Deep cardiac phenotyping by cardiovascular magnetic resonance reveals subclinical focal and diffuse myocardial injury in patients with psoriasis (PSOR‑COR study)

Background Psoriasis vulgaris (PV) is a chronic inflammatory disorder frequently associated with cardiovascular disease (CVD). This study aims to provide a prospective tissue characterization in patients with PV without major CVD using cardiovascular magnetic resonance (CMR). Methods Patients with PV underwent laboratory assessment, a 12-lead and 24-h ECG, and a CMR exam at a 1.5-T scanner. Scan protocol included assessment of left (LV) and right (RV) ventricular function and strain analysis, native and post-contrast T1 mapping, T2 mapping and late gadolinium enhancement (LGE). Results In total, 60 PV patients (median(IQR) age in years: 50.0 (36.0–60.8); 34 men (56.7%)) were recruited and compared to 40 healthy volunteers (age in years: 49.5 (37.3–57.8); 21 men (53.0%)). No differences were found regarding LV and RV function ( p = 0.78 and p = 0.75). Global radial and circumferential strains were lower in patients ( p < 0.001 and p < 0.001, respectively). PV had higher global T1 times (1001 (982–1026) ms vs. 991 (968–1005) ms; p = 0.01) and lower global T2 times (48 (47–49) ms vs. 50


Introduction
Psoriasis is a chronic systemic disorder primarily affecting the skin [1].Multiple forms of psoriasis exist, the most prevalent being psoriasis vulgaris (PV) characterized by erythematous skin plaques with silvery-white scaling [2].All forms have an immune system dysfunction in common, which leads to chronic inflammation [1,3].The pathophysiology has been extensively researched, and most aspects are wellunderstood.Current evidence suggests that interleukins, particularly interleukins (IL)-23 and IL-17, play a crucial role and are targeted by specific monoclonal antibodies [4].These systemic therapies have been proven to be effective in reducing inflammation, skin alterations and disease burden [4,5].Although skin manifestations significantly impact patients' psychological well-being, cardiovascular diseases (CVD) are the primary contributors to morbidity and mortality [6][7][8].The interaction between PV and CVD is complex, with the main factors being the aforementioned inflammatory pathways and the high incidence of CVD risk factors [9][10][11][12].Epidemiological cohort studies have shown that psoriasis is a major risk factor for developing coronary heart disease (CAD) [13,14].Despite recent evidence, guidelinedirected therapies for CVD risk factors have only been partially implemented in this vulnerable cohort [15].This contrasts with the widespread use of systemic cytokine-targeting therapies in PV.However, questions remain about the precise impact of PV and the effects of these new anti-inflammatory agents on the myocardium.Echocardiography studies involving PV patients have reported reduced global strain values [16,17].Furthermore, a prospective trial using coronary computed tomography found an association between left ventricular (LV) mass and non-calcific coronary artery disease in PV patients [18].As CAD and finally myocardial infarction are the endpoints, the question remains whether changes in the myocardium, such as fibrosis and inflammation, might be detectable even earlier.In terms of imaging, cardiovascular magnetic resonance (CMR) can assess myocardial tissue characteristics [19,20].Parametric techniques, such as native and post-contrast T1 mapping for detecting diffuse myocardial fibrosis and T2 mapping for identifying myocardial edema, enable non-invasive differentiation of the myocardium [21].Additionally, CMR can detect focal myocardial fibrosis through late gadolinium enhancement (LGE) imaging [22].In this observational study, our aim was to provide in-depth myocardial characterization of patients with PV who have not experienced major cardiovascular events with a focus on fibrosis and inflammation, using the aforementioned techniques (see Fig. 1).

Study population
We conducted a prospective, exploratory observational study in patients with PV without major CVD, such as known CAD, cardiomyopathies and heart failure of any etiology, atrial fibrillation, severe valvular disease and COVID-19 infection within the last 3 months.Patients were recruited at outpatient dermatologic departments.Inclusion criteria were the following: diagnosed PV, age over 18 years and written informed consent.Exclusion criteria were pregnancy, breastfeeding, absolute contraindications for CMR and glomerular filtration rate < 30 ml/m 2 .The local ethical committee approved the study (EA1/130/21).A healthy volunteer (HV) cohort from previous studies was age and gender matched to the PV cohort [23][24][25].Healthy was defined as the absence of previous cardiac, pulmonary, renal, or systemic disorders.
Patients' treatment was chosen by the dermatologist following current guidelines.Dosages of immunomodulatory agents were chosen based on body weight or as recommended fixed dosages by the manufacturer at the time of treatment.

CMR protocol
All participants underwent a CMR at a 1.5-T scanner (Avanto FIT , Siemens Healthineers, Erlangen, Germany) with an 18-channel surface coil.Scan protocol included cine imaging with a balanced steady-state free precession (bSSFP) sequence in four long axis views including a two-, Fig. 1 CMR protocol of the PCOR-COR study.Depicted are applied sequences (top) with the corresponding evaluation (bottom).bSSFP, balanced steady-state free precession; TRUFI, true fast imaging with steady-state free precession; MOLLI, modified Look-Locker imaging; PSIR, phase-sensitive inversion recovery three-, four-and a right ventricular (RV)-view, as well as a short axis stack (SAX).Fat/water imaging was carried out with a multi-echo sequence as described previously [26].Parametric mapping was acquired in three SAX slices in basal, midventricular and apical locations, based on the previously published 5-out-of-3 approach [27].T1 mapping was carried out with a 5-3-3 modified Look-Locker inversion (MOLLI) sequence.For T2 mapping, a bSSFP-based sequence was used, with the same positioning as the T1 mapping.After the application of 0.2 mmol/kg bodyweight of contrast media (gadoteridol, Prohance®, Bracco Imaging, Konstanz, Germany), LGE images were acquired by a phasesensitive inversion recovery in long axis as well as a SAX stack.Post-contrast T1 mapping for the analysis of synthetic extracellular volume (ECV) was carried out with a prototype MOLLI [28] (Fig. 1).Except not receiving contrast media, the scanner, scan protocol and sequences used in the HV cohort did not differ from the patients' protocol.

Additional tests
Previous medical history and physical exam were performed at the time point of inclusion.Dermatologic evaluation was performed according to current recommendations including dermatologic scores such as Psoriasis Area and Severity Index (PASI) and Dermatologic Life Quality Index (DLQI) [29,30].Based on the therapy form, PV patients were divided into mild PV (mPV), receiving only local therapy, and moderate/severe PV (sPV), receiving systemic immunomodulatory therapy, groups [30].All patients received a blood pressure measurement, a 12-lead electrocardiogram (ECG) as well as a 24-h Holter ECG.On the day of the CMR, a comprehensive blood laboratory panel was drawn including cardiologic (high sensitivity troponin T: local cutoff > 14 ng/L and NT-pro-BNP local cutoff > 125 ng/L) and inflammatory biomarkers as well as a complete blood count.

CMR analysis
All CMR scans were analyzed with dedicated software (CVI42, Calgary, Canada version 5.17.0).Analysis was carried out in accordance with current recommendations and standard operating procedures [31].LV and RV function and mass were analyzed in the SAX cine images with the inclusion of papillary muscles to the myocardial mass.Cardiac strain analysis was carried out by feature tracking as recently published [32].Global values for longitudinal (GLS), radial (GRS) and circumferential (GCS) strains were calculated.T1-and T2-maps were visually assessed for artefacts or incorrect motion correction and accordingly excluded if present.Apical slices were disregarded due to a thin myocardium with increased partial volume effect [24].Additionally, segments with focal myocardial fibrosis seen on LGE were excluded from the final analysis.Endo-and epicardial contours were drawn in all slices with a 5-% offset.Local cutoff values were as follows: T1 > 1037 ms, T2 > 54 ms and ECV > 24%.Fat/water images were inspected visually for fatty infiltration [26].LGE images were visually assessed for focal myocardial fibrosis and scars.Findings were quantified according to location and subtype.For intra-and interreader comparisons, 10 random cases were contoured twice.

Post-hoc subgroup comparisons
Given the common presence of comorbidities which could potentially influence parametric mapping results, especially arterial hypertension and diabetes mellitus type I or II, posthoc subgroup analysis for PV patient without these comorbidities and HV was carried out.In addition, we wanted to examine the effect of immunomodulatory therapy on myocardial changes, providing a subgroup analysis between matched mild PV patients and HV.

Statistical analysis
Continuous variables are presented as mean ± standard deviation (SD) or median with interquartile range (IQR).Categorical variables are represented as total and percent.

Study population
Between February 2022 and March 2023, a total of 64 PV patients were recruited.Four patients had to be excluded, two due to an acute COVID-19 infection, one due to a newly diagnosed left-to-right cardiac shunt and one due to a newly diagnosed apical hypertrophic cardiomyopathy.The remaining 60 patients had a median (IQR) age of 50.0 (36.0-60.8)years.Out of the 60 participants, 34 were men (56.7%).In comparison to the HV, PV had a higher body mass index (BMI) (p = 0.01) (Table 1).
Subgroup comparisons of mPV (N = 24) and sPV (N = 36) showed no significant differences regarding general characteristics, except joint and nail involvement (more common in sPV), arterial hypertension and the use of antihypertensive therapy (more common in mPV) (supplementary Table 1).Details regarding the anti-psoriatic therapy as well as treatment for comorbidities can be found in the supplementary Table 2.
Patients with PV had higher global T1 times (p = 0.01), in basal (p = 0.01) and midventricular slices (p = 0.01) in comparison to the HV.T2 times were lower in the PV cohort.This was significant globally (p < 0.001) as well as in basal (p < 0.001) and in midventricular slices (p < 0.001) (Fig. 3).
There was a significant negative correlation between global T2 times and PASI (r = − 0.342; p = 0.01).One patient had a small focal fatty infiltration in the apex of the LV.LGE was found in 17/60 (28%) of the PV patients.All in a non-ischemic pattern (supplementary Table 4, Fig. 4).
In an additional subgroup comparison of PV patients without arterial hypertension and/or diabetes mellitus type I or II (N = 41/60), the main findings could be confirmed with PV patients having higher T1 times, lower T2 times and reduced GRS as well as GCS (supplementary Table 6).

Comparison of mild to moderate/severe psoriasis
The assessment of mPV and sPV regarding cardiac function, volumes and strain revealed no significant differences except higher RV end-diastolic volume.This, however, was not detectable anymore after adjusting for body surface area (supplementary Table 7).Myocardial tissue differentiation did not reveal any significant findings (Supplementary Table 7, Fig. 3).A further subgroup comparison between mPV and a matched HV subgroup (N = 24) showed lower GRS and GCS in the mPV group.However, in this subgroup comparison, no differences for T1 as well as T2 values were evident.

Discussion
In this first prospective CMR study in patients with PV despite the absence of major CVD, we found evidence of subclinical myocardial injury.The main alterations detected in our study were signs of diffuse and focal myocardial fibrosis which were concordant with reduced deformation indices, potentially signifying subclinical myocardial tissue remodeling.Surprisingly, we did not detect signs of myocardial inflammation in the PV cohort.This might be related to a concomitant use of immunomodulatory therapies by PV patients.
Systemic disorders with a chronic inflammatory background have been frequently associated with CVD as the underlying pathophysiological pathways also affect the vasculature, especially coronary arteries on a macro-and microvascular level as well as the myocytes [33,34].Potential myocardial abnormalities could therefore be related to increased fibrotic tissue in a focal and diffuse distribution as well as evidence of inflammation.A brief report of a retrospective analysis of N = 49 patients with PV revealed that, in comparison to patients with rosacea and atopic dermatitis, 72% of the PV patients had an abnormal CMR, with the main findings including T2 and ECV elevations [35].It should be of note, however, that the studied collective had a cardiologic indication for the scan.Other studies investigating patients with systemic disorders produced similar results.A study by Ntusi et al. included a cohort of N = 39 patients with rheumatic arthritis and no cardiologic symptoms [36].The authors reported, despite a normal LV function, elevated T1 times, correlating with disease activity and in addition a high prevalence of focal myocardial findings (46%).Similar results were noted for systemic lupus erythematosus with elevated T1 findings [37].A study by Mavrogeni et al. revealed an elevated T2-signal ratio in a mixed group with connective tissue disorders [38].Our findings, especially the high prevalence of LGE and higher T1 times, expand these results.In addition, more than a quarter of our cohort had elevated global ECV times.However, a very important divergence is the non-elevated T2 times in our PV cohort.This came as a surprise as we expected higher values in accordance with a chronic inflammatory process [39,40].In addition, we found a negative correlation between the PASI and T2, with higher values in patients with a lower PASI.We can only speculate about the reasons for this finding.Thus, immunomodulatory suppression could be a crucial factor.Ntusi et al. reported reduced inflammatory Fig. 3 Comparison of native parametric myocardial tissue characterization between psoriasis patients and healthy volunteers and moderate and severe psoriasis.Boxplots representing the median (solid inside the box), interquartile range (box) and 1.5*interquartile range (whiskers) for T1 and T2 mapping for patients with psoriasis and healthy volunteers (A and B) as well as mild and moderate/severe psoriasis (C and D).Every value below or above 1.5*interquartile range is marked as an outlier.Significant differences were found between psoriasis and healthy volunteers markers and myocardial inflammation after anti-TNF-alpha treatment in a cohort with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis [41].Our findings might have a similar background as most of our PV patients were treated with potent anti-cytokine monoclonal antibodies.In fact, Makavos et al. followed-up patients with PV undergoing systemic immunomodulatory therapies, showing that specific anti-cytokine antibodies lead to a greater improvement in strain values as traditional anti-inflammatory agents [42].The effect of systemic immunomodulatory might also have impacted the comparison between moderate and severe psoriasis as we did not detect a difference regarding tissue differentiation.The overall low disease activity is also signified by low PASI values in our cohort.Therefore, these findings need further research.Additional research and data in this area might be of value not only for PV but in regards of CVD, as there is evidence for a risk reduction while using systemic immunomodulatory therapies [43,44].
The described findings in our PV cohort might be the first signs of cardiovascular remodeling.The reduced strain values underline the picture of a subclinical involvement in the PV cohort.In the recent American heart failure (HF) guidelines, a four-stage model was proposed, with stage A being patients at risk for HF [45].Mentioned criteria include common CVD risk factors, such as obesity, metabolic syndrome and hypertension, as well as markers of early structural abnormalities such as reduced strain and left ventricular hypertrophy [45].It should be apparent that patients with PV are exceptionally vulnerable, as CVD risk markers are common and, as demonstrated in this study, subclinical structural abnormalities are present.An echocardiographic study by Gorga et al. provided data showing a high prevalence of diastolic dysfunction in patients with PV [46].There might be a related link to heart failure with preserved ejection fraction (HFpEF) [47,48].In conclusion, patients with PV seem to be at risk for HF, in specific HFpEF, and therefore, this connection should be used for developing targeted therapies acting at the molecular level to prevent or reduce the burden of HF.Valuable parameters to be tracked during such treatments could be GRS and GCS, based on the finding that only the radial deformation was impaired in our study.
However, the discussion should also include potential confounders and influencing factors in the analysis of the T1 values.Our PV cohort had a higher BMI.Both factors have been associated with elevated T1 values.Recently, Zhao et al. reported elevated markers of fibrosis as well as inflammation in a cohort of healthy obese probands in comparison to healthy normal-weight adults [49].In the same study, an obese unhealthy group, based on the presence of more than one finding in accordance with a metabolic syndrome, had an even higher fibrotic burden [49].CVD risk factors, and hence factors included in the definition of the metabolic syndrome, had a high prevalence among our PV cohort.The results of the subgroup comparison between PV patients without arterial hypertension and/or diabetes mellitus type I or II are however reassuring and provide evidence for a myocardial tissue alteration not solely being explainable by traditional CVD risk factors.
Future imaging studies addressing the association of PV and CVD should apply methods to detect microvascular changes, such as quantitative stress perfusion CMR or invasive measurements as recent reports noted a high burden of microvascular dysfunction in PV patients [50,51].
Based on the LGE patterns found in the current study, relevant (unrecognized) myocardial infarctions are unlikely given the absence of subendocardial LGE.The subepicardial and intramyocardial fibrosis are described in the literature in association with myocardial inflammation; however, arterial hypertension can also cause such changes, especially intramyocardial ones [52].RV insertion point fibrosis has been observed in healthy cohorts, therefore having an unclear clinical significance [53].Unfortunately, even in the absence of subendocardial LGE, CAD cannot be certainly ruled out as no anatomical testing, such as by coronary computed tomography angiography, was not carried out.Given the recent evidence of large, randomized trials and the recommendation in guidelines, especially in a population with moderate pre-test probability, further research applying noninvasive anatomic testing is warranted [54][55][56].

Limitations
The study is a single center.Additionally, no weight-matched healthy volunteer cohort was available.Due to ethical concerns, no contrast media was given in the healthy volunteer cohort preventing an analysis of LGE and ECV in this cohort.The scan protocol did not include stress perfusion imaging to detect myocardial ischemia as well as no anatomical testing for CAD; therefore, CAD cannot be excluded with certainty.In regards of subgroup comparisons, the compared numbers were rather small, therefore being potentially underpowered to observe statistically significant results.No follow-up data can be provided; therefore, no conclusions regarding the values of elevated T1 times as risk markers can be drawn.Lastly, laboratory assessment did not include high sensitivity CRP.

Conclusion
Patients with psoriasis and no major cardiovascular history have signs of subclinical myocardial injury in the form of a reduced circumferential and radial myocardial strain as well as focal and diffuse fibrosis, potentially signifying a beginning myocardial remodeling process.Non-elevated T2 might be related to the use of systemic anti-cytokine therapies.Further studies are needed to evaluate the effect of immunomodulatory therapies on the myocardium.
Normal distribution was assessed by the Shapiro-Wilk test.Comparisons between PV and HV as well as the subgroups for continuous variables were carried out with unpaired T-tests or Mann-Whitney U tests.Categorical variables were compared with the chi-square test or Fisher's exact test.Correlation analysis was carried out with Pearson's or Spearman's correlation coefficient.A p value of < 0.05 was considered statistically significant.Statistical analysis was carried out with SPSS (SPSS Statistics Version 29.0.0,IBM, Armok, NY, USA).Figures were created with Microsoft Visio (Microsoft Corporation, Redmond, WA, USA).

Fig. 2
Fig. 2 Correlation between PASI at the time of scan and T2 and left ventricular deformation indices.Significant correlations between PASI (Psoriasis Area and Severity Index) and T2 (A), global longitudinal (B), radial (C) and circumferential (D) strain

Fig. 4
Fig. 4 Overview of findings on myocardial tissue injury in patients with psoriasis.Bulls-eye representation of regions with focal fibrosis (right side of the figure).Most often the inferior and lateral walls

Table 1
General characteristics Data provided as absolute and percent or median and interquartile range.BMI body mass index, BSA body surface area, PASI Psoriasis Area and Severity Index, DLQI Dermatologic Life Quality Index.*T-tests, † Mann-Whitney U test, ‡ chi-square test or Fisher's exact test

Table 2
Dermatologic and cardiologic assessment of the psoriasis cohort Data provided as median with interquartile range or absolute and percent.PASI Psoriasis Area and Severity Index, DLQI Dermatologic Life Quality Index, IL interleukin, TNF-alpha tumor necrosis factor alpha

Table 3
Cardiac function and tissue parameters Data provided as absolute and percent or median and interquartile range.LV left ventricle, EDV end-diastolic volume, BSA body surface area, ESV end-systolic volume, SV stroke volume, EF ejection fraction, RV right ventricle, LA left atrium, RA right atrium, *T-tests, † Mann-Whitney U test significant differences regarding myocardial deformation and T1 mapping (Supplementary Table