Pathophysiological Approach Research Articles

MINOCA: A Pathophysiological Approach of Diagnosis and Treatment—A Narrative Review

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a clinical entity characterized by the absence of significant coronary artery obstruction in epicardial arteries (<50%) on coronary angiography in the setting of acute myocardial infarction (AMI). This article aims to provide a narrative review of the pathophysiological mechanisms, diagnostic challenges, and prognosis associated with MINOCA based on pathophysiology regarding the atherosclerotic and non-atherosclerotic causes. Etiological factors, including thromboembolism, coronary artery spasm, spontaneous coronary artery dissection, coronary microvascular disease, and supply–demand mismatch, are addressed. Imaging modalities such as echocardiography, advances in coronary angiography like intravascular ultrasound (IVUS) and optical coherence tomography (OCT), cardiac magnetic resonance (CMR), and coronary computed tomography angiography (CCTA) are also analyzed. MINOCA patients have a better short-term prognosis compared to those with obstructive coronary artery disease but face significant long-term risks, underscoring the need for precise diagnosis and management strategies. Elevated inflammatory markers and specific genetic predispositions are also associated with adverse outcomes in MINOCA. This review focused on MINOCA from a pathophysiological perspective on the diverse underlying mechanisms, the challenges in achieving accurate diagnosis, the importance of a tailored therapeutic approach and the necessity for further investigation of clinical outcomes.

A Review of Biomarkers of Amyotrophic Lateral Sclerosis: A Pathophysiologic Approach.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. The heterogeneous nature of ALS at the clinical, genetic, and pathological levels makes it challenging to develop diagnostic and prognostic tools that fit all disease phenotypes. Limitations associated with the functional scales and the qualitative nature of mainstay electrophysiological testing prompt the investigation of more objective quantitative assessment. Biofluid biomarkers have the potential to fill that gap by providing evidence of a disease process potentially early in the disease, its progression, and its response to therapy. In contrast to other neurodegenerative diseases, no biomarker has yet been validated in clinical use for ALS. Several fluid biomarkers have been investigated in clinical studies in ALS. Biofluid biomarkers reflect the different pathophysiological processes, from protein aggregation to muscle denervation. This review takes a pathophysiologic approach to summarizing the findings of clinical studies utilizing quantitative biofluid biomarkers in ALS, discusses the utility and shortcomings of each biomarker, and highlights the superiority of neurofilaments as biomarkers of neurodegeneration over other candidate biomarkers.

COVID-19 and kidney involvement: pathophysiological approach

Introduction: Due to the great threat posed by COVID-19, the scientific community must have evidence of kidney damage in patients affected by this disease, which would make it possible to carry out actions aimed at its prevention and early detection. Objectives: deepen knowledge about COVID-19 and its impact on the kidney. Methods: a bibliographic review on COVID-19 and kidney was carried out, in research published in Spanish and English, in the PubMed, Scielo, and Dialnet databases. All documents published in the last five years (2019-2023) were selected, which included the keywords: COVID-19, kidney, kidney disease. Conclusions: within the systemic involvement caused by COVID-19, the kidney plays a predominant role in its pathophysiology and as a target organ. Kidney disease is in itself a risk factor for morbidity and mortality and acute kidney failure worsens the prognosis; Hence, it is necessary to delve deeper into these topics every day to direct novel diagnostic and therapeutic strategies

Studi Penggunaan Obat pada Pasien Gastroesophageal Reflux Disease (GERD) Rawat Jalan di RS. Aura Syifa Kediri Periode Januari - November 2022

Background: Gastroesophageal Reflux Disease (GERD) is a pathological condition caused by reflux of contents from the stomach entering the esophagus, with various signs and symptoms involving the esophagus, pharynx, larynx and airway. Gastroesophageal Reflux Disease (GERD) has typical symptoms of heartburn and regurgitation. So that the symptoms that appear will interfere with all activities carried out by someone. Objective: This study is to determine the profile picture of drug use in outpatient Gastroesophageal Reflux Disease (GERD) patients at Aura Syifa Hospital Kediri and to determine the study of drug use in outpatient Gastroesophageal Reflux Disease (GERD) patients at Aura Syifa Hospital Kediri by analyzing the right indications and right doses. Method: This study is a descriptive observational study with retrospective data collection from patient medical record data. Results: The results of a study on the useof drugs in outpatient gastroesophageal reflux disease (GERD) patients at Aura Syifa Hospital Kediri for the period January-November 2022 by analyzing the right indications and correct doses, which were obtained as many as 175 patients. The most GERD patients were women as many as 114 patients and men as many as 61 patients. The most common age for GERD is 56-65 years old and >65 years old. The most widely used drug class is the Proton Pump Inhibitor (PPI) class with a percentage of 38% and the drug in this class that is often used is lansoprazole with 167 prescriptions. The results of a study on drug use in outpatient gastroesophageal reflux disease (GERD) patients at Aura Syifa Hospital Kediri for the period January- November 2022 that meet the rationality of treatment based on the literature of the Indonesian GERD Consensus in 2013 or BNF 2017 or Pharmacotherapy A Pathophysiologic Approach 11th edition in 2020 or Medscape, where the indication is 100% (175 patients) and the right dose is 100% (175 patients).

Systemic iron overload: Review of pathophysiology and clinical-radiological diagnostic approach

Systemic iron overload is a condition that carries significant implications for health, making it crucial to understand its pathophysiology and the precise clinical and radiological diagnostic methods. This article comprehensively reviews the pathophysiology of iron metabolism, highlighting its crucial role in multiple cellular processes and the regulatory mechanisms that maintain its balance in the body. Furthermore, the diagnostic approach to iron overload is analyzed in detail, reviewing the role of various imaging techniques; highlighting magnetic resonance imaging as a method to develop an accurate and non-invasive assessment of iron load in various tissues.

HCM AT THE CROSSROAD

Abstract Introduction Treatment of oHCM frequently requires difficult choices, especially when it is superimposed on other urgent clinical conditions,such as AMI or mechanical complications. Clinical Case A 52–year–old man with known oHCM, who spontaneously quickly discontinued recommended therapy, presents to theED with a sudden episode of dyspnea and presyncope. A firstECG was essentially normal for pathology. After 1h, the patient experiences a sudden episode of chest pain with rapid hemodynamic deterioration and cardiogenic shock(CS). The ECG shows changes compatible with inferolateral MI. The TTE shows severe LVOTO, SAM, severe MR and a suspicious oval image attached to the anterior mitral leaflet. The patient underwent orotracheal intubation, coronary angiography and TEE. Coronary angiography shows a thrombotic occlusion of the proximal circumflex artery, treated with pPCI. TEE confirms a partial rupture of the papillary muscle head. Treatment:The patient‘s CS can be caused by 2different conditions that require treatments with opposing pathophysiological principles. SevereMR due to papillary muscle rupture, as mechanical complication of MI, requires afterload reduction, hemodynamic stabilization with IABP and emergency transfer to a cardiac surgery center. In contrast, the treatment of the underlying pathology(severe LVOTO and severe rMR due to SAM)requires pharmacological stabilization with depression of cardiac contractility and increase in afterload. In the context of cardiogenic shock a rapid choice was required. To help us make the right choice, an Esmolol test was performed. After iv administration of 2mg Esmolol, heart rate was reduced without reduction in BP. The patient was then treated with esmolol in continuous infusion and norepinephrine. In oHCM the ventriculo–arterial coupling is reduced, less than 1. This treatment favored better V–A coupling, ensuring an increase in afterload and a reduction in myocardial contractility. The patient‘s clinical condition rapidly improved, allowing extubation at48h and early mobilization at96h. Myectomy and mitral repair surgery was scheduled 1 month afterPCI. Conclusions Through the use of a short–lived drug such as Esmolol, it was possible to trace the prevailing mechanism of the patient‘s CS. Differently from other cases of CS, to rebalance the V–Acoupling, it was crucial to reduce myocardial contractility and increase afterload. A pathophysiological pharmacological approach ensured a good outcome.

Energetic dysfunction and iron overload in early Parkinson's disease: Two distinct mechanisms?

IntroductionIdentifying biomarkers reflecting cellular dysfunctions in early Parkinson's disease patients (ePD) is needed to develop targeted therapeutic strategies. We aimed to determine if cellular energetic dysfunction related to increased brain sodium concentration would be co-located to microstructural alterations and iron deposition in ePD. MethodsWe prospectively included 12 ePD (mean disease duration 20.0 ± 10.2 months) and 13 healthy controls (HC), scanned with a 7 T 1H and 23Na MRI. Complementary voxel-based and region-based assessments were performed, the latter utilizing a high-resolution multimodal template we created (combining quantitative T1 maps (qT1), transverse relaxation rate (R2*), quantitative magnetic susceptibility mapping (QSM) images) from 200 subjects. This template allowed a precise multiparametric assessment of sodium concentration, QSM, R2*, qT1, mean diffusivity, and fractional anisotropy values. A two-sided p-value<0.05 was considered statistically significant after the Bonferroni correction. ResultsRelative to HC, ePD showed significantly higher sodium concentration in left Substantia nigra (SN) pars reticulata (46.13 mM ± 3.52 vs 38.60 mM ± 6.10, p = 0.038), a subpart of the SN pars compacta (SNc) and ventral tegmental area, Putamen, Globus Pallidum external, accumbens nucleus and claustrum. Significantly increased QSM and R2* values, and decreased T1 values, were limited to the Nigrosomes 1 (Nig) and right SNc (all p < 0.05). QSM values in the Nig were significantly correlated to UPDRS-III scores (r = 0.91,p < 0.001). ConclusionIn ePD, brain sodium accumulation was broad and dissociated from iron accumulation. As with iron accumulation, a sodium-related pathophysiological approach could lead to identifying potential new therapeutic agents and deserves further investigation.

Experimental models of myocardial ischemia: classical approaches and innovations (review)

Myocardial ischemia is the basis for many acute and chronic conditions with great social significance. Therefore, experimental models that describe ischemia development in humans are necessary for a better understanding of the pathophysiology of these conditions and the development of medical and surgical methods of treatment.Aim: To compare current approaches to experimental modeling of myocardial ischemia considering the pathogenetic features of the simulated processes. The manuscript describes the main experimental models of myocardial ischemia: in vitro cellular models, ex vivo isolated heart models, in vivo animal models, the principal components of the ‘heart-on-chip’ model and the possibilities of in silico modeling. The criteria for choosing a specific model of ischemia by pathophysiological approach, advantages and limitations of the models are considered.

An updated review on diabetes mellitus: Exploring its etiology, pathophysiology, complications and treatment approach

Diabetes mellitus, a prevalent chronic metabolic disorder, encompasses types like Type 1 (T1DM), Type 2 (T2DM), and gestational diabetes, marked by elevated blood sugar levels. T1DM, an autoimmune disease, entails genetic susceptibility triggering pancreatic beta cell destruction, necessitating insulin replacement. T2DM, linked to metabolic syndrome and insulin resistance, is influenced by genetics, obesity, inactivity, and ethnicity. Gestational Diabetes Mellitus (GDM) in pregnancy elevates offspring obesity and T2DM risk. Diagnosis involves fasting glucose, oral glucose tolerance, HbA1c tests, and specific antibody assessments. Chronic complications include atherosclerosis, retinopathy, neuropathy, nephropathy, and osmotic cell death, emphasizing glycaemic control. Treatment strategies differ, with T1DM requiring insulin therapy and T2DM involving lifestyle changes, medication, and potential insulin use, underscoring the need to understand diabetes for effective management and improved quality of life.

A Pathophysiological Approach for Selecting Medications to Treat Nociceptive and Neuropathic Pain in Servicemembers.

The prevalence of chronic pain of service members (SMs) in the U.S. is estimated to be higher (roughly 31-44%) compared to that of civilian population (26%). This higher prevalence is likely due to the high physical demands related combat and training injuries that are not immediately resolved and worsen over time. Mental Health America reports that chronic pain can lead to other mental health conditions such as severe anxiety, depression, bipolar disorder, and post-traumatic stress disorder. Such mental health conditions can negatively affect job performance, reduce readiness for military duties, and often lead to patterns of misuse of opioid after SMs entering civilian life. The primary objective of this narrative review is to present a summarized guideline for the treatment of two types of pain that likely affect SMs, namely nociceptive somatic pain and neuropathic pain. This review focused on a stepwise approach starting with nonopioid interventions prior to opioid therapy. The secondary objective of this review is to elucidate the primary mechanisms of action and pathways associated with these two types of pain. We followed the Scale for Assessment of Narrative Review Articles when transcribing this narrative review article to enhance the quality and brevity of this review. This Scale has 0.77% an intra-class coefficient of correlation, 95% confidence interval and 0.88 inter-rater reliability. We searched PubMed, Google Scholar, WorldCAT, and the Cochrane Library for the primary and secondary articles that targeted mechanisms of action, pathways, and pharmacological modalities for nociceptive somatic and neuropathic pain that were published from 2011 to 2022. We excluded articles related to pediatric, some specific pain conditions such as cancer-related pain, palliative care, end-of-life care, and articles that were not written in English language. For pharmacologic selection, we adopted the guidelines from the Policy for Implementation of a Comprehensive Policy on Pain Management by the Military Health Care system for the Fiscal Year 2021; the Clinical Practice Guidance for Opioid Therapy for Chronic Pain by the Department of Defense/Veterans Health Administration (2022); the (2021) Implementation of a Comprehensive Policy on Pain Management by the Military Health Care System; and the (2022) Guideline for Prescribing Opioids for Chronic Painby the Centers for Disease Control. From the knowledge of the mechanisms of action and pathways, we can be more likely to identify the causative origins of pain. As a result, we can correctly diagnose the type of pain, properly develop an efficient and personalized treatment plan, minimize adverse effects, and optimize clinical outcomes. The guideline, however, does not serve as a substitute for clinical judgment in patient-centered decision-making. Medication choices should be individualized judiciously based on the patient's comorbid conditions, available social and economic resources, and the patient's preferences to balance the benefits and risks associated with various pain medications and to achieve optimal pain relief and improve the patient's quality of life.

Diabetes mellitus in acromegaly: prevalence, pathophysiological particulars and treatment strategies

The prevalence of diabetes mellitus in acromegaly is significantly higher than that in the general population. Carbohydrate metabolism abnormalities often precede other phenotypic manifestations of acromegaly. The review presents data on the prevalence of carbohydrate metabolism disorders in acromegaly and describes their pathophysiological characteristics and approaches to treatment.&#x0D; Growth hormone (GH) excess is recognized as a key factor of glucose homeostasis abnormalities due to decreased insulin sensitivity (resulting from active lipolysis) and direct stimulation of insulin secretion. Insulin-like growth factor 1 (IGF1) improves insulin sensitivity; however, the GH diabetogenic effects prevail over the insulin-sensitizing impact of IGF1. Surgical and radiation treatment for somatotropinoma may indirectly improve carbohydrate metabolism, because they decrease the GH levels. Treatment with first generation somatostatin analogues can both improve glycemic control due to decreased GH levels and worsen it due to deterioration of postprandial insulin release, especially in patients with already manifest carbohydrate metabolism disorders. The GH receptor antagonist pegvisomant blocks the effects of excess GH on the target tissues without suppressing insulin secretion, which results in better glucose control; treatment with this agent can be preferred in patients with acromegaly and diabetes mellitus. Management of carbohydrate metabolism disorders in acromegaly is done in accordance with general treatment principles for type 2 diabetes mellitus.

Influence of Perivascular Adipose Tissue on Microcirculation: A Link Between Hypertension and Obesity.

Alterations in microcirculation play a crucial role in the pathogenesis of cardiovascular and metabolic disorders such as obesity and hypertension. The small resistance arteries of these patients show a typical remodeling, as indicated by an increase of media or total wall thickness to lumen diameter ratio that impairs organ flow reserve. The majority of blood vessels are surrounded by a fat depot which is termed perivascular adipose tissue (PVAT). In recent years, data from several studies have indicated that PVAT is an endocrine organ that can produce a variety of adipokines and cytokines, which may participate in the regulation of vascular tone, and the secretory profile varies with adipocyte phenotype and disease status. The PVAT of lean humans largely secretes the vasodilator adiponectin, which will act in a paracrine fashion to reduce peripheral resistance and improve nutrient uptake into tissues, thereby protecting against the development of hypertension and diabetes. In obesity, PVAT becomes enlarged and inflamed, and the bioavailability of adiponectin is reduced. The inevitable consequence is a rise in peripheral resistance with higher blood pressure. The interrelationship between obesity and hypertension could be explained, at least in part, by a cross-talk between microcirculation and PVAT. In this article, we propose an integrated pathophysiological approach of this relationship, in order to better clarify its role in obesity and hypertension, as the basis for effective and specific prevention and treatment.

Frontotemporal-TDP and LATE Neurocognitive Disorders: A Pathophysiological and Genetic Approach.

Frontotemporal lobar degeneration (FTLD) belongs to a heterogeneous group of highly complex neurodegenerative diseases and represents the second cause of presenile dementia in individuals under 65. Frontotemporal-TDP is a subgroup of frontotemporal dementia characterized by the aggregation of abnormal protein deposits, predominantly transactive response DNA-binding protein 43 (TDP-43), in the frontal and temporal brain regions. These deposits lead to progressive degeneration of neurons resulting in cognitive and behavioral impairments. Limbic age-related encephalopathy (LATE) pertains to age-related cognitive decline primarily affecting the limbic system, which is crucial for memory, emotions, and learning. However, distinct, emerging research suggests a potential overlap in pathogenic processes, with some cases of limbic encephalopathy displaying TDP-43 pathology. Genetic factors play a pivotal role in both disorders. Mutations in various genes, such as progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), have been identified as causative in frontotemporal-TDP. Similarly, specific genetic variants have been associated with an increased risk of developing LATE. Understanding these genetic links provides crucial insights into disease mechanisms and the potential for targeted therapies.

Critical review of diagnosis in rhinology and its therapeutical implications

Diagnosis in rhinology is currently based on the concept of inflammation (chronic rhinosinusitis [CRS]) or the clinical concept of chronic nasal dysfunction (CND). The complementarity between these two approaches can be discussed by a critical review of the literature structured by the analysis of the fundamental and diagnostic bases and the therapeutic implications linked to each. The concept of CRS is based on the anatomical continuity of the nasal and sinus respiratory mucosa and molecular biology data, seeking to analyze the mechanisms of chronic inflammation and to identify proteins and biomarkers involved in the different supposed endotypes of chronic inflammation of this mucosa. The concept of CND seeks to analyze medical, instrumental or surgical diagnostic and therapeutic strategies, taking account of both inflammatory and non-inflammatory causes impacting the anatomy or physiology of each of the three noses (olfactory, respiratory and sinus) that make up the mid-face sinonasal organ of evolution-development (Evo-Devo) theory. Thus, the concept of CRS offers an endotypic approach, based on biological characterization of mucosal inflammation, while the concept of CND offers a compartmentalized phenotypic and pathophysiological approach to sinonasal diseases. The joint contribution of these two concepts in characterizing nasal functional pathology could in future improve the medical service provided to patients.

Chronic prurigo

Chronic prurigo is avery debilitating skin condition characterized by the development of multiple pruriginous nodules, papules or plaques due to aprolonged scratching behavior as aresult of chronic itch. Patients often experience anxiety, depression or sleep impairment leading to asubstantial decrease in quality of life. Due to the complex pathophysiology and diversity in clinical presentation, managing chronic prurigo remains achallenge. Disease-specific guidelines provide appropriate diagnostic measures and recommend astep-wise therapeutic approach. With the increase of pharmaceutical interest in chronic prurigo, several innovative therapies including monoclonal antibodies and small molecules are currently being investigated for chronic prurigo. This continuing medical education (CME) article provides an overview on various aspects of chronic prurigo, especially on epidemiology, pathophysiology, clinical presentation, diagnostic and therapeutic approach, and innovate therapeutic options.

Vasoplegic Syndrome and Anaesthesia: A Narrative Review.

Vasoplegic syndrome (VS) is defined as low systemic vascular resistance, normal or high cardiac output, and resistant hypotension unresponsive to vasopressor agents and intravenous volume. VS is a frequently encountered complication in cardiovascular and transplantation surgery, burns, trauma, pancreatitis, and sepsis. The basis of the pathophysiology is associated with an imbalance of vasodilator and vasoconstrictive structure in vascular smooth muscle cells and is highly complex. The pathogenesis of VS has several mechanisms, including overproduction of iNO, stimulation of ATP-dependent K+ channels and NF-κB, and vasopressin receptor 1A (V1A-receptor) down-regulation. Available treatments involve volume and inotropes administration, vasopressin, methylene blue, hydroxocobalamin, Ca++, vitamin C, and thiamine, and should also restore vascular tone and improve vasoplegia. Other treatments could include angiotensin II, corticosteroids, NF-κB inhibitor, ATP-dependent K+ channel blocker, indigo carmine, and hyperbaric oxygen therapy. Despite modern advances in treatment, the mortality rate is still 30-50%. It is challenging for an anaesthesiologist to consider this syndrome's diagnosis and manage its treatment. Our review aims to review the diagnosis, predisposing factors, pathophysiology, treatment, and anaesthesia approach of VS during anaesthesia and to suggest a treatment algorithm.

Acute Fatty Liver of Pregnancy - Case Series

With a prevalence of 0,01-0,03%, acute fatty liver in pregnancy (AFLP) is a rare and dangerous complication of pregnancy and is difficult to distinguish from other, sometimes more common, pregnancy diseases such as HELLP syndrome, aHUS and TTP because of its mostly non-specific symptoms. Due to its rarity, AFLP is often not obvious to the obstetrician as a possible differential diagnosis. Yet early diagnosis and the fastest possible delivery is the only causal therapy and is important for the mortality rate. In the present manuscript, the pathophysiology, diagnosis and therapy of acute fatty liver in pregnancy are highlighted for the clinical routine based on case descriptions from three university hospitals, and reference is made to possible findings that are helpful in establishing the diagnosis. The angiogenic preeclampsia marker sFlt-1 plays a role and provides new opportunities to consider pathophysiological approaches.

Acute heart failure and valvular heart disease: A scientific statement of the Heart Failure Association, the Association for Acute CardioVascular Care and the European Association of Percutaneous Cardiovascular Interventions of the European Society of Cardiology.

Acute heart failure (AHF) represents a broad spectrum of disease states, resulting from the interaction between an acute precipitant and a patient's underlying cardiac substrate and comorbidities. Valvular heart disease (VHD) is frequently associated with AHF. AHF may result from several precipitants that add an acute haemodynamic stress superimposed on a chronic valvular lesion or may occur as a consequence of a new significant valvular lesion. Regardless of the mechanism, clinical presentation may vary from acute decompensated heart failure to cardiogenic shock. Assessing the severity of VHD as well as the correlation between VHD severity and symptoms may be difficult in patients with AHF because of the rapid variation in loading conditions, concomitant destabilization of the associated comorbidities and the presence of combined valvular lesions. Evidence-based interventions targeting VHD in settings of AHF have yet to be identified, as patients with severe VHD are often excluded from randomized trials in AHF, so results from these trials do not generalize to those with VHD. Furthermore, there are not rigorously conducted randomized controlled trials in the setting of VHD and AHF, most of the data coming from observational studies. Thus, distinct to chronic settings, current guidelines are very elusive when patients with severe VHD present with AHF, and a clear-cut strategy could not be yet defined. Given the paucity of evidence in this subset of AHF patients, the aim of this scientific statement is to describe the epidemiology, pathophysiology, and overall treatment approach for patients with VHD who present with AHF.

A CASE SERIES ON PANCREATICOPLEURAL FISTULA

A pancreaticopleural fistula (PPF) is a rare condition that causes thoracic symptoms such as dyspnea and chest pain secondary to exudative pleural effusions. While PPF is a very rare complication with only 52 cases reported between 1960 and 2007, they typically occur in patients who are male, middle aged, and have a history of chronic alcohol use and chronic pancreatitis (Aswani and Hira, 2015; Francisco et al., n.d.; Valeshabad et al., 2018; Ali et al., 2009). The fistula between the pancreas and pleural cavity causes large, rapidly accumulating, and recur- rent pleural effusions which cause symptoms that can be difficult to differentiate from other acute thoracic pathologies (Francisco et al., n. d.). As a result, it is essential that providers have a high index of suspicion for PPF in these appropriate populations. We present a case study with 2 patients who reported to our institute, to review the typical presentation, pathophysiology, and current approach to treatment of PPF.

Seasonality in Synergism with Multi-Pathogen Presence Leads to Mass Mortalities of the Highly Endangered Pinna nobilis in Greek Coastlines: A Pathophysiological Approach.

Mortalities of Pinna nobilis populations set at risk the survival of the species from many Mediterranean coastline habitats. In many cases, both Haplosporidium pinnae and Mycobacterium spp. are implicated in mass mortalities of P. nobilis populations, leading the species into extinction. In the context of the importance of these pathogens' role in P. nobilis mortalities, the present study investigated two Greek populations of the species hosting different microbial loads (one only H. pinnae and the second both pathogens) by the means of pathophysiological markers. More specifically, the populations from Kalloni Gulf (Lesvos Island) and from Maliakos Gulf (Fthiotis), seasonally sampled, were chosen based on the host pathogens in order to investigate physiological and immunological biomarkers to assess those pathogens' roles. In order to determine if the haplosporidian parasite possesses a major role in the mortalities or if both pathogens are involved in these phenomena, a variety of biomarkers, including apoptosis, autophagy, inflammation and heat shock response were applied. The results indicated a decreased physiological performance of individuals hosting both pathogens in comparison with those hosting only H. pinnae. Our findings provide evidence for the synergistic role of those pathogens in the mortality events, which is also enhanced by the influence of seasonality.