Happy Heart Syndrome: When Joy Becomes a Cardiac Event

INTRODUCTION

Takotsubo syndrome (TTS) has emerged as a distinct cardiovascular condition characterized by transient left ventricular (LV) dysfunction that mimics acute coronary syndrome (ACS), typically in response to stressful triggers.^[1,2] While traditionally associated with negative emotional experiences such as grief, fear, and/or interpersonal conflicts, leading to its popular characterization as “broken heart syndrome,” recent research has unveiled a fascinating variant known as “happy heart syndrome,” where positive emotional events precipitate similar presentation and cardiac manifestations.^[3-7] This review examines the current understanding of happy heart syndrome (HHS), synthesizing evidence regarding its epidemiology, clinical characteristics, pathophysiological mechanisms, and therapeutic implications.

PATHOPHYSIOLOGY

The pathophysiology of TTS and HHS is still incompletely understood and represents a brain-heart interaction with complex interplay between emotional processing, neurohormonal activation with sympathetic and catecholamine excess, and cardiovascular response [Figure 1]. Several key mechanisms have been proposed:

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Figure 1: Pathophysiological mechanisms of happy heart syndrome. (HPA: Hypothalamic-pituitary- adrenal axis, ADAM17: A disintegrin and metalloproteinase 17, HHS: Happy heart syndrome, TTS: Takotsubo syndrome).

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DEMOGRAPHIC FEATURES

HHS demonstrates distinct demographic patterns compared to its negative emotion-triggered counterpart, BHS. While both variants predominantly affect postmenopausal women (mean age 67–69 years), HHS shows a significantly higher prevalence in male patients, 18.9% compared to 5.0% in BHS, as seen in the largest TTS registry.^[2,5,7] This gender distribution difference suggests potential variations in emotional processing and cardiovascular response between males and females in the context of positive versus negative emotional stimuli. Age distribution is similar, with 85% of cases occurring in patients over the age of 50.^[7,22] Rates of cardiovascular disease and comorbidities are similar in those presenting with HHS versus BHS and include hypertension (~67%), dyslipidemia (~47%), coronary artery disease (CAD) (~8%), diabetes (~5%), and psychiatric disorders (~7%).^[2,7,24,25] Notably, HHS patients may have lower rates of anxiety and depression compared to traditional TTS patients.^[25]

CLINICAL PRESENTATION AND DIAGNOSIS

Despite the different triggers, several aspects remain consistent between HHS and BHSs. A diagnostic approach for systematic evaluation has been elucidated in Figure 2.

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Figure 2: Diagnostic algorithm for happy heart syndrome. (ACS: Acute coronary syndrome, CAD: Coronary artery disease, CK: Creatine kinase, HHS: Happy heart syndrome, LVEDP: Left ventricular end diastolic pressure, LVOT: Left ventricular outflow tract, NT-proBNP: N-Terminal pro- B-type natriuretic peptide, QTc: Corrected QT interval, RWMA: Regional wall motion abnormality, STEMI: ST-elevation myocardial infarction).

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• Clinical presentation: Clinical features on presentation are similar for HHS and BHS. Patients typically present with clinical syndrome initially indistinguishable from acute myocardial infarction (MI), with chief complaint of chest pain (80–90%) and dyspnea (25%). However, presentation may include symptoms and signs of heart failure, syncope, respiratory distress, and shock.^[7,8]

• Electrocardiographic (ECG) changes: ECG findings are also similar in both HHS and BHS and may include ST elevation (usually anterior precordial leads V2-V5 and limb leads II and augmented vector right, inferior ST elevation alone is distinctly uncommon), T-wave inversion (often more prominent and broadly distributed than in ACS), QT prolongation, abnormal Q waves and left bundle branch block (5%). ST depression is uncommon (<10%) and may help in differentiating from ACS. Pronounced corrected QT interval prolongation (>500 ms) may help to differentiate from ST-elevation myocardial infarction (STEMI) retrospectively but shouldn’t guide prospective diagnosis. Most patients are in sinus rhythm, but arrhythmias such as atrial fibrillation (5%) may occur at presentation. Normal ECGs are atypical.^[7,8]

• Cardiac biomarkers: Biomarkers of myocardial necrosis such as cardiac troponins and creatine kinase, and LV dysfunction such as N-Terminal pro-B-type natriuretic peptide are usually elevated. However, the peak values of these biomarkers are substantially lower than similar presentations with ACS, and the level of LV dysfunction is out of proportion to what might be expected based on the levels of these biomarkers.^[7,8]

• Echocardiography: An echocardiogram shows regional wall motion abnormalities in a typical pattern that extends beyond the distribution of a single coronary artery.^[7,8] Four distinct patterns of LV dysfunction is seen in TTS: (1) Apical ballooning pattern with hypokinesia, akinesia, or dyskinesia of the mid to apical myocardial segments and involving the anterior, inferior, and lateral walls (a circumferential pattern), (2) Midventricular pattern with hypokinesia, akinesia, or dyskinesia of the mid ventricular segments only and apical sparing, (3) Basal form with basal segments involved only, and (4) Focal TTS, mostly resulting in anterolateral hypokinesis. TTS usually shows symmetrical regional abnormalities involving the mid-ventricular segments of the anterior, inferior, and lateral walls (a circumferential pattern). Although the apical ballooning pattern is more common in BHS, midventricular involvement with apical sparing appears to occur relatively more frequently in HHS [Figure 3].^[6,7,26,27] This difference in ventricular contraction patterns may reflect underlying variations in the distribution and activation of sympathetic nervous system components.

  

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  Figure 3: 2D echocardiogram, apical 4-chamber view, during systole, demonstrating contraction of the apex (white arrowhead), mid-ventricular ballooning (orange line), and basal segments (white arrow); right ventricular contraction is normal (LV: Left ventricle, LA: Left atrium, RV: Right ventricle, RA: Right atrium).

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• Coronary Angiography and left ventriculography: Urgent coronary angiography is often essential in TTS to exclude an ACS (STEMI or non-ST elevation myocardial infarction), as patients present with chest pain and ST changes. Epicardial coronary arteries may be normal and thus aid in the diagnosis of TTS, but bystander CAD may be present in ~10% of cases, and as such, careful examination of the coronary anatomy in correlation with LV dysfunction is essential in distinguishing TTS from MI. The hallmark of LV dysfunction in TTS is that the regional wall motion abnormalities extend beyond the distribution of the coronary artery (left anterior descending artery). Left ventriculography at the time of cardiac catheterization is extremely useful to establish the diagnosis by demonstrating the classical pattern of TTS as described above. Furthermore, hemodynamics are performed to assess the LV end-diastolic pressure and measure LV outflow tract (LVOT) gradient which suggests LVOT obstruction and portends a poorer prognosis. Evaluation for LVOT obstruction is important because it is present in up to 20% of cases and directly alters management. Dynamic LVOT obstruction can precipitate or worsen hypotension and cardiogenic shock, and its presence contraindicates inotropes and nitrates, which may aggravate the obstruction; a short- acting beta-blocker (e.g., esmolol), cautious volume, and low-dose vasopressors are preferred instead.^[7,8]

• Cardiac Magnetic Resonance Imaging (MRI): Cardiac magnetic resonance imaging (CMR) provides a comprehensive assessment of myocardial structure and function in HHS, offering unique insights into tissue characterization and differential diagnosis but is challenging to use in the acute setting and generally reserved for the subacute phase, particularly if the diagnosis is not clear on echocardiography and cardiac catheterization. MRI helps to identify the typical wall motion abnormalities in TTS described above, in addition to quantification of left and right ventricular function, any complications such as apical thrombosis, and allows for characterization of myocardial tissue (edema, inflammation, and/or necrosis). There is typically an absence of late gadolinium enhancement (LGE) on delayed contrast sequences in most cases [Figure 4], which helps in differentiating TTS from ACS and many cases of myocarditis.^[6,8,28-30] Absence of LGE shows absence of irreversible myocardial injury and predicts normalization of LV function with time.

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Figure 4: (A) CMR performed 1 month after the onset of the condition (happy heart syndrome) showed STIR in the entire circumference of the left ventricular apical region, with a high signal and almost transmural LGE in the same region (red arrows). (B) CMR 6 months after the onset showed normalization, with the high signals for STIR and LGE having disappeared. (CMR: Cardiac magnetic resonance imaging, LGE: Late gadolinium enhancement, STIR: Short-tau inversion recovery).

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OUTCOMES

HHS and TTS in general are usually considered a benign and reversible condition with rapid recovery of LV function in days to weeks. However, the hemodynamic and electrical instability that may accompany the acute phase of presentation may result in serious life-threatening adverse events. In fact, recent data indicate that rates of cardiogenic shock and death approach that of treated ACS patients. Common in-hospital adverse events include acute heart failure (15–40%), mitral regurgitation, cardiogenic shock (5–15%), atrial fibrillation (5–15%), LV thrombus (2–8%), tachyarrhythmias and bradyarrhythmias (2–5%), and death (1.4%).^[6-8] Reported long-term mortality is 2.7%.^[7]

Current evidence suggests numerically lower but statistically similar in-hospital adverse outcomes and long-term mortality in patients presenting with HHS versus BHS.^[6-8]

MANAGEMENT

There is no definitive treatment of TTS, and prospective clinical trials are lacking in HHS or BHS. Management is therefore based on expert opinion and extrapolated from the treatment of heart failure, LV dysfunction, and ACS in general. Treatment depends on the severity of symptoms, the presence of heart failure, and the hemodynamic stability of the patient [Figure 5]. In the setting of mild TTS with LV ejection fraction (LVEF) >45% and no signs of heart failure, observation with consideration of an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker usually suffices. In those with heart failure and LVEF <45%, ACE inhibitors or angiotensin receptor blockers (ARBs) and beta-blockers are recommended for LV dysfunction and may potentially facilitate LV recovery.^[8,31] Diuretics and nitrates may be added in case of volume overload or pulmonary edema.

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Figure 5: Management pathway for happy heart syndrome (LVEF: Left ventricular ejection fraction, ACE: Angiotensin converting enzyme, ARBs: Angiotensin receptor blockers, ECMO: Extracorporeal membrane oxygenation, LVAD: Left ventricular assist device).

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For patients with severe heart failure and shock, treatment depends on whether LVOT obstruction is present (~20% of cases of TTS) or not.^[31-33] Inotropic agents (e.g. dobutamine, milrinone) may be used in the absence of LVOT obstruction but may cause or worsen LVOT obstruction if it is present. Vasopressor drugs may be required if severe hypotension is present, and a peripherally acting vasopressor at low doses may be particularly helpful in cases of LVOT obstruction. Diuretics should be used very judiciously in those with LVOT obstruction. Nitrates may worsen LVOT obstruction and should therefore be avoided in this setting. A short- acting beta-blocker (e.g., esmolol) may be helpful in the presence of LVOT obstruction. For patients with shock and LVOT obstruction, treatment is challenging and requires an intensive care setting. If medical therapy is not sufficient, mechanical support may be considered (e.g., intra-aortic balloon pump, extracorporeal membrane oxygenation, and/ or LV Assist Device).^[8,31-33]

While there are no clinical trial data, retrospective analyses of registries show a potential benefit of ACE inhibitors or ARBs on 1-year survival and no significant benefit of beta- blockers in reducing in-hospital and one-year outcomes.^[2,34] Nevertheless, given the potential for benefit, many experts advocate the use of beta-blockers.

Antiplatelet and statin therapy have no role in the treatment of HHS itself. The myocardial injury in HHS results from catecholamine-mediated myocardial stunning rather than atherothrombotic plaque rupture, and there is no evidence that HHS increases the subsequent risk of ACS.^[6-8] The elevated troponin in this setting reflects transient myocyte injury and should not be interpreted as evidence of coronary atherothrombosis. Regarding indications, aspirin and a statin are often started empirically at first contact because the presentation is clinically indistinguishable from ACS; once urgent coronary angiography excludes obstructive coronary disease, these agents can be stopped, as they offer no benefit in the absence of CAD. Continuation is indicated only when concomitant (bystander) CAD is demonstrated, which occurs in about 10% of cases, or when the patient independently meets criteria for lipid-lowering therapy on the basis of cardiovascular risk assessment; this remains relevant because patients with HHS frequently have hypertension and dyslipidaemia, so risk-factor evaluation is important even after recovery of LV function. Regarding duration, there is no basis for a fixed 6-month course of aspirin and a statin as prophylaxis against ACS, and this practice is not supported by evidence. Where bystander CAD is confirmed, aspirin and a statin should be continued long term as guideline-directed secondary prevention for the coronary disease, and not for a predefined period linked to the HHS episode; dual antiplatelet therapy is indicated only if coronary stenting has been performed, for the duration recommended by contemporary coronary guidelines. Where the coronary arteries are normal, no antiplatelet or statin therapy is required after the acute evaluation.^[7,8,31]

The presence of LV thrombus requires anticoagulation for 3 months with repeat imaging thereafter; unnecessary concomitant antiplatelet therapy in this setting would add bleeding risk without benefit.^[8,31] Psychiatric disorders such as depression and anxiety, if present, may benefit from psychotherapy and medications such as antidepressants and anxiolytics, although there are no firm data.^[8,31]

RECURRENCE AND PREVENTION

Recurrence of HHS is relatively uncommon but represents an important clinical consideration for long-term patient management. Current data from large registry studies and meta-analyses indicate that the recurrence rate of TTS is approximately 1–11.4%.^[23] Most recurrences occur within the first 5 years after the initial event. A variable TTS pattern at recurrence is common in up to 20% of recurrence cases, and interestingly, recurrence may involve similar positive emotional stimuli or different triggers, including both positive and negative emotional experiences.^[23,34]

Several factors may increase the risk of HHS recurrence, including demographic factors such as advanced age, female gender, and psychiatric comorbidities, as well as medical comorbidities including hypertension, diabetes, and chronic kidney disease.^[12,23,25] Emotional factors such as high emotional reactivity, anxiety disorders, and depression also contribute to recurrence risk, along with lifestyle factors including high stress levels and poor coping mechanisms.^[25]

Prevention strategies for HHS encompass both primary prevention of first episodes and secondary prevention of recurrence. Primary prevention focuses on emotional regulation techniques and stress management, treatment of underlying psychiatric conditions, and optimal control of cardiovascular risk factors including blood pressure and diabetes management.^[24,25] Secondary prevention strategies for recurrence prevention involve a comprehensive approach combining pharmacological and non-pharmacological interventions. Pharmacological approaches include long-term beta-blocker therapy, which, in theory, may reduce recurrence risk by blunting catecholamine effects, ACE inhibitors or ARBs for patients with persistent LV dysfunction, anxiolytics for patients with significant anxiety or emotional reactivity, and antidepressants when indicated for mood disorders.^[4,8,25,31] However, non-randomized data show that beta blockers after discharge do not appear to prevent recurrence whereas ACE inhibitors or ARBs are associated with lower rates of recurrence.^[23]

Non-pharmacological approaches are equally important and include psychosocial interventions such as cognitive behavioral therapy and stress reduction techniques, patient education regarding recognition of triggers and early warning signs, lifestyle modifications including regular exercise, adequate sleep, and avoidance of excessive emotional stimuli, and family counseling to educate family members about trigger recognition.^[8,25] Regular follow-up care is essential and should include clinical evaluation every 6–12 months, echocardiography to assess LV function recovery, monitoring for development of new symptoms, and ongoing psychological assessment and support to ensure comprehensive long-term management.^[8,12]

CONCLUSION

HHS represents a fascinating variant of TTS that challenges traditional understanding of emotional stress and cardiovascular function. While less common than its negative emotion-triggered counterpart, it demonstrates distinct features including higher male prevalence and predominant midventricular ballooning patterns. The syndrome generally carries a favorable prognosis, with low reported in-hospital mortality and rare late complications. Understanding these unique characteristics not only provides insights into the complex brain-heart axis but also highlights the need for tailored therapeutic approaches. Future large-scale studies and detailed mechanistic investigations will be crucial for advancing our understanding of this intriguing condition.