Cesare de Gregorio

Kounis syndrome (KS) is a largely underdiagnosed cause of acute coronary syndromes triggered by allergic or hypersensitivity reactions. The syndrome results from complex immune cell activation with the release of vasoactive and prothrombotic mediators leading to coronary vasospasm (type I KS) or thrombosis of plaque (type II KS), stent (type III KS) or coronary artery bypass graft (type IV KS). Despite increasing recognition over the past few decades, its pathophysiological mechanisms, diagnostic boundaries, and therapeutic implications remain incompletely understood. A comprehensive diagnostic approach, including signs, symptoms, biochemical findings, electrocardiography, echocardiography, coronary angiography, and multimodality imaging, as well as invasive assessment in selected cases, can be recommended, although its implementation in routine practice remains limited. Available data indicate that angiographically documented epicardial coronary spasm is observed in only a minority of patients, while normal or non-obstructive coronary arteries are frequently encountered. Emerging data from provocative testing, invasive coronary functional assessment, cardiac magnetic resonance and nuclear imaging suggests that coronary microvascular dysfunction may contribute substantially to the clinical phenotype, expanding the traditional concept of allergic epicardial vasospasm. Current evidence supports the recognition of type I KS as a distinct allergic vasomotor acute coronary syndrome within the myocardial infarction non-obstructive coronary artery (MINOCA) spectrum, deserving greater recognition in future diagnostic classifications and clinical practice guidelines. This narrative review critically appraises current evidence, integrating historical perspectives with contemporary insights into classification, pathophysiology, triggers, diagnostic strategies and therapeutic approaches, focusing on the most frequent manifestation represented by the vasospastic variant.

Kounis syndrome is an acute coronary syndrome occurring in the context of an allergic, hypersensitivity, or anaphylactic reaction. Its established classification includes coronary vasospasm, coronary atherosclerotic plaque thrombosis, and hypersensitivity-associated coronary stent thrombosis. Coronary artery bypass graft (CABG) involvement has recently emerged as a potential fourth (Type IV) variant but remains poorly characterized, with evidence limited to a few published case reports. We performed a focused literature review to identify all published cases of suspected or confirmed Kounis syndrome involving arterial or venous coronary bypass grafts. The available evidence encompasses anaphylaxis-associated myocardial infarction due to saphenous vein graft thrombosis, hypersensitivity-related thrombosis of a drug-eluting stent implanted within a saphenous vein graft, diffuse vasospasm involving arterial and venous bypass conduits, and probable transient graft vasomotor dysfunction. These observations support recognition of bypass graft spasm and thrombosis as distinct manifestations of allergic coronary disease. Saphenous vein grafts appear particularly vulnerable because accelerated atherosclerosis, endothelial dysfunction, disturbed shear stress, and a highly thrombogenic substrate may amplify the consequences of mast-cell activation. Early recognition requires simultaneous assessment of the allergic reaction, native coronary arteries, and all bypass conduits. Electrocardiography, coronary angiography, serum tryptase, and, when appropriate, intracoronary imaging and thrombus histology may improve diagnostic confidence. This is the first review specifically dedicated to Kounis syndrome involving coronary bypass grafts. Although current evidence remains limited, this review provides a comprehensive synthesis of the available literature and identifies the major diagnostic and therapeutic knowledge gaps that should guide future investigations.

Kounis syndrome (KS) is an increasingly recognized cause of acute coronary syndromes triggered by allergic or hypersensitivity reactions. The syndrome results from a complex interplay between mast-cell degranulation and platelet activation during allergic reactions, leading to the release of vasoactive, pro-inflammatory and prothrombotic mediators. These mechanisms may induce coronary vasospasm (type I KS) or thrombosis of plaque (type II KS), stent (type III KS) or coronary artery bypass graft (type IV KS). KS remains largely underdiagnosed in routine clinical practice, with significant gaps in epidemiology, diagnosis and management. This narrative review critically appraises current evidence, integrating historical perspectives with contemporary insights into classification, pathophysiology, triggers, diagnostic strategies and thera-peutic approaches, focusing on the most frequent manifestation represented by vasospastic variant. Despite increasing recognition over the past three decades, its true pathophysiological mechanisms, diagnostic boundaries, and therapeutic implications remain incompletely understood. Available data indicate that angiographically documented epicardial coronary spasm is observed in only a minority of patients, while normal or non-obstructive coronary arteries are frequently encountered. Emerging evidence from provocative testing, coronary physiology assessment, cardiac magnetic resonance and nuclear imaging suggests that coronary microvascular dysfunction may contribute substantially to the clinical phenotype, expanding the traditional concept of allergic epicardial vasospasm. A comprehensive diagnostic approach, including signs, symptoms, biochemical findings, electrocardiography, echocardiography, coronary angiography, and multimodality imaging including invasive assessment in selected cased, can be recommended, although its implementation in routine practice remains limited. Current evidence supports the recognition of type I KS as a distinct allergic vasomotor acute coronary syndrome within the myocardial infarction non-obstructive cor-onary artery (MINOCA) spectrum, deserving greater recognition in future diagnostic classifications and clinical practice guidelines.

Kounis syndrome is defined as the occurrence of acute coronary events in the setting of allergic, hypersensitivity, or anaphylactic reactions. It is mediated by mast cell activation and the interaction of inflammatory cells, including T lymphocytes and macrophages. This process leads to the release of multiple inflammatory mediators, such as platelet-activating factor, histamine, neutral proteases (tryptase and chymase), arachidonic acid metabolites, cytokines, and chemokines. Kounis syndrome represents a unique form of acute vascular disorder that may involve not only the coronary arteries but also peripheral, cerebral, and mesenteric vessels as well as the venous system. Contrast media are widely used in diagnostic imaging to enhance visualization and characterization of pathological conditions. These agents can be administered via several routes, including oral, intravenous, intra-arterial, or rectal administration. Although most hypersensitivity reactions to contrast media are mild to moderate, severe complications such as anaphylaxis, cardiac arrest, and Kounis syndrome may occur. In particular, contrast media-induced Kounis syndrome has been associated with significant clinical consequences, including an increased risk of life-threatening cardiac events.

Among cardiomyopathies, the hypertrophic phenotype is the most common, and hypertrophic cardiomyopathy (HCM) phenocopies represent a heterogeneous group of conditions. They are defined by a left ventricular wall thickness ≥15 mm in the absence of other causes such as loading conditions, ischemia, or valvular disease. Although they mimic similar clinical and morphological features, their etiologies are distinct and include genetic, metabolic, and infiltrative mechanisms. Therefore, accurate classification and differential diagnosis are crucial for effective management and treatment. Sarcomeric HCM is the most frequent form, accounting for up to 60% of cases. However, numerous non-sarcomeric phenocopies exist, including amyloidosis, Fabry disease, glycogen storage disorders, RASopathies, and mitochondrial diseases. Clinical and imaging findings are essential to distinguish these entities from sarcomeric HCM. Electrocardiography, echocardiography, advanced modalities such as cardiac magnetic resonance (CMR), and specific laboratory tests all play a central role in guiding diagnosis. Genetic testing provides key insights into mutations and inheritance patterns, further supporting definitive diagnosis. Correct identification of an HCM phenocopy carries important therapeutic implications, as disease-specific treatments can significantly improve prognosis. For example, targeted therapies exist for amyloidosis, Fabry disease, and certain metabolic or mitochondrial disorders, underlining the clinical relevance of an accurate diagnosis. This review aims to provide an overview of HCM phenocopies and assist clinicians in diagnostic reasoning. The first part addresses classification according to pathophysiological mechanisms, clinical features, and genetic background. The second part focuses on the stepwise approach to differential diagnosis, integrating clinical assessment, laboratory evaluation, ECG, echocardiography, and CMR findings.

In the past decade, advancements in knowledge on the immune system have partially unveiled the complex interplay between the heart and the immune system. This new branch of cardiology is now called cardio-immunology. It encompasses different areas from preclinical to translational and purely clinical research aiming to identify the relationship between the immune system and different cardiovascular diseases. Inflammatory cardiomyopathies are a heterogeneous subgroup of non-ischaemic cardiomyopathies characterized by left ventricular, or biventricular, dysfunction after an inflammatory insult. Recently, genetic testing allowed to identify specific genotype–phenotype correlation in the diagnosis and, mostly, in the prognosis of different cardiomyopathies. Some pathogenic variants might lead to a clinical phenotype in overlap with inflammatory myocardial diseases and inflammation can be found in cardiac magnetic resonance or endomyocardial biopsies of different cardiomyopathies. Although prognostic predictors of adverse events and indication to immunosuppressive therapies have been identified in myocarditis, data are lacking in the context of genetic cardiomyopathies presenting myocardial inflammation. As for pericardial diseases, genetic variants in immune-related genes, such as IL1B have been described, specifically in recurrent pericarditis. A growing body of evidence starting form genetics and cardio-immunology are trying to elucidate the basic mechanisms of the disease and may play a significant role in the understanding the pathophysiology and potentially the treatment of patients. Some examples are represented by arrhythmogenic cardiomyopathy presenting with hot-phases or biopsy-proven myocarditis presenting genetic mutations in specific genes as TTN or DSP. The aim of this review paper is to highlight the current knowledge and the unmet clinical needs, providing a practical and concise guidance for specific areas of research and management of patients affected by myo-pericardial diseases with overlap between genetics and inflammation, ranging from genetic testing to medical and device therapy.

Among cardiomyopathies, the hypertrophic phenotype is the most common, and hypertrophic cardiomyopathy (HCM) phenocopies represent a heterogeneous group of conditions. They are defined by a left ventricular wall thickness ≥15 mm in the absence of other causes such as loading conditions, ischemia, or valvular disease. Although they mimic similar clinical and morphological features, their aetiologies are distinct and include genetic, metabolic, and infiltrative mechanisms. Therefore, accurate classification and differential diagnosis are crucial for effective management and treatment. Sarcomeric HCM is the most frequent form, accounting for up to 60% of cases. However, numerous non-sarcomeric phenocopies exist, including amyloidosis, Fabry disease, glycogen storage disorders, RASopathies, and mitochondrial diseases. Clinical and imaging findings are essential to distinguish these entities from sarcomeric HCM. Electrocardiography, echocardiography, advanced modalities such as cardiac magnetic resonance (CMR), and specific laboratory tests all play a central role in guiding diagnosis. Genetic testing provides key insights into mutations and inheritance patterns, further supporting definitive diagnosis. Correct identification of an HCM phenocopy carries important therapeutic implications, as disease-specific treatments can significantly improve prognosis. For example, targeted therapies exist for amyloidosis, Fabry disease, and certain metabolic or mitochondrial disorders, underlining the clinical relevance of an accurate diagnosis. This review aims to provide an overview of HCM phenocopies and assist clinicians in diagnostic reasoning. The first part addresses classification according to pathophysiological mechanisms, clinical features, and genetic background. The second part focuses on the stepwise approach to differential diagnosis, integrating clinical assessment, laboratory evaluation, ECG, echocardiography, and CMR findings.

Mast cell degranulation and other interacting and linked cells, including T-lymphocytes, macrophages, eosinophils, and platelets, as well as a range of inflammatory mediators produced during an anaphylactic or allergic reaction, constitute the main causes of Kounis syndrome. Acute ischemia episodes, coronary spasm, atheromatous plaque erosion/rupture, and platelet activation can all be caused by histamine, tryptase, arachidonic acid derivatives, and chymase in the Kounis syndrome cascade. Kounis syndrome can be triggered by a variety of factors, including medications, hymenopteran stings, metals, foods, environmental exposures, illnesses, and immunizations. In addition, some unusual, rare, intriguing, and significant causes of Kounis syndrome have been discovered recently, namely the “kiss of death”, where human kissing and pet kissing can induce fatal Kounis syndrome. Moreover, the clinical conundrum is that several of the main drugs and substances used to treat myocardial infarction and Kounis syndrome, such as adrenaline (epinephrine), aspirin, atropine, clopidogrel, corticosteroids, heparins, protamine sulfate, and hirudotherapy can also initiate it. Therefore, physicians should be aware of this clinical discrepancy to prevent catastrophic consequences.

The degranulation of mast cells and other interacting and linked cells, including T-lymphocytes, macrophages, eosinophils, and platelets, as well as a range of inflammatory mediators produced during an anaphylactic or allergic reaction, are the main causes of Kounis syndrome. Acute ischemia episodes, coronary spasm, atheromatous plaque erosion/rupture, and platelet activation can all be caused by histamine, tryptase, arachidonic acid derivatives, and chymase in the Kounis syndrome cascade. Kounis syndrome is not a single-organ vascular disease, but rather a multisystem and multidisciplinary condition. Kounis syndrome can be brought on by a variety of factors, including medications, hymenopteran stings, metals, foods, environmental exposures, illnesses, and immunizations. In addition, some unusual, rare, intriguing, and significant causes of Kounis syndrome have been discovered recently. These include: The kiss of death where human kissing and pet kissing can induce fatal Kounis syndrome. Moreover, the clinical conundrum is that several of the main drugs and substances used to treat myocardial infarction and Kounis syndrome, including adrenaline (epinephrine), aspirin, atropine, clopidogrel, corticosteroids, heparins, protamine sulfate and hirudotherapy can also induce it. Therefore, physicians should be aware of this clinical discrepancy to prevent catastrophic undesirable circumstances.

This narrative review explains the history of anaphylactic or hypersensitivity reactions, their connection to the cardiovascular system, and Kounis syndrome, which is linked to hypersensitivity. Additional subjects discussed include immunoglobulin E and serum tryptase, common pathways of allergic and nonallergic cardiovascular events, current perspectives on Kounis syndrome, allergic myocardial infarction, allergic angina, and the impact of COVID-19 and its vaccination on Kounis syndrome. Kounis syndrome is a distinct kind of acute vascular disease that affects the coronary, cerebral, mesenteric, peripheral, and venous systems. Kounis syndrome is currently used to describe coronary symptoms linked to disorders involving mast cell activation and inflammatory cell interactions, such as those involving T-lymphocytes and macrophages, which further induce allergic, hypersensitive, anaphylactic, or anaphylactic insults. Platelet activating factor, histamine, neutral proteases like tryptase and chymase, arachidonic acid products, and a range of cytokines and chemokines released during the activation process are among the inflammatory mediators that cause it. Proinflammatory cytokines are primarily produced by mast cells in COVID-19 infections. Mast cell-derived proteases and eosinophil-associated mediators are also more prevalent in the lung tissues and sera of COVID-19 patients. As a modern global threat to civilization, COVID-19 is linked to chemical patterns that can activate mast cells; therefore, allergic stimuli are usually the reason. Virus-associated molecular patterns can activate mast cells, but allergic triggers are typically the cause. By activating SARS-CoV-2 and other toll-like receptors, a variety of proinflammatory mediators, including IL-6 and IL-1β, are released, potentially contributing to the pathology of COVID-19.