RIGHT VENTRICULAR INVOLVEMENT IN TAKOTSUBO CARDIOMYOPATHY

RIGHT VENTRICULAR INVOLVEMENT IN TAKOTSUBO CARDIOMYOPATHY

U. Vinitha Sri *, A. Sushmitha, B. Sendilkumar, Rohit Gouttam, M. Gesavardhini and G. Rajkumar

School of Allied Health Science, Vinayaka Mission Research Foundation (DU), Salem, Tamil Nadu, India.

ABSTRACT: Takotsubo cardiomyopathy (TTC) is a transient cardiac condition characterized by acute left ventricular dysfunction. While traditionally considered a left ventricular disorder, growing evidence suggests that right ventricular (RV) involvement is more common and clinically significant than initially thought. This review provides a comprehensive overview of RV involvement in TTC, focusing on its prevalence, pathophysiology, clinical presentation, diagnostic approaches, and management considerations. Recent studies estimate the prevalence of RV involvement in TTC at 25-50% of cases. The pathophysiology is complex, involving catecholamine surge, microvascular dysfunction, and ventricular interdependence. RV involvement is associated with worse clinical outcomes, including higher mortality and complication rates. Diagnosis relies on multimodal imaging, primarily echocardiography and cardiac MRI, along with biomarkers and hemodynamic assessment. Management of TTC with RV involvement requires a tailored approach, balancing supportive care with potential need for mechanical circulatory support. Challenges in diagnosis and management include differentiating from other conditions and limited RV-specific therapies. Special populations, such as the elderly and those with chronic lung disease, present unique considerations. Recent advances in imaging techniques and biomarker research show promise for improving early detection and risk stratification. Future perspectives include developing standardized diagnostic criteria, exploring targeted therapies, and establishing large-scale registries to advance our understanding of this complex condition. In conclusion, RV involvement in TTC significantly influences patient prognosis and management. Clinicians should maintain a high index of suspicion for RV involvement in all TTC cases and tailor their approaches accordingly. Continued research is crucial for enhancing our understanding and improving care for this patient population.

Keywords: Takotsubo cardiomyopathy, Right ventricular dysfunction, Stress-induced cardiomyopathy, Biventricular involvement, Cardiac imaging

INTRODUCTION: Takotsubo cardiomyopathy (TTC), also known as stress cardiomyopathy or broken heart syndrome, is a transient cardiac condition characterized by acute left ventricular dysfunction. First described in Japan in 1990 by Sato et al. ¹, TTC has gained significant attention in the cardiovascular community due to its unique pathophysiology and clinical presentation. While traditionally considered a left ventricular disorder, increasing evidence suggests that right ventricular (RV) involvement is more common and clinically significant than initially thought ².

This review aims to provide a comprehensive overview of right ventricular involvement in Takotsubo cardiomyopathy, focusing on its prevalence, pathophysiology, clinical presentation, diagnostic approaches, classification, hemodynamic impact, prognostic implications, management considerations, and future perspectives. By examining the current literature and recent advances, we seek to enhance understanding of this important aspect of TTC and its implications for patient care.

Prevalence and Recognition: The prevalence of RV involvement in TTC has been underestimated for years. Initial reports focused primarily on left ventricular abnormalities, with right ventricular dysfunction considered a rare occurrence. However, recent studies have challenged this notion, suggesting that RV involvement is far more common than previously believed.

A meta-analysis by Pelliccia et al. in 2017 reported that RV involvement occurs in approximately 25-30% of TTC cases ³. However, some single-center studies have reported even higher rates, with RV dysfunction observed in up to 50% of patients with TTC ⁴. The growing recognition of RV involvement is attributed to several factors:

1. Improved Imaging Techniques: Advanced echocardiographic methods and cardiac magnetic resonance imaging (MRI) have enabled better visualization and assessment of RV structure and function ⁵.
2. Increased Awareness: As knowledge of TTC has expanded, clinicians have become more attuned to the possibility of RV involvement, leading to more frequent evaluation and documentation ⁶.
3. Standardized Criteria: The development of diagnostic criteria for RV involvement in TTC has facilitated more consistent reporting and comparison across studies ⁷.

It is important to note that the true prevalence of RV involvement may still be underestimated, as some cases may be missed due to the transient nature of TTC and variability in imaging practices across institutions.

Pathophysiology: The exact mechanisms underlying RV involvement in TTC are not fully understood, but several theories have been proposed. The hallmark catecholamine surge affecting both ventricles is a primary factor, with the RV potentially more susceptible due to its thinner wall ¹. Coronary microvascular dysfunction may extend to the right coronary system, while ventricular interdependence can lead to RV impairment secondary to LV dysfunction ^{2, 3}. Acute pulmonary hypertension resulting from left-sided failure can strain the RV, and diffuse myocardial edema may affect both ventricles ⁴. Some researchers propose an autonomic nervous system imbalance as a contributing factor ⁵. Understanding these pathophysiological mechanisms is crucial for developing targeted therapies and improving outcomes in patients with RV involvement in TTC.

Clinical Presentation: The clinical presentation of TTC with RV involvement can be diverse and may differ from cases with isolated left ventricular involvement. The clinical manifestations are shown in Fig. 1.

Common features include:

• Dyspnea and Fatigue: These symptoms are often more pronounced in patients with biventricular involvement compared to those with isolated left ventricular TTC ¹⁵.
• Right-Sided Heart Failure Signs: Jugular venous distension, peripheral edema, and hepatomegaly may be observed in cases with significant RV dysfunction ¹⁶.
• Hypotension and Cardiogenic Shock: Biventricular involvement is associated with a higher risk of hemodynamic instability and cardiogenic shock ¹⁷.
• Chest Pain: Similar to classical TTC, patients may experience acute chest pain mimicking acute coronary syndrome ¹⁸.
• Syncope or Pre-Syncope: Reduced cardiac output due to biventricular involvement can lead to cerebral hypoperfusion and syncope ¹⁹.
• Electrocardiographic Changes: While ST-segment elevation or T-wave inversion in precordial leads is common in TTC, patients with RV involvement may show these changes in right precordial leads (V1-V3) as well ²⁰.

Arrhythmias: Both atrial and ventricular arrhythmias can occur, with some studies suggesting a higher incidence in patients with RV involvement ²¹.

FIG. 1: CLINICAL MANIFESTATIONS OF RV INVOLVEMENT IN TTC

It's important to note that RV involvement may not always be clinically apparent and requires a high index of suspicion. Some patients may present with predominantly left-sided symptoms, and RV dysfunction may only be detected on imaging studies.

Diagnostic Approach: Diagnosing RV involvement in TTC requires a multimodal approach. Echocardiography remains the primary tool, assessing regional wall motion abnormalities, RV ejection fraction, TAPSE, and other parameters ⁶. Cardiac MRI provides detailed evaluation of RV structure, function, and tissue characterization, including myocardial edema and fibrosis ⁷. Coronary angiography is essential to rule out obstructive coronary artery disease ⁸. Cardiac biomarkers, while not specific to RV involvement, may be more pronounced in biventricular cases ⁹. Electrocardiography may show changes in right precordial leads, and hemodynamic assessment through right heart catheterization can reveal elevated right-sided pressures and reduced cardiac output ^{10, 11}. Nuclear imaging techniques, though less commonly used, can provide additional information on myocardial perfusion and metabolism ¹². The RV involvement in TTC diagnosed with different parameters is detailed in Table 1 and Fig. 2 illustrates TAPSE measurement.

TABLE 1: RV INVOLVEMENT IN TTC

RV: Right Ventricle, TAPSE: Tricuspid Annular Plane Systolic Excursion, FAC: Fractional Area Change, RVOT: Right Ventricular Outflow Tract, IVC: Inferior Vena Cava, RA: Right Atrium, MI: Myocardial Infarction, LGE: Late Gadolinium Enhancement.

FIG. 2: TAPSE MEASUREMENT

Classification of Right Ventricular Involvement: RV involvement in TTC can be classified based on the extent and pattern of dysfunction and showed in Fig. 3:

1. Isolated RV Involvement: Rare cases where only the right ventricle is affected, with preserved left ventricular function ²⁸.
2. Biventricular Involvement: Both left and right ventricles show characteristic wall motion abnormalities. This is the most common form of RV involvement in TTC ²⁹.
3. RV Sparing: Classic left ventricular TTC without significant RV dysfunction ³⁰.
4. Focal RV Involvement: Only specific segments of the RV (e.g., free wall or apex) are affected ³¹.
5. Global RV Dysfunction: The entire right ventricle shows reduced contractility ³².

Some researchers have proposed more detailed classification systems based on the combination of left and right ventricular involvement patterns, but these are not yet widely adopted in clinical practice ³³.

FIG. 3: INVOLVEMENT OF HEART CHAMBERS IN TTC

Hemodynamic Impact: RV involvement in TTC can have significant hemodynamic consequences. Biventricular dysfunction leads to a more pronounced reduction in overall cardiac output compared to isolated left ventricular TTC ¹³. Elevated right-sided pressures can result in systemic venous congestion, affecting organ perfusion, particularly in the liver and kidneys ¹⁴. Interventricular dependence can further impair left ventricular filling through septal shift, exacerbating the overall hemodynamic compromise ¹⁵. Pulmonary hypertension, secondary to left ventricular dysfunction, increases RV afterload and may worsen RV function ¹⁶. Additionally, RV dilatation and dysfunction can lead to functional tricuspid regurgitation, further complicating the hemodynamic picture ¹⁷. Understanding these alterations is crucial for appropriate management, particularly in cases requiring mechanical circulatory support.

Prognostic Implications: Several studies have demonstrated that RV involvement in TTC is associated with worse clinical outcomes. A meta-analysis found that RV involvement was associated with a 3.5-fold increase in short-term mortality ¹⁸. Patients with RV involvement are more likely to experience complications such as cardiogenic shock, respiratory failure, and need for mechanical ventilation ¹⁹.

RV dysfunction is associated with prolonged hospitalization and increased resource utilization ²⁰. Some studies suggest a higher risk of TTC recurrence in patients with RV involvement, although data on this is limited ²¹. While TTC is generally considered reversible, patients with RV involvement may experience a more prolonged recovery of ventricular function ²². The impact on long-term outcomes remains an area of ongoing research, with some studies suggesting persistent subclinical cardiac dysfunction in a subset of patients ²³.

Management Considerations: Managing TTC with RV involvement requires a tailored approach. Supportive care, including careful fluid management and treatment of precipitating factors, remains the mainstay ²⁴. Hemodynamic support may involve inotropes, although caution is advised given the potential role of catecholamines in TTC pathogenesis ²⁵. Severe cases may require mechanical circulatory support such as ECMO or biventricular assist devices ²⁶. Anticoagulation should be considered due to the risk of intracardiac thrombus formation ²⁷. Beta-blockers and ACE inhibitors/ARBs, while often used in TTC, should be administered cautiously in cases of significant RV dysfunction ²⁸. Pulmonary vasodilators may be beneficial in cases complicated by significant pulmonary hypertension ²⁹. Close monitoring and management of arrhythmias is essential, as is serial imaging to monitor ventricular function recovery ³⁰.

Special Populations: Certain populations present unique challenges in RV involvement in TTC. Elderly patients have a higher likelihood of RV involvement and worse outcomes ³¹. Those with chronic lung disease may have pre-existing pulmonary hypertension, predisposing to RV involvement and complicating management ³². Postoperative patients may be at higher risk for TTC with RV involvement ³³. Some studies suggest a higher prevalence of RV involvement in TTC patients with underlying psychiatric conditions ³⁴. While rare, TTC can occur during pregnancy or the postpartum period, presenting unique management challenges in this population ³⁵.

Challenges in Diagnosis and Management: Several challenges exist in diagnosing and managing RV involvement in TTC. Differentiating from conditions such as acute pulmonary embolism or right ventricular infarction can be difficult ³⁶. Limited RV-specific therapies and variability in imaging practices across institutions may lead to suboptimal management and potential underdiagnosis ³⁷. The transient nature of TTC means that the timing of assessment can significantly impact the detection of RV involvement ³⁸. Balancing hemodynamic support while avoiding excessive catecholamine stimulation is challenging, and the optimal duration and intensity of long-term follow-up remain unclear ³⁹.

Recent Advances: Recent advances have improved our understanding and management of RV involvement in TTC. Novel imaging techniques, such as speckle tracking and 3D echocardiography, have enhanced detection and quantification of RV dysfunction ⁴⁰. Research into novel biomarkers, genetic susceptibility, and targeted therapies addressing catecholamine-induced cardiotoxicity shows promise for future management strategies. Artificial intelligence algorithms are being developed to improve early detection and risk prediction in TTC, including RV involvement.

Future Perspectives: Looking ahead, several areas warrant further investigation. Development of standardized diagnostic criteria for RV involvement in TTC is needed to facilitate consistent reporting and research comparisons. Further studies into the pathophysiology, particularly at the cellular and molecular level, may identify potential therapeutic targets. Development of management protocols specifically addressing the unique hemodynamic challenges of biventricular TTC is crucial. Prospective studies to better understand long-term implications and potential preventive measures for high-risk populations are needed. Exploration of novel therapeutic approaches, including cell-based therapies and targeted molecular interventions, holds promise. Establishment of large-scale, international registries will facilitate data pooling and advance our understanding of this complex condition.

CONCLUSION: Right ventricular involvement in Takotsubo cardiomyopathy is a significant clinical entity that has gained increasing recognition in recent years. Its prevalence, estimated at 25-50% of TTC cases, underscores the importance of comprehensive cardiac evaluation in these patients. The complex pathophysiology, involving catecholamine surge, microvascular dysfunction, and ventricular interdependence, presents unique diagnostic and therapeutic challenges. RV involvement is associated with worse clinical outcomes, including higher mortality and complication rates, emphasizing the need for early recognition and targeted management strategies. Advances in imaging techniques, particularly echocardiography and cardiac MRI, have improved our ability to detect and characterize RV dysfunction in TTC. However, challenges remain in standardizing diagnostic criteria and optimizing management approaches. The hemodynamic impact of RV involvement necessitates careful consideration in therapeutic decision-making, particularly regarding fluid management and the use of inotropic support.

As our understanding of RV involvement in TTC evolves, several areas warrant further investigation. These include the development of RV-specific therapies, exploration of genetic and molecular mechanisms, and long-term follow-up studies to elucidate the lasting impact of this condition. The establishment of large-scale registries and collaborative research efforts will be crucial in advancing our knowledge and improving patient outcomes.

In conclusion, right ventricular involvement represents an important aspect of Takotsubo cardiomyopathy that significantly influences patient prognosis and management. Clinicians should maintain a high index of suspicion for RV involvement in all TTC cases and tailor their diagnostic and therapeutic approaches accordingly. Future research focusing on the unique aspects of RV involvement in TTC holds promise for enhancing our understanding and improving care for this complex patient population.

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: Nil

REFERENCES:

1. Sato H, Tateishi H and Uchida T: Tako-tsubo-like left ventricular dysfunction due to multivessel coronary spasm. In: Kodama K, Haze K, Hori M, eds. Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure. Tokyo: Kagakuhyoronsha Publishing Co; 1990; 56-64.
2. Templin C, Ghadri JR and Diekmann J: Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med 2015; 373(10): 929-938.
3. Pelliccia F, Kaski JC, Crea F and Camici PG: Pathophysiology of Takotsubo Syndrome. Circulation 2017; 135(24): 2426-2441.
4. Fitzgibbons TP and Madias JE: Pathophysiology of Biventricular Takotsubo Cardiomyopathy. JACC Heart Fail 2020; 8(10): 829-831.
5. Lyon AR, Bossone E and Schneider B: Current state of knowledge on Takotsubo syndrome: a Position Statement from the Taskforce on Takotsubo Syndrome of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2016; 18(1): 8-27.
6. Citro R, Bossone E and Parodi G: Clinical profile and in-hospital outcome of Takotsubo syndrome in men: Results from a multicenter Italian registry. Int J Cardiol 2018; 273: 67-72.
7. Eitel I, von Knobelsdorff-Brenkenhoff F and Bernhardt P: Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. JAMA 2011; 306(3): 277-286.
8. Ghadri JR, Wittstein IS and Prasad A: International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology. Eur Heart J 2018; 39(22): 2032-2046.
9. Citro R, Lyon AR and Meimoun P: Standard and advanced echocardiography in takotsubo (stress) cardiomyopathy: clinical and prognostic implications. J Am Soc Echocardiogr 2015; 28(1): 57-74.
10. Kagiyama N, Okura H and Tamada T: Impact of right ventricular involvement on the prognosis of takotsubo cardiomyopathy. Eur Heart J Cardiovasc Imaging 2016; 17(2): 210-216.
11. Arcari L, Nucifora G and Badano LP: Biventricular involvement in transient global left ventricular dysfunction. JACC Cardiovasc Imaging 2019; 12(3): 517-519.
12. Kurowski V, Kaiser A and von Hof K: Apical and midventricular transient left ventricular dysfunction syndrome (tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest 2007; 132(3): 809-816.
13. Santoro F, Mallardi A and Leopizzi A: Current Knowledge and future challenges in takotsubo syndrome: part 2-treatment and prognosis. J Clin Med 2021; 10(3): 468.
14. Almendro-Delia M, Núñez-Gil IJ and Lobo M: Short- and long-term prognostic relevance of cardiogenic shock in takotsubo syndrome: results from the retako registry. JACC Heart Fail 2018; 6(11): 928-936.
15. Ghadri JR, Kato K and Cammann VL: Long-Term prognosis of patients with takotsubo syndrome. J Am Coll Cardiol 2018; 72(8): 874-882.
16. Kato K, Lyon AR, Ghadri JR and Templin C: Takotsubo syndrome: aetiology, presentation and treatment. Heart 2017; 103(18): 1461-1469.
17. Medina de Chazal H, Del Buono MG and Keyser-Marcus L: Stress cardiomyopathy diagnosis and treatment: JACC State-of-the-Art Review. J Am Coll Cardiol 2018; 72(16): 1955-1971.
18. Pelliccia F, Pasceri V and Patti G: Long-Term Prognosis and Outcome Predictors in Takotsubo Syndrome: A Systematic Review and Meta-Regression Study. JACC Heart Fail 2019; 7(2): 143-154.
19. Citro R, Radano I and Parodi G: Long-term outcome in patients with Takotsubo syndrome presenting with severely reduced left ventricular ejection fraction. Eur J Heart Fail 2019; 21(6): 781-789.
20. Yoshikawa T: Takotsubo cardiomyopathy, a new concept of cardiomyopathy: clinical features and pathophysiology. Int J Cardiol 2015; 182: 297-303.
21. Singh K, Carson K and Shah R: Meta-analysis of clinical correlates of acute mortality in takotsubo cardiomyopathy. Am J Cardiol 2014; 113(8): 1420-1428.
22. Dias A, Núñez Gil IJ and Santoro F: Takotsubo syndrome: State-of-the-art review by an expert panel - Part 2. Cardiovasc Revasc Med 2019; 20(2): 153-166.
23. Templin C, Hänggi J and Klein C: Altered limbic and autonomic processing supports brain-heart axis in Takotsubo syndrome. EHJ 2019; 40(15): 1183-1187.
24. Ghadri JR, Wittstein IS and Prasad A: International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management. Eur Heart J 2018; 39(22): 2047-2062.
25. Ansari U, El-Battrawy I and Fastner C: Clinical outcomes associated with catecholamine use in patients diagnosed with Takotsubo cardiomyopathy. BMC Cardiovasc Disord 2018; 18(1): 54.
26. Bonacchi M, Maiani M, Harmelin G and Sani G: Extracorporeal membrane oxygenation in refractory cardiogenic shock due to takotsubo cardiomyopathy. Ann Thorac Surg 2009; 88(5): 1672-1674.
27. de Gregorio C, Grimaldi P and Lentini C: Left ventricular thrombus formation and cardioembolic complications in patients with Takotsubo-like syndrome: a systematic review. Int J Cardiol 2008; 131(1): 18-24.
28. Santoro F, Ieva R and Ferraretti A: Safety and feasibility of levosimendan administration in takotsubo cardiomyopathy: a case series. Cardiovasc Ther 2013; 31(6): 133-e137.
29. Kyuma M, Tsuchihashi K and Shinshi Y: Effect of intravenous propranolol on left ventricular apical ballooning without coronary artery stenosis (ampulla cardiomyopathy): three cases. Circ J 2002; 66(12): 1181-1184.
30. Redfors B, Vedad R and Angerås O: Mortality in takotsubo syndrome is similar to mortality in myocardial infarction - A report from the SWEDEHEART registry. Int J Cardiol 2015; 185: 282-289.
31. Schneider B, Athanasiadis A and Schwab J: Complications in the clinical course of tako-tsubo cardiomyopathy. Int J Cardiol 2014; 176(1): 199-205.
32. El-Battrawy I, Santoro F and Stiermaier T: Prevalence, Management, and Outcome of Adverse Rhythm Disorders in Takotsubo Syndrome: Insights From the International Multicenter GEIST Registry. Heart Rhythm 2020; 17(9): 1458-1466.
33. Stiermaier T, Moeller C and Oehler K: Long-term excess mortality in takotsubo cardiomyopathy: predictors, causes and clinical consequences. Eur J Heart Fail 2016; 18(6): 650-656.
34. Templin C, Ghadri JR and Napp LC: Takotsubo (Stress) Cardiomyopathy. N Engl J Med 2015; 373(27): 2689-2691.
35. Jellis C, Martin J, Narula J and Marwick TH: Assessment of Nonischemic Myocardial Fibrosis. J Am Coll Cardiol 2010; 56(2): 89-97.
36. Pasceri V, Patti G and Cammarota G: Usefulness of Early Invasive Management after Takotsubo Syndrome. Am J Cardiol 2016; 118(6): 826-830.
37. Scally C, Rudd A and Mezincescu A: Persistent long-term structural, functional, and metabolic changes after stress-induced (takotsubo) cardiomyopathy. Circulation 2018; 137(10): 1039-1048.
38. Sharkey SW, Windenburg DC and Lesser JR: Natural history and expansive clinical profile of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol 2010; 55(4): 333-341.
39. Tornvall P, Collste O, Ehrenborg E and Järnbert-Petterson H: A Case-Control Study of Risk Markers and Mortality in Takotsubo Stress Cardiomyopathy. J Am Coll Cardiol 2016; 67(16): 1931-1936.
40. Citro R, Okura H and Ghadri JR: Multimodality imaging in takotsubo syndrome: a joint consensus document of the European Association of Cardiovascular Imaging (EACVI) and the Japanese Society of Echocardiography (JSE). J Echocardiogr 2020; 18(4): 199-224.
    

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    How to cite this article:

    Sri VU, Sushmitha A, Sendilkumar B, Gouttam R, Gesavardhini M and Rajkumar G: Right ventricular involvement in takotsubo cardiomyopathy. Int J Pharm Sci & Res 2025; 16(7): 1767-73. doi: 10.13040/IJPSR.0975-8232.16(7).1767-73.

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