The prognostic impact of right ventricular-pulmonary arterial coupling in heart failure: a systematic review and meta-analysis.

The echocardiographic tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio is a non-invasive surrogate of right ventricular-pulmonary arterial (RV-PA) coupling which corresponds well with the respective invasively derived index. Recently, a wealth of observational data has arisen, outlining its prognostic value in heart failure (HF) patients. To systematically appraise and quantitatively synthesize the evidence of the prognostic value of TAPSE/PASP ratio in left-sided HF regardless of etiology or left ventricular ejection fraction. A systematic literature review was conducted in electronic databases to identify studies reporting the association of TAPSE/PASP ratio with outcomes in patients with HF and, when appropriate, a random-effects meta-analysis was conducted to quantify the unadjusted and adjusted hazard ratios [(a)HRs] for all-cause death and the composite outcome of all-cause death or HF hospitalization. Eighteen studies were deemed eligible encompassing 8,699 HF patients. The applied cut-off value for RV-PA uncoupling varied substantially from 0.27 to 0.58 mm/mmHg, and in most studies values lower than the applied cutoff conveyed dismal prognosis. Eleven studies reported appropriate data for meta-analysis. TAPSE/PASP reduction by 1 mm/mmHg was independently associated with all-cause death (pooled aHR=1.32 [1.06-1.65]; p=0.01; I2=56%) and the composite outcome (pooled aHR=3.48 [1.67-7.25]; p<0.001; I2=0%). When a TAPSE/PASP cutoff value of 0.36 mm/mmHg was applied it yielded independent association with all-cause death (pooled aHR=2.84 [2.22-3.64]; p<0.001; I2=82%). RV-PA coupling assessed by echocardiographic TAPSE/PASP ratio appears to be an independent outcome predictor for HF patients.

Hypoglycemic Drugs in Patients with Diabetes Mellitus and Heart Failure: A Narrative Review.

Over the last few years, given the increase in the incidence and prevalence of both type 2 diabetes mellitus (T2DM) and heart failure (HF), it became crucial to develop guidelines for the optimal preventive and treatment strategies for individuals facing these coexisting conditions. In patients aged over 65, HF hospitalization stands out as the predominant reason for hospital admissions, with their prognosis being associated with the presence or absence of T2DM. Historically, certain classes of glucose-lowering drugs, such as thiazolidinediones (rosiglitazone), raised concerns due to an observed increased risk of myocardial infarction (MI) and cardiovascular (CV)-related mortality. In response to these concerns, regulatory agencies started requiring CV outcome trials for all novel antidiabetic agents [i.e., dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter-2 inhibitors (SGLT2is)] with the aim to assess the CV safety of these drugs beyond glycemic control. This narrative review aims to address the current knowledge about the impact of glucose-lowering agents used in T2DM on HF prevention, prognosis, and outcome.

The prognostic value of right ventricular longitudinal strain in heart failure: a systematic review and meta-analysis.

BACKGROUND: Right ventricular (RV) dysfunction is a well-recognized adverse prognostic feature in patients with heart failure (HF). Recently, many single-center studies have demonstrated that RV longitudinal strain assessed using speckle tracking echocardiography might be a powerful prognosticator in HF. OBJECTIVES: To systematically appraise and quantitatively synthesize the evidence of the prognostic value of echocardiographic RV longitudinal strain, across the entire spectrum of left ventricular ejection function (LVEF) in HF. METHODS: A systematic literature review was conducted in electronic databases to identify every study reporting the predictive role of RV global longitudinal strain (RV GLS) and RV free wall longitudinal strain (RV FWLS) in HF subjects. A random-effects meta-analysis was conducted to quantify the adjusted and unadjusted hazard ratios [(a)HRs] for all-cause-mortality and for the composite outcome of all-cause mortality or HF-related hospitalization for both indices. RESULTS: Twenty-four studies were deemed eligible and 15 of these provided appropriate quantitative data for the meta-analysis, encompassing 8,738 patients. Each 1% worsening in RV GLS and RV FWLS was independently associated with increased risk of all-cause mortality (pooled aHR = 1.08 [1.03-1.13]; p < 0.01; I2 = 76% and 1.05 [1.05-1.06]; p < 0.01; I2 = 0%, respectively) and the composite outcome (pooled aHR = 1.10 [1.06-1.15]; p < 0.01; I2 = 0% and 1.06 [1.02-1.10]; p < 0.01; I2 = 69%, respectively) for patients with HF. The subgroup analysis of HF patients with LVEF < 45% yielded similar results, with worsening in RV GLS and RV FWLS retaining strong association with the two outcomes. CONCLUSION: Echocardiographic RV GLS and RV FWLS appear to have powerful prognostic value across the range of HF.

Prescription Rates and Prognostic Implications of Optimally Targeted Guideline-Directed Medical Treatment in Heart Failure and Atrial Fibrillation: Insights From The MISOAC-AF Trial.

ABSTRACT: Heart failure (HF) and atrial fibrillation (AF) commonly coexist in real-life clinical practice. Among patients with HF with reduced ejection fraction (HFrEF) or HF with mildly reduced ejection fraction (HFmrEF), guidelines call for evidence-based target doses of renin-angiotensin-aldosterone system inhibitors and beta-blockers. However, target doses of guideline-directed medical treatment (GDMT) are often underused in real-world conditions, including HF-AF comorbidity. This retrospective cohort study of a randomized trial (Motivational Interviewing to Support Oral AntiCoagulation adherence in patients with nonvalvular AF) included hospitalized patients with AF and HFrEF or HFmrEF. Optimally targeted GDMT was defined as intake of evidence-based target doses of renin-angiotensin-aldosterone system and beta-blockers at 3 months after discharge. Rates of optimally targeted GDMT achievement across the baseline estimated glomerular filtration rate (eGFR) were assessed. Independent predictors of nontargeted GDMT and its association with all-cause mortality and the composite of cardiovascular death or HF hospitalization were assessed by regression analyses. In total, 374 patients with AF and HFrEF or HFmrEF were studied. At 3 months after discharge, 30.7% received target doses of GDMT medications. The rate of optimally targeted GDMT was reduced by 11% for every 10 mg/min/1.73 m 2 decrease in baseline eGFR [adjusted ß = 0.99; 95% confidence interval (CI), 0.98-0.99] levels. After a median 31-month follow-up period, 37.8% patients in the optimally targeted GDMT group died, as compared with 67.8% (adjusted hazard ratio: 1.49; 95% CI, 1.05-2.13) in the nontargeted GDMT group. The risk of cardiovascular death or HF hospitalization was also higher in these patients (adjusted hazard ratio: 1.60; 95% CI, 1.17-2.20). Target doses of all HF drugs were reached in roughly one-third of patients with AF and HFrEF or HFmrEF 3 months after hospital discharge. Nontargeted GDMT was more frequent across lower eGFR levels and was associated with worse outcomes.

Association of clinical, laboratory and imaging biomarkers with the occurrence of acute myocardial infarction in patients without standard modifiable risk factors - rationale and design of the "Beyond-SMuRFs Study".

BACKGROUND: Acute myocardial infarction (AMI) remains the leading cause of mortality worldwide. The majority of patients who suffer an AMI have a history of at least one of the standard modifiable risk factors (SMuRFs): smoking, hypertension, dyslipidemia, and diabetes mellitus. However, emerging scientific evidence recognizes a clinically significant and increasing proportion of patients presenting with AMI without any SMuRF (SMuRF-less patients). To date, there are no adequate data to define specific risk factors or biomarkers associated with the development of AMIs in these patients. METHODS: The ''Beyond-SMuRFs Study'' is a prospective, non-interventional cohort trial designed to enroll patients with AMI and no previous coronary intervention history, who undergo coronary angiography in two academic hospitals in Thessaloniki, Greece. The rationale of the study is to investigate potential relations between SMuRF-less AMIs and the clinical, laboratory and imaging profile of patients, by comparing parameters between patients with and without SMuRFs. Complete demographic and comprehensive clinical data will be recorded, Venous blood samples will be collected before coronary angiography and the following parameters will be measured: total blood count, standard biochemistry parameters, coagulation tests, hormone levels, glycosylated hemoglobin, N- terminal pro-B-type natriuretic peptide and high-sensitivity troponin T levels- as well as serum levels of novel atherosclerosis indicators and pro-inflammatory biomarkers. Furthermore, all participants will undergo a complete and comprehensive transthoracic echocardiographic assessment according to a pre-specified protocol within 24 h from admission. Among others, 2D-speckle-tracking echocardiographic analysis of cardiac chambers and non-invasive calculation of myocardial work indices for the left ventricle will be performed. Moreover, all patients will be assessed for angiographic parameters and the complexity of coronary artery disease using the SYNTAX score. Multivariable linear and logistic regression models will be used to phenotypically characterize SMuRF-less patients and investigate independent clinical, laboratory, echocardiographic and angiographic biomarkers-predictors of SMuRF-less status in AMI.The first patient was enrolled in March 2022 and completion of enrollment is expected until December 2023. DISCUSSION: The ''Beyond-SmuRFs'' study is an ongoing prospective trial aiming to investigate potential clinical, laboratory and imaging biomarkers associated with the occurrence of AMIs in SMuRF-less patients. The configuration of these patients' profiles could lead to the development of personalized risk-stratification models predicting the occurrence of cardiovascular events in SΜuRF-less individuals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05535582 / September 10, 2022.

Association of stress induced hyperglycemia with angiographic findings and clinical outcomes in patients with ST-elevation myocardial infarction.

BACKGROUND: Stress induced hyperglycemia (SIH) is common among patients with ST-elevation myocardial infarction (STEMI), even in patients without diabetes mellitus. However, evidence regarding its role on the angiographic outcomes and the prognosis of patients presenting with STEMI is scarce. METHODS: This study included 309 consecutively enrolled STEMI patients undergoing primary percutaneous coronary intervention (pPCI). Patients were diagnosed with SIH if blood glucose on admission was > 140 mg/dl. Also, patients had to fast for at least 8 hours before blood sampling. The objective was to assess whether SIH was associated with major adverse cardiovascular and cerebrovascular (MACCE) events and explore its relationship with angiographic predictors of worse prognosis such as poor initial TIMI flow, intracoronary thrombus burden, distal embolization, and presence of residual thrombus after pPCI. RESULTS: SIH in diabetic and non-diabetic patients was associated with a higher incidence of LTB (aOR = 2.171, 95% CI 1.27-3.71), distal embolization (aOR = 2.71, 95% CI 1.51-4.86), and pre-procedural TIMI flow grade = 0 (aOR = 2.69, 95% CI 1.43-5.04) after adjusting for relevant clinical variables. Importantly, during a median follow-up of 1.7 years STEMI patients with SIH with or without diabetes experienced increased occurrence of MACCE both in univariate (HR = 1.92, 95% CI 1.19-3.01) and multivariate analysis (aHR = 1.802, 95% CI 1.01-3.21). CONCLUSIONS: SIH in STEMI patients with or without diabetes was independently associated with increased MACCE. This could be attributed to the fact that SIH was strongly correlated with poor pre-procedural TIMI flow, LTB, and distal embolization. Large clinical trials need to validate SIH as an independent predictor of adverse angiographic and clinical outcomes to provide optimal individualized care for patients with STEMI.

Hyperhaemolytic transfusion reaction in two ß-thalassaemia major patients: The role of eculizumab.

WHAT IS KNOWN AND OBJECTIVE: Hyperhaemolytic transfusion reactions are rare life-threatening events predominantly affecting patients with haemoglobinopathies. We report two cases in ß-thalassaemia major patients on chronic transfusion therapy and highlight the role of eculizumab in its management. CASE SUMMARY: Patient 1 presented with intravascular haemolysis on day 7 (D7) post-transfusion and responded to treatment with corticosteroids and intravenous immunoglobulin. However, patient 2 presented with severe symptomatic anaemia (D4 post-transfusion) unresponsive to the aforementioned measures. Eculizumab administration led to resolution of the hyperhaemolysis. WHAT IS NEW AND CONCLUSION: We report the successful management of hyperhaemolysis with eculizumab in a ß-thalassemia major patient.

Should we incorporate obstructive sleep apnea in CHA2DS2-VASc score?

Atrial fibrillation (AF) is considered a significant challenge in cardiovascular medicine related to significant morbidity and mortality. Obstructive sleep apnea (OSA) is associated with stroke and constitutes an important risk factor for AF. However, it is still ambiguous whether OSA is independently related to stroke or systemic embolism in AF patients, and whether or not OSA should be included in CHA2DS2-VASc score. In a recent study, the presence of OSA in patients with AF was associated with higher rates of adverse events, namely stroke and systemic embolism. Patients with OSA have higher CHA2DS2-VASc scores and mean CHA2DS2-VASc scores that increase with OSA severity. The addition of OSA to CHA2DS2-VASc resulted in improved discrimination, but this improvement was modest and clinically non-significant. However, cardiovascular risk factors that accompany OSA and not OSA per se might be responsible for the increased thromboembolic risk in these patients. It is noteworthy that patients with OSA with CHA2DS2-VASc <2 had a higher incidence of stroke compared to those without. Unfortunately, the event rates for stroke in these patients were too low to reach statistically validated conclusions. Therefore, it seems reasonable to suggest that in borderline stroke risk patients (CHA2DS2-VASc <2), the presence of OSA should be taken into account in the treatment decision. More studies are needed to elucidate whether or not OSA should be incorporated in CHA2DS2-VASc score.

Is HbA1c an ideal biomarker of well-controlled diabetes?

HbA1c is a biomarker with a central role in the diagnosis and follow-up of patients with diabetes, although not a perfect one. Common comorbidities encountered in patients with diabetes mellitus, such as renal insufficiency, high output states (iron deficiency anaemia, haemolytic anaemia, haemoglobinopathies and pregnancy) and intake of specific drugs could compromise the sensitivity and specificity of the biomarker. COVID-19 pandemic poses a pressing challenge for the diabetic population, since maintaining optimal blood glucose control is key to reduce morbidity and mortality rates. Alternative methods for diabetes management, such as fructosamine, glycosylated albumin and device-based continuous glucose monitoring, are discussed.

Diagnosing a Patient with Erdheim-Chester Disease during the COVID-19 Pandemic.

Background: Erdheim-Chester disease (ECD) is a rare hematopoietic neoplasm of histiocytic origin characterized by an insidious course. The coronavirus disease 2019 (COVID-19) pandemic has put an enormous strain on healthcare systems worldwide both directly and indirectly, resulting in the disruption of healthcare services to prevent, diagnose and manage non-COVID-19 disease. Case Presentation: We describe the case of a 58-year-old male patient with sporadic episodes of self-resolving mild fever and anemia of chronic disease with onset two years before the current presentation. Positron emission/computed tomography scan revealed the presence of moderately hypermetabolic perirenal tissue masses. In order to achieve diagnosis, repeated perirenal tissue biopsies were performed, and the diagnostic evaluation was complicated by the strain put on the healthcare system by the COVID-19 pandemic. The patient contracted SARS-CoV-2 and required hospitalization, but recovered fully. No further ECD target organ involvement was documented. Treatment options were presented, but the patient chose to defer treatment for ECD. Conclusion: A high index of suspicion and multidisciplinary team collaboration is paramount to achieve diagnosis in rare conditions such as ECD. Disruptions in healthcare services in the pandemic milieu may disproportionately affect people with rare diseases and further study and effort is required to better meet their needs in the pandemic setting.

Circadian Pattern of Acute Myocardial Infarction and Atrial Fibrillation in a Mediterranean Country: A study in Diabetic Patients.

Background and objectives: The circadian pattern seems to play a crucial role in cardiovascular events and arrhythmias. Diabetes mellitus is a complex metabolic disorder associated with autonomic nervous system alterations and increased risk of microvascular and macrovascular disease. We sought to determine whether acute myocardial infarction (AMI) and atrial fibrillation (AF) follow a circadian pattern in diabetic patients in a Mediterranean country. Materials and Methods: This retrospective study included 178 diabetic patients (mean age: 67.7) with AMI or AF who were admitted to the coronary care unit. The circadian pattern of AMI and AF was identified in the 24-h period (divided in 3-h and 1-h intervals). Patients were also divided in 3 groups according to age; 40-65 years, 66-79 years and patients older than 80 years. A chi-square goodness-of-fit test was used for the statistical analysis. Results: AMI seems to occur more often in the midnight hours (21:00-23:59) (p < 0.001). Regarding age distribution, patients between 40 and 65 years were more likely to experience an AMI compared to other age groups (p < 0.001). Autonomic alterations, working habits, and social reasons might contribute to this phenomenon. AF in diabetic patients occurs more frequently at noon (12:00-14:59) (p = 0.019). Conclusions: Diabetic patients with AMI and AF seem to follow a specific circadian pattern in a Mediterranean country, with AMI occurring most often at midnight hours and AF mostly at noon. Autonomic dysfunction, glycemic fluctuations, intense anti-diabetic treatment before lunch, and patterns of insulin secretion and resistance may explain this pattern. More studies are needed to elucidate the circadian pattern of AMI and AF in diabetic patients to contribute to the development of new therapeutic approaches in this setting.

Prognostic relevance of pre-procedural plasma volume status estimation in patients undergoing transcatheter aortic valve implantation: A meta-analysis.

BACKGROUND: To systematically evaluate the prognostic utility of estimated plasma volume status (ePVS) on the outcomes of patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: The exposure variable of interest was the ePVS, enumerating the percentage change of the actual plasma volume from the ideal plasma volume, and being calculated on the basis of weight and hematocrit using sex-specific constants. A random-effects meta-analysis was performed after a systematic literature search in PubMed, Scopus and Web Of Science. RESULTS: The systematic literature search yielded 5 eligible observational cohort studies encompassing a total of 7,121 patients undergoing TAVI. The meta-analysis suggested that "high ePVS" status was independently associated with increased risk for 1-year all-cause mortality (pooled adjusted hazard ratio: 1.63, 95 % confidence intervals: 1.36-1.95) compared to "low ePVS". Also, the pooled unadjusted odds for 1-year mortality, 30-day mortality, peri-procedural stroke, major bleeding, and acute kidney injury were significantly increased in the "high ePVS" group of patients. Conversely, the unadjusted risk of pacemaker implantation and major vascular complications did not differ significantly between the 2 groups. CONCLUSIONS: Plasma volume expansion appears to be linked with a worse peri-procedural and long-term prognostic course in TAVI. Its use in clinical practice could refine risk stratification and candidate selection practices.

The Role of Cardiovascular Magnetic Resonance Imaging in the Assessment of Mitral Regurgitation.

Mitral regurgitation (MR), a primary cause of valvular disease in adults, affects millions and is growing due to an ageing population. Cardiovascular magnetic resonance (CMR) has emerged as an essential tool, offering insights into valvular and myocardial pathology when compared to the primary imaging modality, echocardiography. This review highlights CMR's superiority in high-resolution volumetric assessment and tissue characterization, including also advanced techniques like late gadolinium enhancement imaging, parametric mapping, feature tracking and 4D flow analysis. These techniques provide a deeper understanding of MR's pathophysiology and its effect on cardiac chambers, enabling CMR to surpass echocardiography in predicting hard clinical outcomes and left ventricular (LV) remodelling post mitral valve surgery. Despite its advantages, CMR's application faces limitations like cost, lack of standardization, and susceptibility to arrhythmia artifacts. Nonetheless, as technological advancements continue and new evidence emerges, CMR's role in MR assessment is set to expand, offering a more nuanced and personalized approach to cardiac care. This review emphasizes the need for further research and standardized protocols to maximize CMR's potential in MR management.

The prognostic impact of diastolic dysfunction after transcatheter aortic valve replacement: A systematic review and meta-analysis.

BACKGROUND: Diastolic dysfunction (DD) is a long-established marker of disease progression in patients with aortic valve stenosis (AS), indicating valvular myocardial damage. Recently, substantial observational data have emerged demonstrating that worse pre-operative DD assessed using echocardiography is associated with adverse long-term clinical outcomes after transcatheter aortic valve replacement (TAVR). AIM: To systematically appraise and quantitatively synthesize current evidence on the prognostic impact of echocardiographic severe DD derived by echocardiography before TAVR. METHODS: A systemic literature review was undertaken in electronic databases to identify studies reporting the predictive value of severe DD in AS subjects undergoing TAVR. A random-effects meta-analysis was conducted to quantify the adjusted and unadjusted hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACEs) for the presence of severe DD. RESULTS: Ten studies were deemed eligible for inclusion. Of those, 9 provided appropriate quantitative data for the meta-analysis, encompassing a total of 4,619 patients. The presence of severe DD was associated with increased risk for all-cause mortality (pooled unadjusted HR=2.56 [1.46-4.48]; p<0.01; I2=76 %) and MACEs (pooled unadjusted HR=1.82 [1.29-2.58]; p<0.01; I2=86 %). When adjusted for clinically-relevant parameters, the presence of severe DD retained independent association with all-cause mortality (pooled adjusted HR=2.35 [1.26-4.37]; p<0.01; I2=79 %) and MACEs (pooled adjusted HR= 2.52 [1.72-3.65]; p<0.01; I2=0 %). In subgroup analysis there was no difference on post-TAVR risk between the use of different diastolic function grading scores. CONCLUSION: Presence of severe DD assessed by echocardiography pre-TAVR is a major determinant of long-term adverse outcomes after the procedure.

Two Cases of Testicular Tuberculosis and Review of the Recent Literature.

In this review, two cases of testicular tuberculosis (TB) are presented, and another 58 cases published in PubMed between January 1, 2012, and July 31, 2023, are reviewed. Testicular TB remains a disease mainly of the developing world, with one notable exception - the infections caused as a result of Bacillus Calmette-Guérin infusion immunotherapy for bladder cancer. Its clinical course is subacute; however, it might get disseminated and become life-threatening; therefore, prompt diagnosis is very important. The diagnosis can be quite challenging, and testicular tissue is the sample with the highest diagnostic yield, either for microbiological or histopathological diagnosis. On the other hand, its treatment follows the standard guidelines for TB treatment; however, the avoidance of an unnecessary orchiectomy is important.

Current Trends in Stroke Biomarkers: The Prognostic Role of S100 Calcium-Binding Protein B and Glial Fibrillary Acidic Protein.

Stroke is the third leading cause of death in the developed world and a major cause of chronic disability, especially among the elderly population. The major biomarkers of stroke which are the most promising for predicting onset time and independently differentiating ischemic from hemorrhagic and other stroke subtypes are at present limited to a few. This review aims to emphasize on the prognostic role of S100 calcium-binding protein b (S100B), and Glial Fibrillary Acidic Protein (GFAP) in patients with stroke. An electronic search of the published research from January 2000 to February 2024 was conducted using the MEDLINE, Scopus, and Cochrane databases. The implementation of S100B and GFAP in existing clinical scales and imaging modalities may be used to improve diagnostic accuracy and realize the potential of blood biomarkers in clinical practice. The reviewed studies highlight the potential of S100B and GFAP as significant biomarkers in the prognosis and diagnosis of patients with stroke and their ability of predicting long-term neurological deficits. They demonstrate high sensitivity and specificity in differentiating between ischemic and hemorrhagic stroke and they correlate well with stroke severity and outcomes. Several studies also emphasize on the early elevation of these biomarkers post-stroke onset, underscoring their value in early diagnosis and risk stratification. The ongoing research in this field should aim at improving patient outcomes and reducing stroke-related morbidity and mortality by developing a reliable, non-invasive diagnostic tool that can be easily implemented in several healthcare settings, with the ultimate goal of improving stroke management.

Hodgkin Lymphoma Presenting as Cardiac Tamponade in a Young Female.

Hodgkin lymphoma (HL) is an uncommon malignancy that is characterized by Hodgkin or Reed-Sternberg cells. Cardiac implications of HL remain one of the least investigated subjects. There are few case reports in the literature of cardiac tamponade in HL patients. We describe a case of a 21-year-old female patient who presented with cardiac tamponade as an initial presentation of HL. Any pericardial effusion significant for tamponade requires immediate drainage and fluid analysis for thorough investigation. Prompt identification and timely intervention are crucial in effectively addressing these complex situations. Therefore, clinicians should maintain heightened awareness in such cases.

Serum Prolactin Levels and Mortality in Adults Without Prolactinoma: A Meta-Analysis.

CONTEXT: Prolactin (PRL) is a highly versatile, multifunctional hormone synthesized and secreted by lactotroph cells of the anterior pituitary. Its metabolic role has been extensively studied even in normoprolactinemic populations. Recently, a wealth of observational data have outlined the potential prognostic value of PRL in various clinical settings. OBJECTIVE: This systematic review aims to systematically evaluate and quantitatively synthesize the association between serum PRL levels and risk of mortality in adults without prolactinoma. METHODS: A systematic literature search was conducted up to June 10, 2023, to identify studies reporting the association of serum PRL levels with clinical outcomes of adults without prolactinoma. A random-effects meta-analysis was conducted to quantify the adjusted hazard ratios [(a)HRs] for all-cause and cardiovascular death (CVD) during follow-up. RESULTS: Twenty-eight studies were deemed eligible reporting the outcomes of adults without prolactinoma, in whom serum PRL levels were measured for risk-stratification. Fourteen studies reported appropriate data for meta-analysis encompassing a total of 23 596 individuals. Each unit of PRL increase was independently associated with increased risk of all-cause (pooled aHR = 1.17 [1.08-1.27]; I2 = 48%) and CV mortality (pooled aHR = 1.54 [1.14-2.09]; I2 = 89%). Individuals belonging to the highest PRL category had significantly higher risk for all-cause (pooled aHR = 1.81 [1.43-2.30]; I2 = 65%) and CV (pooled aHR = 1.59 [1.04-2.42]; I2 = 82%) mortality compared to their lowest-PRL category counterparts. The association between PRL levels and in-hospital death did not reach statistical significance. CONCLUSION: PRL levels seem to be an independent predictor for mortality. Further validation is warranted before its role as a risk-stratification tool can be delineated in clinical practice.