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

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 well-understood. 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 [6‐8]. 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 [9‐12]. Epidemiological cohort studies have shown that psoriasis is a major risk factor for developing coronary heart disease (CAD) [13, 14]. Despite recent evidence, guideline-directed 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).

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 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 non-invasive anatomic testing is warranted [54‐56].

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.

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.