Cardiogenic shock (CS) is defined as end-organ hypoperfusion resulting from deficient cardiac output despite adequate preload, caused by a structural or functional cardiac dysfunction.1 Regardless of numerous evidence-based therapeutic advances in modern cardiovascular medicine, CS remains a life-threatening acute condition with an in-hospital mortality rate as high as 40–50%, a figure that has not diminished over the last two decades.2

Takotsubo syndrome (TTS) is characterized by acute transient left ventricular systolic dysfunction, typically triggered by emotional or physical stress, in the absence of culprit coronary artery disease. The classical etiopathogenic theory suggests that TTS is caused by massive sympathetic nervous system activation and subsequent catecholamine-induced myocardial injury.3,4 CS complicates 5–20% of TTS cases, contributing to a poorer prognosis.5–7 Short-term mortality rates of cardiogenic shock due to Takotsubo syndrome (CS-TTS), though not as high as in CS secondary to acute myocardial infarction, remain substantial, ranging between 10–15%.8

During the acute phase of CS, hemodynamic stabilization is typically pursued through the administration of vasoactive and inotropic medications, which adjust vascular tone and enhance myocardial contractility, providing a time window for recovering while addressing the underlying cause of CS development.9 However, these drugs frequently induce cardiac arrhythmias, exacerbate or initiate myocardial ischemia, and can lead to peripheral ischemia.10 Increasing vasopressor and inotrope doses has been shown to be associated with higher mortality in patients with CS.11,12 In the context of CS-TTS, a condition triggered by massive microvascular catecholamine release, inotropes can have additional specifical harmful effects, such as increasing in left ventricular outflow tract obstruction (LVOTO) or worsening of mitral regurgitation due to systolic anterior movement (SAM) of the mitral leaflets: this complexity makes management of CS in this population particularly challenging.13–15

In order to objectively quantify the degree of pharmacological hemodynamical support, several scoring systems have been proposed. In 1995, Wernowsky et al. numerically described the combined doses of dopamine, dobutamine, and epinephrine, assigning each drug a coefficient that gives them an arbitrary equivalent value in the calculation.16 This inotropic score (IS) was upgraded in 2010 by Gaeies et al., who incorporated the doses of dopamine, dobutamine, and epinephrine into the calculation, resulting in the Vasoactive-Inotropic Score (VIS).17 Several corrections of the VIS have been proposed, adding to the calculation levosimendan,18 phenylephrine,19 enoximone,20,21 and olprinone.22 Lastly, Belletti et al. suggested the use of a more comprehensive score that incorporates the doses of terlipressin, methylene blue, and angiotensin-II, in addition to the previously mentioned medications.23

The VIS was initially validated as an independent predictor of clinical outcomes after cardiac surgery in pediatric patients.24 Subsequently, the prognostic value of the VIS has been demonstrated in adult patients after cardiothoracic surgery25,26 and, more recently, in patients with CS of nonsurgical etiology.27,28 However, data are lacking on whether a higher level of pharmacological hemodynamic support is associated with higher mortality in CS-TTS. Therefore, the aim of this study was to describe the pharmacological hemodynamic support employed in CS-TTS and to evaluate its prognostic value as quantified by VIS, examining its association with both short- and long-term outcomes.

The main findings of this study are as follows: 1) half of the patients with CS-TTS received vasopressors or inotropes, with noradrenaline and dobutamine being the most commonly used agents; 2) the degree of drug support did not significantly differ based on the type of TTS trigger; 3) a high level of pharmacological hemodynamical support, as quantified by VIS, was associated with worse short- and long-term outcomes.

The observed in-hospital mortality rates (4%–47%) in our study differ from the 10–15% previously reported for CS-TTS. This discrepancy may result from differences in patient selection, as our cohort specifically included individuals requiring vasoactive or inotropic support, representing more severe cases. Additionally, stratification by VIS revealed a wide mortality range, with lower-risk patients showing rates consistent with prior studies, while those with high VIS experienced significantly worse outcomes. Variability in comorbidities and management strategies across centers could also have contributed to these findings.30

The prognostic value of VIS has been consistently reported in several studies involving post-cardiothoracic surgery patients25,26 and, more recently, in patients with non-surgical causes of CS.27,28 In contrast to previous cohorts of CS of different etiologies, where the use of vasoactive and inotropic drugs has been reported in more than 90% of patients,31 such drugs were employed in only half of our CS-TTS cohort. This disparity may reflect not only the historically reported milder clinical course of CS-TTS compared to other causes of CS,8 but also a potential hesitancy in administering vasopressors and inotropes in CS-TTS due to concerns about potential side effects in this complex clinical scenario.

In a cohort of 493 with CS of multiple causes requiring inotropes or vasopressors, Na et al.27 reported a 30-day mortality as low as 5% in patients with VIS 1–10, which progressively increased to 10%, 20%, and 26% with VIS of 11–20, 21–38, and 39–85, respectively, reaching 61% in patients with VIS greater than 85. After multivariable analysis, the fourth and fifth VIS quintiles were associated with higher in-hospital mortality, while no significant differences were found between the first versus second or third VIS quintiles. In another cohort of 836 patients with CS secondary to acute myocardial infarction, Choi et al.28 found worse 6-month mortality rates in the third and fourth VIS quartiles (VIS ranges of 30–90, and >90, respectively). These findings, consistent across studies, reinforce the association between higher VIS and worse outcomes, even though direct comparisons between studies are challenging due to the variability in VIS ranges used for stratification. Moreover, these CS cohorts included patients with a more profound shock stage then patients from our cohort, as speculated from their higher serum lactate levels and extended use of mechanical circulatory support, with ECMO being employed in one-third of patients from both cohorts. In our study, patients in the high VIS tertile had a worse 30-day and 1-year mortality, while no differences were found between the low and middle VIS tertiles. This aligns with previous literature: overall, a high VIS is associated with worse outcome of CS, whereas the same cannot be said for low to intermediate VIS. In our cohort, we observed an increasing incidence of major bleeding across the VIS tertiles, reaching nearly 10% in the highest tertile. Although the statistical power is limited due to the small group sizes, this finding may be clinically relevant, particularly when considering therapeutic strategies in patients with severe CS-TTS. It is reasonable to hypothesize that the increased use of mechanical support in the highest tertile, combined with greater organ dysfunction, could have contributed to a higher predisposition to bleeding, possibly exacerbated by shock-induced coagulopathy. These data suggest that major bleeding may represent a significant complication in patients with high VIS, highlighting the need to carefully balance the use of mechanical and pharmacological support in such cases.

Interestingly, vasopressors carry a weight in VIS calculation that is about 5- to 10-fold higher than inotropes. For instance, in a patient receiving dobutamine 5 mg/kg/min and norepinephrine 0.15 mcg/kg/min, VIS would be 20, the same value as a patient only receiving norepinephrine at 0.2 mcg/kg/min. While it seems reasonable to assign a higher specific weight to vasopressors in patients with primary distributive shock, such as that typically observed after cardiothoracic surgery (for which VIS was originally developed), this may not be universally applicable to other types of shock.16,17 In this regard, mixed shock phenotypes represent a significant challenge, as they often combine elements of both distributive and CS, with distinct temporal dynamics that may affect VIS interpretation.32 In cases of CS-TTS triggered by physical insults such as infections, early stages are characterized by distributive shock complicated by myocardial dysfunction or by a mixed shock state in which a systemic insult simultaneously induces myocardial dysfunction and vasodilation; these presentations typically dominate during the first 24 h, the period in which VIS is calculated. In contrast, CS complicated by inappropriate vasodilation often emerges as a later phase in the clinical course, which may not be adequately captured by VIS at the 24-h mark. This temporal variation highlights the potential limitations of VIS as a static measure when applied to dynamic and evolving shock phenotypes.

Furthermore, outcome data stratified by the type of hemodynamic support suggest that patients treated with inotropes alone tend to have better outcomes than those receiving vasopressors alone, while those requiring combined inotropic and vasopressor support exhibit the worst outcomes (Fig. 3). This latter group likely reflects patients with more severe shock, as indicated by their higher VIS. These findings underscore the importance of considering the predominant shock phenotype and its temporal evolution when interpreting VIS. While inotropes may play a more central role in distributive or early mixed shock states, vasopressors appear to gain greater relevance in severe vasodilatory phases.33 Understanding these dynamics is essential for tailoring treatment strategies in complex conditions such as CS-TTS, where the interplay between myocardial dysfunction and vasodilation may evolve over time.

Recently, Vila-Sanjuán and collaborators found that inotropic or vasoactive treatments did not worsen ventricular function or cause LVOTO in TTS patients.34 This challenges the traditional recommendation of these drugs based on the adrenergic hypothesis of TTS. Preclinical studies indicate that norepinephrine, epinephrine, or isoprenaline can reproduce TTS's characteristic reversible apical ballooning and basal hypercontractility.35,36 Additionally, previous studies using various animal models have been able to trigger patterns similar to TTS, which worsened with higher doses of inotropic drugs.37 However, local catecholamine release at the myocardial level may occur independently of systemic increases through the hypothalamic-pituitary-adrenal axis. Neural impulses trigger norepinephrine release from sympathetic nerve terminals in the myocardium, which may explain why plasma catecholamine levels are not always elevated. Additionally, catecholamines directly released into the myocardium could be more toxic than those in the bloodstream.38 This highlights the complexity of TTS's pathophysiology beyond the adrenergic theory and suggests that inotropic and vasoactive treatments are unlikely to worsen the condition: the higher mortality in the high VIS tertile may reflect greater patient severity rather than a direct toxic effect of these drugs on the heart.

To determine whether VIS functions as an independent prognostic score beyond the severity of shock, it is crucial to consider global severity classifications, such as the SCAI staging, which has previously demonstrated predictive value in CS-TTS.39 Notably, VIS and SCAI are intrinsically linked, as the use of inotropic and vasoactive drugs is a fundamental component of the SCAI shock stages. When VIS and SCAI were analyzed together in relation to in-hospital mortality (Supplemental Table 2), the predictive value of VIS diminished and ultimately lost statistical significance. This finding suggests that a comprehensive clinical score reflecting overall shock severity, such as SCAI, holds greater prognostic relevance than one based solely on pharmacological variables. These results reinforce the idea that VIS primarily serves as a marker of illness severity rather than as an independent and modifiable prognostic factor.

Altogether, our study found that high VIS was associated with worse 30-day and 1-year mortality, while low and intermediate VIS had similar mortality rates.

Inotropes are employed in half of the patients with CS-TTS. In CS-TTS, a higher VIS in the first 24 h is associated with worse outcomes, while no differences emerged between low and intermediate VIS. Further prospective studies are needed to confirm these findings.

MT: data collection, statistical analysis, drafting and reviewing the manuscript.

SVS: data collection and reviewing the manuscript.

RV: data collection and reviewing the manuscript.

JS: data collection and reviewing the manuscript.

MMS: data collection and reviewing the manuscript.

JRR: data collection and reviewing the manuscript.

AM: data collection and reviewing the manuscript.

EBP: data collection and reviewing the manuscript.

MA: data collection and reviewing the manuscript.

MCP: data collection and reviewing the manuscript.

AU: data collection, statistical analysis, drafting and reviewing the manuscript.

ING: data collection and reviewing the manuscript.

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