Cardiovascular Magnetic Resonance in Survivors of Critical Illness: Cardiac Abnormalities Are Associated With Acute Kidney Injury

Background The objective of this study was to investigate cardiac abnormalities in intensive care unit (ICU) survivors of critical illness and to determine whether temporary acute kidney injury (AKI) is associated with more pronounced findings on cardiovascular magnetic resonance. Methods and Results There were 2175 patients treated in the ICU (from 2015 until 2021) due to critical illness who were screened for study eligibility. Post‐ICU patients without known cardiac disease were prospectively recruited from March 2021 to May 2022. Participants underwent cardiovascular magnetic resonance including assessment of cardiac function, myocardial edema, late gadolinium enhancement, and mapping including extracellular volume fraction. Student t test, Mann‐Whitney U test, and χ2 tests were used. There were 48 ICU survivors (46±15 years of age, 28 men, 29 with AKI and continuous kidney replacement therapy, and 19 without AKI) and 20 healthy controls who were included. ICU survivors had elevated markers of myocardial fibrosis (T1: 995±31 ms versus 957±21 ms, P<0.001; extracellular volume fraction: 24.9±2.5% versus 22.8±1.2%, P<0.001; late gadolinium enhancement: 1% [0%–3%] versus 0% [0%–0%], P<0.001), more frequent focal late gadolinium enhancement lesions (21% versus 0%, P=0.03), and an impaired left ventricular function (eg, ejection fraction: 57±6% versus 60±5%, P=0.03; systolic longitudinal strain: 20.3±3.7% versus 23.1±3.5%, P=0.004) compared with healthy controls. ICU survivors with AKI had higher myocardial T1 (1002±33 ms versus 983±21 ms; P=0.046) and extracellular volume fraction values (25.6±2.6% versus 23.9±1.9%; P=0.02) compared with participants without AKI. Conclusions ICU survivors of critical illness without previously diagnosed cardiac disease had distinct abnormalities on cardiovascular magnetic resonance including signs of myocardial fibrosis and systolic dysfunction. Findings were more abnormal in participants who experienced AKI with necessity of continuous kidney replacement therapy during their ICU stay. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT 05034588.


Isaak et al CMR in Survivors of Critical Illness
C ritical illness syndromes are characterized by different acutely life-threatening clinical conditions that usually require intensive care unit (ICU) treatment and, if survived, can lead to physical, cognitive, and psychological impairment. 1 Several mechanisms promoting cardiovascular disease in response to critical illness have been described. 2 Immunometabolic changes, sustained inflammatory cascades, and activation of neurohormonal signaling pathways appear to contribute to fibrotic cardiac remodeling, atherosclerosis, and cardiac dysfunction. 3 Specifically, increased exposure to catecholamines, oxidative stress, and altered mitochondrial function were found to be involved in these changes. 3,4 In a previous study, biomarkers of cardiac failure were associated with reduced long-term survival in patients after ICU treatment. 5 Further studies indicate an increased risk of cardiovascular events in post-ICU patients with severe sepsis. 6,7 Severe sepsis is often accompanied by acute kidney injury (AKI), a condition that is one of the most common complications of critical illness. 8 AKI is a predictor of short-and long-term adverse cardiovascular events 9 and increases the risk of cardiovascular mortality by 86%. 10 Reciprocal effects between cardiac and kidney disease are referred to as cardiorenal syndrome (CRS), with type 3 CRS describing cardiac disease as a result of AKI. 11 In AKI, hemodynamic and metabolic alterations, and activation of the renin-angiotensinaldosterone system and inflammatory pathways are associated with direct cardiodepressant effects. 9 The most commonly described cardiac sequelae after AKI are congestive heart failure and acute myocardial infarction. 10,12 Severe cases of AKI, which often require continuous kidney replacement therapy (CKRT), appear to have a particularly negative impact on this outcome. 13,14 However, the extent and manner in which critical illness and AKI contribute to myocardial injury requires further investigation. Previous cardiovascular magnetic resonance (CMR) studies have already detected myocardial tissue alterations in patients with chronic kidney disease (type 4 CRS). 15,16 In this cross-sectional study, CMR was performed in ICU survivors of critical illness without previously known cardiac disease to investigate the extent of subclinical myocardial abnormalities such as fibrosis, inflammation, or ventricular dysfunction. Based on the latest evidence of type 3 CRS, 9 we hypothesized that AKI during ICU treatment would lead to more pronounced myocardial abnormalities.

METHODS
The data that support the findings of this study are available from the corresponding author upon reasonable request. This cross-sectional study was approved by the institutional ethics committee (approval ID: 519/20). All participants gave written informed consent before CMR. The study is registered at clini caltr ials.gov (identifier: NCT 05034588).

Study Participants
Survivors of critical illness with past treatment in the ICU were screened for study eligibility. Post-ICU participants were subdivided into (1) participants who had recovered from AKI with necessity of CKRT during critical illness (AKI group), and (2) participants without acute or chronic kidney injury during critical illness (non-AKI group). Only participants with history of AKI including temporary CKRT (stage 3 according to Kidney Disease: Improving Global Outcomes) with subsequent recovery of kidney function after ICU treatment were included. Convalescence was defined according to the Kidney Disease: Improving Global Outcomes guidelines as glomerular filtration rate ≥60 mL/min per 1.73 m 2 in the absence of CKRT. 17 To exclude patients with chronic kidney disease and due to the institutional ethics regulations, only participants with a glomerular filtration rate ≥45 mL/min per 1.73 m 2 at the time of MRI were included. Intensive care scores (Simplified Acute Physiology Score II [excluding Glasgow Coma Scale calculation] and Therapeutic Intervention Scoring System-10) were derived from medical records. The control group consisted of healthy subjects without previous ICU stay and no cardiac disease history who underwent CMR for study control reasons. Controls had normal CMR results without structural abnormalities.

CMR Protocol
All CMR examinations were performed using a clinical 1.5T whole-body system (1.5 Ingenia; Philips Medical Systems, Best, the Netherlands). ECG-gated steady state free-precession cine sequences, T2-weighted shortτ inversion-recovery sequences, and late gadolinium enhancement (LGE) based on segmented inversion recovery gradient echo sequences were acquired in standard orientations. Myocardial T1 and T2 mapping was obtained in apical, midventricular, and basal end-diastolic short-axis view using the modified look-locker inversion recovery scheme and the gradient and spin-echo sequence sequence. 18 For contrast enhancement, a bolus of 0.2 mmol/kg body weight of gadoterate meglumine (Clariscan; GE Healthcare) was administered.

Image Analysis
Two experienced cardiovascular radiologists (J.A.L., A.I.) performed image analysis in consensus agreement blinded to the clinical data using appropriate software (IntelliSpace Portal Version 12; Philips Medical System). Functional analysis including the assessment of ventricular volumes, function, mass, and feature-tracking strain (systolic global longitudinal [GLS], global circumferential strain, and global radial strain) were analyzed as previously described. 18,19 LGE was assessed visually (presence of enhancement) and semiquantitatively (full width at half maximum method). 19 Myocardial edema was evaluated visually (presence of regional hyperintensity on T2-weighted images) and quantitatively using T2 mapping. 18,20 Myocardial T1 relaxation times and hematocrit corrected extracellular volume fraction (ECV) were calculated, as previously described. 18,20 T1, T2, and ECV values were measured using a global approach.

Statistical Analysis
Statistical analysis was performed using SPSS Statistics (version 26; IBM, Armonk, NY) and Prism (version 8.4.3; GraphPad Software). Participant characteristics are reported as mean±standard deviation, median and interquartile range (IQR), or as percentages and absolute frequencies. Normal distribution was assessed visually using normal distribution plots and supplemented by the Shapiro-Wilk test. Continuous variables were compared using the independent 2-sample Student t test (normally distributed variables) or the Mann-Whitney U test (not normally distributed variables). Independence between dichotomous variables was tested using the χ 2 test (when cell count >5) and Fisher exact test (when cell count ≤5). One-way analysis of variance with subsequent Tukey multiple comparison tests was performed to compare CMR characteristics between the ICU subgroups and healthy controls. Continuous nonparametric variables between the 2 ICU subgroups were compared using the Kruskal-Wallis test. Correlations between continuous variables were tested using Pearson correlation coefficients. The level of statistical significance was set at P<0.05.

General Characteristics of ICU Survivors
A total of 2175 patients with past ICU treatment due to critical illness was retrospectively screened for study eligibility ( Figure 1). From March 2021 to May 2022, 68 participants prospectively underwent CMR: 48 ICU survivors of critical illness (mean age±standard deviation, 46±15 years; 42% women) and 20 healthy control participants (mean age±standard deviation, 48±14 years; 45% women). The main reasons for ICU admission were acute respiratory distress syndrome (11/48, 23%), sepsis (9/48, 19%), trauma (9/48, 19%), cerebral hemorrhage/ The AKI group consisted of 29 of 48 (60%) participants, and the non-AKI group consisted of 19 of 48 (40%) participants. The AKI group received temporary CKRT over a median duration of 12 days (IQR, 6-36 days). Over the clinical course, return of normal kidney function was observed in all AKI participants, as defined by the Kidney Disease: Improving Global Outcomes guidelines (median of the last measured glomerular filtration rate before CMR, 96 mL/min per 1.73 m 2 ; IQR, 72-117 mL/min per 1.73 m 2 ). AKI and non-AKI participants did not differ in terms of length of ICU stay, duration of mechanical ventilation, or intensive care scoring; however, the AKI group had higher absolute scores in all these categories (  (Table 2). Between the AKI and the non-AKI group, there was no difference for left ventricular ejection fraction, GLS, and global circumferential strain (Table 3). Compared with healthy controls, left ventricular GLS was impaired  LGE was present in 10 of 48 ICU survivors (21%) and not detectable in healthy controls (P=0.03). From the participants with visible LGE, 5 of 10 (50%) had an ischemic pattern, 4 of 10 (40%) had a nonischemic pattern, and 1 of 10 (10%) showed pericardial enhancement (Figure 4). Focal LGE lesions were more frequently observed in the AKI group than in the healthy control group ( (Figure 2).

Correlations Between Clinical and CMR Parameters
In

DISCUSSION
The main findings of this cross-sectional study are (1) that survivors of critical illness without prior known  (2) that these abnormalities were more pronounced after transient severe AKI. Our findings suggest that survival of acute critical illness requiring intensive care can be associated with clinically unrecognized cardiac sequelae, and those cardiac abnormalities appear to be exacerbated by severe AKI. Critical illness causes an acute state of stress that affects the body and heart in several ways, including dysregulated proinflammatory and immunosuppressive mechanisms as well as neurohormonal and electrolyte disturbances associated with fibrotic cardiac remodeling. 3 Regardless of its cause, focal and diffuse myocardial fibrosis can induce arrhythmia and left ventricular dysfunction affecting long-term cardiovascular outcome. 21,22 We found positive LGE (as a marker of focal fibrosis) in 21% of ICU survivors of critical illness. Accordingly, quantitative LGE values were also elevated in the post-ICU group. In a previous study, Ferreira et al found LGE in a nonischemic pattern to be a catecholamine-related feature. 4 Because upregulation of catecholamines is a common response to acute critical illness 23 and patients in shock are often treated with vasopressors and inotropes, 24 the nonischemic LGE patterns we observed may be fibrotic correlates after catecholamine-induced inflammation. Critical illness has further been shown to favor atherosclerotic processes including coronary heart disease, 3 which would be consistent with the appearance of ischemic LGE lesions in ICU survivors of critical illness. Focal ischemic LGE lesions could have also been induced by embolic myocardial infarction or vasospasm. Myocardial infarction is also a known complication of AKI. 10 Compared with healthy controls, we found elevated myocardial T1 and ECV values in combination with normal myocardial T2 values in ICU survivors of critical Profibrotic potential has been found to be associated with both chronic and acute kidney disease, with prolonged activation of the renin-angiotensin-aldosterone system appearing to promote cardiac fibrosis. 25,26 Moreover, in a previous CMR study, Edwards et al 27 reported signs of diffuse myocardial fibrosis in patients with early chronic kidney disease (type 4 CRS).
Findings of more pronounced myocardial fibrosis after recovered AKI are also consistent with the apparent concept that AKI is an indicator of more severe critical illness, as indicated by higher intensive care scoring for this group (eg, Simplified Acute Physiology Score II or Therapeutic Intervention Scoring System-10).  In line with previous literature describing sepsis as a common cause of AKI, 8 AKI frequently co-occurred with sepsis as underlying disease in our cohort. Sepsis has also been shown to contribute to cardiac disease: In a recent CMR study, Muehlberg et al 28 demonstrated myocardial edema and active inflammation in ICU patients during acute septic shock. None of the participants in our study showed signs of myocardial inflammation, because T2 relaxation times were within the normal reference range and no visual edema was present. The absence of active inflammation was not surprising, because only participants who recovered from critical illness were included. Our results support the hypothesis that the long-term tissue repair processes following AKI may foster the development of myocardial fibrosis. 29 However, because the time to CMR after ICU treatment was long in our study, ongoing chronic inflammatory processes shortly after critical illness may have been missed. 3 Two previous echocardiography studies found left ventricular dysfunction to be common during critical illness. 30,31 Our results further suggest a long-term impact of critical illness on cardiac function. About 17% of the ICU survivors of critical illness had a mean left ventricular ejection fraction of <50%, which, in combination with clinical symptoms, could in principle be classified as heart failure with midrange ejection fraction. 32 Focal left ventricular hypokinesia was present in 21% of ICU survivors of critical illness after AKI, but in only 5% without AKI. Furthermore, participants with AKI had more reduced GLS and global circumferential strain values, indicating impaired myocardial contractility. Edwards et al 27 and Hayer et al 33 observed similar impairment of GLS in patients with early and advanced chronic kidney disease, linking kidney dysfunction to systolic impairment. Our study shows that participants with AKI have more pronounced signs of cardiac dysfunction after critical illness, even when kidney function has apparently fully recovered. Because all ICU survivors of critical illness had an unremarkable history of cardiac disease, our results demonstrate that CMR may allow for detection of previously undiagnosed but prognostically relevant myocardial findings. This observation is of particular interest, because with the COVID-19 pandemic increased ICU admission rates were observed. Our study showed that ICU survivors of critical illness may have relevant cardiac abnormalities independent of severe COVID-19 that may represent a possible structural component of the post-intensive care syndrome. Some limitations have to be mentioned because of the observational form of this study. The sample size was moderate, and statistical tests may be underpowered. However, recruiting survivors of critical illness who are still eligible for CMR examination is challenging. Some differences in clinical diagnoses and treatment remained that might be confounding factors on cardiac involvement in this study. Although patients with systemic diseases with potential cardiac involvement were excluded, cardiac abnormalities might also have been present as unrecognized/subclinical conditions before the ICU stay. Also, time between ICU treatment and CMR varied. Participants in the AKI group were more frequently diagnosed with sepsis, which could be a confounding factor, because sepsis has been shown to cause myocardial injury. 6,7 More pronounced cardiac injury might have been present in patients with chronic-to-acute kidney disease. Lastly, our findings can only be generalized to patients with AKI requiring CKRT.
In conclusion, we showed that survivors of critical illness have unrecognized cardiac abnormalities suggestive of myocardial fibrosis and systolic dysfunction. These findings were observed in participants without known cardiac disease, indicating effects of critical illness and AKI on cardiovascular health. Transient AKI requiring CKRT was associated with more pronounced signs of myocardial fibrosis and systolic dysfunction. Because these cardiac findings may be associated with poor long-term outcomes, survivors of critical illness could benefit from close cardiovascular monitoring. Unrecognized fibrotic and functional myocardial abnormalities in ICU survivors of critical illness may also be associated with physical impairment in postintensive care syndrome. In the present era, it is important to highlight that such cardiac abnormalities may generally occur in ICU survivors, regardless of COVID-19 disease. Future studies should further investigate the prognostic value of such cardiac abnormalities detectable by CMR in patients after critical illness as well as in patients after AKI.