link between
negative emotions, such as grief, fear, or anger, and the development
of takotsubo cardiomyopathy is well-established, a growing body of
research has begun to explore the intriguing role of positive emotions
in this cardiac disorder.4 The understanding of the impact of positive
emotional experiences on cardiac health is still in its infancy, and this
narrative review aims to explore the emerging evidence surrounding
the potential protective effects of positive emotions in the context of
takotsubo cardiomyopathy.
Conventionally, the influence of emotions on cardiovascular health
has focused predominantly on negative emotions and their detrimental

2 Curr Probl Cardiol, December 2023

effects on the heart.5 However, researchers are now shedding light on
the potential beneficial impact of positive emotions, such as joy, love,
happiness, and gratitude, in mitigating the risk and severity of cardio-
vascular diseases, including takotsubo cardiomyopathy.4,6 The proposed
mechanisms through which positive emotions may confer cardiovascu-
lar protection will be explored, including their effects on autonomic
nervous system regulation, inflammation, endothelial function, and psy-
chological stress buffering.
Furthermore, the review will also analyze the implications of these
findings in clinical practice. Understanding the role of positive emotions
in takotsubo cardiomyopathy could pave the way for novel therapeutic
approaches and interventions that harness the power of positivity to
enhance cardiac resilience and recovery in affected individuals. As
research in this area continues to evolve, it is crucial to consolidate and
critically evaluate the existing literature to identify knowledge gaps and
potential avenues for further investigation. By doing so, we can gain
deeper insights into the intricate relationship between positive emotions
and takotsubo cardiomyopathy, ultimately improving patient outcomes
and fostering a holistic approach to cardiovascular health and well-
being.

Methods
To explore the role of positive emotions in Takotsubo Cardiomyopa-
thy, a comprehensive literature search was conducted using traditional
research methods due to the absence of advanced digital databases.
The search was carried out in major medical libraries, academic jour-
nals, and relevant publications dating back to the early 1990s when
Takotsubo Cardiomyopathy was first described. Keywords used for the
search included “Takotsubo Cardiomyopathy,” “broken heart syn-
drome,” “positive emotions,” “happiness,” “joy,” and “gratitude.” Data
extraction was performed manually by reviewing the selected articles.
Information such as study objectives, methodology, sample characteris-
tics, positive emotion assessment tools, outcomes related to Takotsubo
Cardiomyopathy, and the potential influence of positive emotions were
recorded in a structured manner. Given the narrative nature of this
review, a qualitative synthesis approach was employed. Data from the
selected studies were analyzed thematically, and common themes
related to the role of positive emotions in Takotsubo Cardiomyopathy
were identified.

Curr Probl Cardiol, December 2023 3

Main Text

Understanding Takotsubo Cardiomyopathy

Clinical Presentation. Takotsubo Cardiomyopathy presents a wide

range of clinical manifestations that closely resemble acute coronary syn-
drome (ACS), making it a challenging condition to diagnose accu-
rately.1,7-12 The symptoms and physical findings can vary, but the
hallmark feature is the transient weakening of the left ventricle, resulting
in characteristic abnormalities in cardiac imaging.13

Chest Pain. Chest pain is the most common presenting symptom in Takot-
subo Cardiomyopathy, affecting around 80% of patients.11,12 The pain is
often described as sudden and severe, resembling angina or a heart attack.
It may radiate to the arms, shoulders, back, or neck, and is usually trig-
gered by emotional or physical stressors.14

Shortness of Breath. Dyspnea, or difficulty breathing, is another common

symptom experienced by individuals with Takotsubo Cardiomyopathy.1
The compromised pumping ability of the left ventricle leads to fluid accu-
mulation in the lungs, causing a sensation of breathlessness or rapid
breathing.15

Palpitations and Lightheadedness. Some patients may report palpitations, a

sensation of rapid or irregular heartbeats, or lightheadedness, which could
be a result of abnormal cardiac rhythms or hemodynamic changes.1,15

Electrocardiogram (ECG) Changes. The ECG in Takotsubo Cardiomyopa-

thy often shows characteristic abnormalities. These changes may mimic
those seen in ACS, including ST-segment elevation or depression, T-wave
inversions, and QT interval prolongation.16-19 The ECG abnormalities are
usually transient and tend to normalize as the condition resolves.

Troponin Elevation. Troponin is a protein released into the bloodstream

when the heart muscle is damaged.20 In Takotsubo Cardiomyopathy, tro-
ponin levels may be elevated, leading to the initial suspicion of a heart
attack.21 However, the degree of troponin elevation is often milder com-
pared to typical ACS.

Left Ventricular Dysfunction. One of the distinctive features of Takotsubo

Cardiomyopathy is the transient left ventricular dysfunction observed on

4 Curr Probl Cardiol, December 2023

cardiac imaging.22 Echocardiography or cardiac magnetic resonance
imaging (MRI) reveals the characteristic “apical ballooning” or
“takotsubo” appearance of the left ventricle during systole.23 This pattern
shows the apex of the heart becoming enlarged and rounded, while the
base remains relatively normal.

Absence of Significant Coronary Artery Blockages. A critical differentiating

factor from ACS is the absence of significant coronary artery blockages on
coronary angiography. In Takotsubo Cardiomyopathy, the coronary arter-
ies typically appear normal or may show minimal atherosclerosis.24,25

Etiology and Triggers

The etiology of Takotsubo Cardiomyopathy remains an active area of
research, and despite significant advances in understanding, it continues
to present complexities and uncertainties. The condition’s unique pre-
sentation, often triggered by emotional or physical stress, has led
researchers to explore a range of potential mechanisms involved in its
pathogenesis.

Sympathetic Nervous System Imbalance. The autonomic nervous sys-

tem, particularly the sympathetic branch, plays a crucial role in regulating
cardiovascular function.26 During periods of stress or emotional arousal,
the sympathetic nervous system is activated, leading to the release of cat-
echolamines, such as adrenaline (epinephrine) and noradrenaline (norepi-
nephrine), into the bloodstream.27 In Takotsubo Cardiomyopathy, the
sudden surge of catecholamines can lead to a state of sympathetic overac-
tivity, resulting in increased heart rate, heightened contractility, and vaso-
constriction of blood vessels.28 Excessive sympathetic stimulation can
create a state of “stunned myocardium,” where the heart muscle becomes
temporarily weakened and dysfunctional.29 This effect is particularly
prominent in the apex of the left ventricle, leading to the characteristic
apical ballooning observed in Takotsubo Cardiomyopathy.

Coronary Microvascular Dysfunction. Coronary microvascular dysfunc-

tion, involving abnormalities in the smaller blood vessels that supply the
heart muscle, has been implicated in the pathogenesis of Takotsubo Car-
diomyopathy.30 During periods of stress, microvascular circulation may
undergo transient changes, resulting in reduced blood flow to certain
regions of the heart.31 The combination of increased sympathetic tone
and impaired coronary microvascular function can contribute to

Curr Probl Cardiol, December 2023 5

myocardial ischemia and subsequent stunning of the heart muscle.32 This
phenomenon further supports the notion that the condition does not
involve significant coronary artery blockages, distinguishing it from typi-
cal heart attacks.

Hormonal Imbalances. Hormonal factors, particularly the decline of

estrogen in postmenopausal women, have been proposed as potential con-
tributors to the development of Takotsubo Cardiomyopathy.33 Estrogen is
known to have cardioprotective effects, including the promotion of vaso-
dilation and antioxidant properties.34 Postmenopausal women have lower
estrogen levels, which may render their hearts more susceptible to the
effects of stress-induced catecholamine release.35 Additionally, changes
in other hormones, such as thyroid hormones, may also play a role in the
pathogenesis of the condition.36

Inflammatory and Immune Response. Growing evidence suggests that

inflammation and immune activation might be involved in the develop-
ment of Takotsubo Cardiomyopathy.37 Elevated levels of inflammatory
markers, such as C-reactive protein (CRP) and interleukins, have been
observed in affected patients. The release of inflammatory mediators may
contribute to myocardial injury and dysfunction, promoting the develop-
ment of the characteristic apical ballooning seen in Takotsubo Cardiomy-
opathy.38 However, the exact relationship between inflammation and the
condition’s pathogenesis requires further investigation.

Genetic Predisposition. While most cases of Takotsubo Cardiomyopa-

thy are considered sporadic, there is evidence suggesting a possible
genetic predisposition to the syndrome.39 Certain genetic variations may
influence an individual’s susceptibility to stress-induced cardiac injury or
modulate the response to sympathetic activation.40 Studies exploring
familial cases and genetic associations are ongoing to identify potential
genes or genetic pathways linked to Takotsubo Cardiomyopathy.

The Impact of Negative Emotions

Negative emotions, such as grief, fear, anger, and psychological stress,
have been widely recognized as significant triggers for Takotsubo Cardio-
myopathy.3 The relationship between emotional distress and the develop-
ment of this cardiac syndrome has been extensively studied, shedding
light on the complex interactions between the mind and the heart.41

6 Curr Probl Cardiol, December 2023

 Numerous clinical studies and case reports have investigated the role
of negative emotions in triggering Takotsubo Cardiomyopathy.1-5,41 Here
is a brief overview of some key findings from these studies:

Emotional Triggers. A significant proportion of Takotsubo Cardiomyop-

athy cases are preceded by acute emotional stressors, with one of the
most common triggers being the sudden loss of a loved one.42 Emotional
triggers can also include fear, anxiety, anger, and other intense emotional
experiences.1 Studies have shown that the emotional stress associated
with these triggers can lead to the release of stress hormones, particularly
catecholamines, which may contribute to the transient left ventricular
dysfunction observed in Takotsubo Cardiomyopathy.43

Psychological Stress. Chronic psychological stress has also been linked

to an increased risk of Takotsubo Cardiomyopathy.44 High levels of
stress, whether due to work-related pressures, personal challenges, or
other life events, can chronically activate the sympathetic nervous sys-
tem, leading to prolonged exposure to stress hormones.45 This persistent
sympathetic overactivity can potentially contribute to the development of
myocardial stunning and left ventricular dysfunction.

Positive Emotions and Cardiovascular Health

Traditionally, the focus in cardiovascular research has been primarily
on risk factors related to lifestyle and negative emotions, such as anxiety
and depression. However, an emerging body of evidence suggests that
positive emotions might also play a protective role in cardiovascular
health. Studies have shown that individuals who experience more positive
emotions tend to have lower rates of cardiovascular events, such as heart
attacks and strokes, and a reduced risk of developing cardiovascular dis-
eases. Positive emotions have been associated with various health-related
behaviors that can influence cardiovascular health, including better die-
tary choices, regular exercise, improved sleep quality, and lower rates of
smoking and alcohol consumption.46 Furthermore, positive emotions
may contribute to improved coping mechanisms, resilience to stress, and
social support, all of which can positively affect cardiovascular health.

Potential Mechanisms of Cardiovascular Protection. While the pre-

cise mechanisms through which positive emotions exert their cardiovas-
cular benefits are not fully understood, several potential pathways have
been proposed:

Curr Probl Cardiol, December 2023 7

Autonomic Nervous System Regulation. Positive emotions, particularly feel-
ings of joy and happiness, have been linked to a shift in the balance of the
autonomic nervous system towards parasympathetic dominance.47 This
shift leads to reduced sympathetic nervous system activity and decreased
release of stress hormones, promoting overall relaxation and heart rate
variability, which is considered a marker of better cardiovascular health.

Endothelial Function and Vascular Health. Endothelial cells lining the blood
vessels play a crucial role in maintaining vascular health and regulating blood
flow. Positive emotions have been associated with improved endothelial func-
tion, leading to better vasodilation and blood vessel health.46 Enhanced endo-
thelial function can improve blood flow and reduce the risk of atherosclerosis,
a condition characterized by plaque buildup in the arteries.

Psychological Stress Buffering. Positive emotions have been shown to

buffer the adverse effects of psychological stress on the cardiovascular
system.48 When individuals experience positive emotions, their stress
response may be less intense, reducing the impact of stress-induced sym-
pathetic nervous system activation and subsequent cardiovascular strain.

Positive Emotions and Takotsubo Cardiomyopathy

While the majority of research on Takotsubo Cardiomyopathy has
focused on the impact of negative emotions and emotional stress as trig-
gers, a limited number of studies have explored the potential role of posi-
tive emotions in this unique cardiac condition.4,6,49 These studies aimed
to investigate whether positive emotional experiences could confer any
cardiovascular protection or influence the occurrence and outcomes of
Takotsubo Cardiomyopathy. The studies investigating the role of positive
emotions in Takotsubo Cardiomyopathy have yielded some interesting
findings and key observations:

Correlation With Emotional Well-Being. Cross-sectional studies have

demonstrated that individuals with higher levels of positive emotions
tend to report better emotional well-being and overall life satisfaction.
However, the specific impact of positive emotions on the occurrence or
outcomes of Takotsubo Cardiomyopathy requires further investigation.50

Potential Protective Effect. Some case-control studies have suggested

that individuals who experience higher levels of positive emotions may
have a reduced risk of developing Takotsubo Cardiomyopathy. These

8 Curr Probl Cardiol, December 2023

observations hint at a potential protective effect of positive emotions on
the heart under emotional stress.

Coping Mechanisms. Studies exploring coping strategies have shown

that individuals who use positive coping mechanisms, such as seeking
social support, finding meaning in difficult situations, and engaging in
positive reframing, may be less susceptible to Takotsubo Cardiomyopa-
thy. These coping strategies, which are often associated with positive
emotions, could contribute to better cardiovascular outcomes. Given that
the prevalence of the “happy heart syndrome” is only 1.1% among all
TTS cases, “happy” events may necessitate more potent stimuli to induce
a substantial emotional response than negative emotions. Perhaps the
threshold to influence the cardiovascular system is higher when happy
events are processed. Alternatively, this might be simply explained by
the propensity of certain individuals to emotional events. At this point,
given the lack of data, we cannot speculate if individuals with preceding
happy events developing TTS would have suffered similar consequences
with preceding negative emotions. Therefore, it is plausible that the indi-
vidual’s brain biochemistry, processing, and response to emotions are dis-
tinct and can explain this observed phenomenon.6

Limited Sample Size. One significant challenge in studying positive emo-

tions in Takotsubo Cardiomyopathy is the limited number of cases avail-
able for research. Takotsubo Cardiomyopathy is a relatively rare condition,
and recruiting a sufficient sample size can be difficult, particularly when
specifically targeting individuals with positive emotional experiences.

Complex Interplay of Emotions

It is essential to acknowledge that emotions are complex and multifac-
eted. Positive emotions may interact with negative emotions and stress
responses dynamically, making it challenging to isolate the individual
impact of positive emotions on Takotsubo Cardiomyopathy.

Clinical Implications and Therapeutic Perspectives

The emerging research on positive emotions and their potential impact
on cardiovascular health, including Takotsubo Cardiomyopathy, has impor-
tant clinical implications and offers promising therapeutic perspectives.
Integrating positive psychology into cardiac care can provide a holistic
approach to improve patient outcomes and enhance overall well-being.

Curr Probl Cardiol, December 2023 9

Harnessing Positive Emotions in Cardiac Care. Emotional Support and
Counseling. Providing emotional support and counseling to patients with
cardiovascular conditions can help them cope with stress, anxiety, and
negative emotions. Encouraging patients to focus on cultivating positive
emotions, such as joy, gratitude, and hope, may contribute to a more posi-
tive outlook and improve overall emotional well-being.

Mindfulness-Based Interventions. Mindfulness-based interventions, such as

mindfulness meditation and yoga, have been shown to promote positive
emotions and reduce stress. These practices can be incorporated into car-
diac care to help patients manage emotional distress and enhance emo-
tional resilience.

Positive Coping Strategies. Encouraging patients to adopt positive coping

strategies, such as seeking social support, engaging in enjoyable activities,
and finding meaning in challenging situations, may help them better navi-
gate emotional stress and cope with the challenges of living with a cardio-
vascular condition. Enhancing Social Support: Social support has been
associated with improved cardiovascular outcomes. Strengthening social
connections and encouraging positive interactions with family, friends, and
support groups can foster a sense of belonging and emotional well-being.

Promoting Gratitude and Acts of Kindness. Gratitude practices, such as

keeping a gratitude journal or expressing gratitude towards others, have
been shown to increase positive emotions. Encouraging patients to
engage in acts of kindness and express appreciation may positively
impact their emotional and cardiovascular health.

Implications for Cardiac Rehabilitation. Comprehensive Lifestyle

Interventions. Cardiac rehabilitation programs can incorporate elements
of positive psychology to complement traditional lifestyle interventions.
Integrating stress management techniques, mindfulness practices, and
positive coping strategies can enhance the overall effectiveness of cardiac
rehabilitation in improving patient outcomes.

Emotional Well-Being Assessment. Including assessments of emotional

well-being and positive emotions in routine cardiac rehabilitation evalua-
tions can provide valuable insights into patients’ emotional health. Identi-
fying individuals at risk of emotional distress can guide personalized
interventions to support their emotional recovery and cardiovascular
health.

10 Curr Probl Cardiol, December 2023

Group Support and Peer Interaction. Group-based cardiac rehabilitation
programs can create a supportive and encouraging environment for
patients to share experiences and engage in positive social interac-
tions. This camaraderie can foster positive emotions and emotional
resilience.

Education on Emotional Health. Educating patients about the impact of

emotional health on cardiovascular outcomes can empower them to take
an active role in managing their emotional well-being. Patients can be
informed about the benefits of positive emotions, stress reduction techni-
ques, and strategies to foster emotional resilience.

Holistic Approach to Recovery. Emphasizing a holistic approach to recov-

ery in cardiac rehabilitation can address not only the physical aspects of
cardiovascular health but also the emotional, psychological, and social
aspects. This comprehensive approach can lead to better patient engage-
ment and long-term adherence to positive lifestyle changes.

Limitations

Limited Research on Positive Emotions. One of the primary limitations

in studying the role of positive emotions in Takotsubo Cardiomyopathy is
the scarcity of research in this specific area. Positive emotions have his-
torically received less attention in cardiovascular research compared to
negative emotions, resulting in a paucity of data and a smaller pool of
studies to conclude from.

Small Sample Size. Takotsubo Cardiomyopathy is a relatively rare con-

dition, and recruiting a sufficient number of patients with the condition
who also report positive emotions can be challenging. The small sample
sizes in some studies may limit the generalizability of findings and the
ability to detect significant associations.

Retrospective Design. Many studies investigating the impact of positive

emotions on Takotsubo Cardiomyopathy have employed retrospective
designs, which may introduce recall bias and reduce the ability to estab-
lish causality between positive emotions and the condition.

The Subjectivity of Emotional Assessment. Assessing and quantifying

positive emotions can be subjective, relying on self-reported measures or

Curr Probl Cardiol, December 2023 11

psychological questionnaires. These methods may not fully capture the
complexity and nuances of emotional experiences, leading to potential
measurement limitations.

Confounding Factors. Emotional experiences are influenced by various

factors, including individual personality traits, cultural background, and
social context. These confounding factors can complicate the interpreta-
tion of study results and make it challenging to isolate the independent
impact of positive emotions on Takotsubo Cardiomyopathy.

Future Directions

Longitudinal Studies. Longitudinal studies that follow individuals over

time, assessing changes in positive emotions and their relationship to the
occurrence and outcomes of Takotsubo Cardiomyopathy, would provide
more robust evidence of any potential causal relationships. Interventional
Studies: Randomized controlled trials exploring the effects of positive
emotion-based interventions in patients at risk of Takotsubo Cardiomyop-
athy or those with the condition could shed light on the therapeutic poten-
tial of positive emotions in cardiac care.

Mechanistic Studies. Further research is needed to elucidate the specific

mechanisms through which positive emotions may influence cardiovascu-
lar health and Takotsubo Cardiomyopathy. Experimental studies focusing
on the physiological, hormonal, and neurological pathways involved can
provide a deeper understanding of these mechanisms.

Cultural Considerations. Taking cultural and individual differences into

account when studying positive emotions is crucial. Cross-cultural stud-
ies could help identify how cultural backgrounds influence emotional
experiences and the subsequent impact on cardiovascular health.

Integration into Clinical Practice. Future research should explore prac-

tical ways to integrate positive psychology approaches into routine car-
diac care and rehabilitation. Developing evidence-based interventions
and guidelines for promoting positive emotions in cardiac patients can
enhance the overall management of cardiovascular conditions.

Emotions and Recurrence Risk. Investigating the potential relationship

between positive emotions and the risk of Takotsubo Cardiomyopathy

12 Curr Probl Cardiol, December 2023

recurrence could have important clinical implications for long-term
patient care and secondary prevention strategies.

Conclusion
In conclusion, while the research on positive emotions and Takotsubo
Cardiomyopathy is still in its early stages, it offers promising insights
into the potential benefits of fostering positive emotional experiences in
cardiac care. Positive emotions may play a protective role, enhance cop-
ing mechanisms, and contribute to overall emotional resilience in individ-
uals with cardiovascular conditions. As we continue to explore this
exciting field, it becomes increasingly evident that incorporating positive
psychology into clinical practice and cardiac rehabilitation could lead to
more holistic and patient-centered approaches to cardiovascular care.
Addressing the limitations and pursuing future research directions will
undoubtedly pave the way for improved patient outcomes and a deeper
understanding of the interplay between emotions and heart health.

Declaration of Competing Interest

The authors declare that they have no known competing financial inter-
ests or personal relationships that could have appeared to influence the
work reported in this paper.

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