Cardiovascular diseases remain the leading cause of death worldwide and in our country as well, with healthcare costs estimated at about €19-24 billion, of which €11-16 billion are direct costs and €5-8 billion indirect costs, according to the Italian Society for Cardiovascular Prevention (Siprec). According to a World Heart Federation (WHF) report, deaths have increased by 60% globally: from 12.1 million in 1990 to 20.5 million in 2021. Based on ISTAT data for the same year (the latest available) in Italy they caused 217,523 fatalities (but the estimate today is over 240,000), followed by cancers with 174,511: together they account for more than 55% of total deaths.
In reality, the global mortality rate has fallen from 354.5 deaths per 100,000 people in 1990 to 239.9 deaths per 100,000 people (data available, 2019), thanks to better pharmacological treatments and improved control of risk factors. The apparent contradiction is explained by the combination of two factors: aging and population growth. A warning sign is then the increase of certain conditions, such as myocarditis and pericarditis, from Covid onward, especially among young men. What more can be done at the level of prevention policies, lifestyle, screening and of course new therapies? The preventive factor is fundamental.
The Prevention Factor
The report highlighted that hypertension, air pollution, tobacco use, and hypercholesterolemia are the principal factors. According to Professor Fausto Pinto, co-author of the report and former president of the WHF, it is possible to prevent up to 80% of premature heart attacks and strokes. “It is estimated that about 47,000 deaths are attributable to the lack of cholesterol control,” said Furio Colivicchi, past president of ANMCO, the National Association of Hospital Cardiologists, and director of Clinical Cardiology and Rehabilitation at San Filippo Neri Hospital in Rome. The emphasis is on changing lifestyles, aiming to counteract the pathogenic atherosclerotic factors, such as dyslipidemia with a pro-inflammatory diet, smoking, high blood pressure, diabetes mellitus, physical inactivity, and obesity. Today, however, attention is directed toward the chronic low-grade inflammatory and oxidative state known as inflammaging, which contributes to the progression of atherosclerotic plaque, stress, and even electromagnetic pollution.
The Siprec reiterates that the first players in prevention must be primary care physicians, who have the task of identifying at-risk patients, for example those who may develop diabetes and, if diabetic, develop chronic complications. In Italy, however, only about 50% of patients with cardiovascular disease adhere properly to treatments. According to the public-awareness campaign by the Pubblicità Progresso Foundation Take your health to heart: Adhering to therapies saves lives, realized with the endorsement of regional ambulatory cardiologists associations (ARCA), the Italian Federation of General Practitioners (Fimmg), the Italian Society of General Practitioners and Primary Care (SIMG), the Federation of Italian Pharmacist Orders (Fofi) and other associations, helping patients in Europe to take prescribed therapies correctly could save around 200,000 lives and reduce healthcare costs by about €125 billion per year. Every year, the campaign notes, the world comes shockingly close to 19 million deaths.
Insulin Resistance
The link between cardiovascular disease and insulin resistance, whose global prevalence is estimated at up to about half of the general population, has long been the focus of studies by Serafino Fazio, former Professor of Internal Medicine at the University of Naples Federico II, internist and cardiologist, who has published several papers on the topic. The goal is to stimulate the scientific community and policymakers to promote a screening campaign to implement preventive control mechanisms (in Italy, about 4 million people are estimated to have diabetes, of which 3.5 million are type 2).
“Insulin resistance is a cause of hypercholesterolemia,” he explains. “A person who is insulin resistant has elevated total cholesterol, higher LDL, lower HDL, and elevated triglycerides. It is also the main cause of essential hypertension, the most common form.”
L’insulin in excess leads to increased renal sodium retention and creates an excess volume in the blood vessels. There is also a disturbance of vascular homeostasis because nitric oxide formation is reduced in favor of endothelin-1, a vasoconstrictive peptide, and there is stimulation of the sympathetic nervous system with increased norepinephrine. All prerequisites for the development of hypertension. When associated with insulin resistance, it is also a growth factor: it drives endothelial dysfunction that underlies atherosclerosis, which in turn is linked to higher thrombosis risk; it causes hypertension, kidney damage, but also increases cancer risk and the risk of neurodegenerative diseases and aging. The latest studies correlate insulin resistance and high insulin levels with higher all-cause mortality.”
Lifestyle
Movement is one of the keys, together with diet, to counteract it. “Insulin resistance is determined by several factors not yet fully understood, but the main one is an inadequate lifestyle, where inactivity plays the largest role. Insulin receptors are very numerous in the muscles we use to walk: if they are not sufficiently stimulated, they diminish or become less active. In insulin resistance, receptors at the hepatic level are also altered, where excess insulin can promote the development of nonalcoholic fatty liver disease. A daily walk of 10,000 steps (adjusted for age) at a brisk pace for about an hour, 4-5 days a week, is enough to stimulate them and prevent or reduce insulin resistance. There is a debate, namely whether obesity comes first or insulin resistance: I actually believe insulin resistance comes first, as demonstrated by the use of GLP-1 receptor agonists. In fact, with their use, improvement in insulin resistance occurs well before weight loss.”
Governing Nutrition
The second key aspect is diet: the rising prevalence of overweight and obesity signals a dangerous drift away from a balanced diet. “Obesity and cardiovascular risks have risen dramatically, including among children. Campania is among the regions with the highest rate of childhood obesity in Europe, and this is due to a shift in lifestyle. There is an excess of hypercaloric and ultra-processed foods, often sweetened; vegetables consumption has declined, and vegetables are low in calories but rich in compounds that can prevent damage from insulin resistance. Prepackaged foods loaded with additives are purchased, which can be harmful to health.”
The diet must be balanced and varied in its composition among fats, proteins, and carbohydrates: if one direction is overdone, imbalances arise. It must be highly varied. We need to restore food culture starting in schools. Carbohydrates should be reduced especially when driving insulin resistance. Alcohol, in excess, also contributes to insulin resistance at the hepatic level and promotes fatty liver. But a glass of red wine a day, for a healthy person, can confer benefits from tannins, polyphenols, and flavonoids. The right balance lies in moderation.”
The Importance of Screening
Professor Fazio advocates extending screening for insulin resistance among general practitioners. “The search for insulin resistance and the measurement of fasting insulin are performed by very few doctors. The most reliable index for this diagnosis is the HOMA-IR (Homeostasis Model Assessment of Insulin Resistance), which is based on simultaneous fasting insulin and glucose measurements. A normal value in adults is between 0.23 and 2.5; if it is higher, insulin resistance is present.” Also integrative medicine can contribute. “Years ago I studied berberine, a natural substance that Indian and Chinese medicine have used for over two centuries to control diabetes. It acts to sensitize the body to insulin, similar to metformin, the drug used for type 2 diabetes. If lifestyle changes and natural products cannot resolve the issue, the solution may be metformin or newer-generation drugs, such as GLP-1 receptor agonists like semaglutide or SGLT-2 inhibitors for more severe forms.”
For Professor Fazio, too much emphasis over the years has been placed on cholesterol as the main trigger of cardiovascular disease, exaggerating its role. “It is not inherently a killer, as it has been portrayed. It is the only fat in our body that is not simply metabolized away; the body stores it in every part where it’s needed. It is an antioxidant substance that protects membranes, about 30% of our brain is cholesterol, and it forms the basic chemical structure of major steroid hormones and vitamin D; it is extremely important for the immune system, regulation of cell proliferation, modulation of inflammation, and metabolism. It is a nutrient for the immune system, which mainly works at night; and that is why cholesterol production peaks at night. The induction of a hepatic enzyme, HMG-CoA reductase, by certain hormones—especially insulin—drives cholesterol production, so cholesterol can be a protective component of immunity. Today we must acknowledge the serious issue of electromagnetic pollution, which the mainstream view often denies as biologically relevant.”
Inflammation as a Trigger
According to Massimo Fioranelli, a physician, specialist in Cardiology and Internal Medicine, the key to the cardiovascular disease problem is chronic low-grade inflammation, which often presents with few symptoms.
“This overactivation of the immune system, which resides about 80% in our gastrointestinal system, triggers the production of inflammatory cytokines. When we see a patient, we can easily recognize inflammatory compromise. If the intestine is altered—whether constipated or diarrheal—it is typically an inflammatory effect. Another marker of systemic inflammation is marked asthenia, swelling or abdominal pain, insomnia, which is typically driven by the overexpression of interleukin-6. When a person sleeps little and poorly, with nocturnal awakenings, especially between 3 and 4 a.m., there is usually an inflammatory pathology at work.”
Loss of muscle mass is also an index of inflammation; a sarcopenic patient with reduced muscle mass points to systemic inflammation. We have simple blood tests we can perform, such as evaluating an elevated high-sensitivity C-reactive protein or rising cholesterol, which indicates how the body is compensating for inflammation, alterations in protein fractions, refractory anemias, and so on. But more than simply lowering cholesterol, one should ask why a body, evolved over 3 million years, is mounting this kind of response. It is up to the physician to understand the pathophysiological mechanism behind these manifestations.”
Genetic Traits and Stress
Indeed, the issue is complex. And if one wishes, it can extend to the genetic level. Professor Giuseppe Remuzzi, director of the Mario Negri Institute for Pharmacological Research, notes, for example, that the flip side of inheriting Neanderthal-era traits is, for instance, “the predisposition to diabetes through genes that influence fat metabolism, which Neanderthals needed to defend against cold temperatures or as a source of energy”; and that “without Neanderthal genes, heart attack or stroke would not exist because back then vigorous coagulation helped seal wounds quickly and prevent fatal bleeding” (Giuseppe Remuzzi, Le impronte del signor Neanderthal, Solferino). Still, there are modern life aspects that are undeniably related and on which we can act.
“Inflammation is a natural mechanism of adaptation and defense for living organisms. If cardiovascular diseases become a social problem, it means that the quality of life at baseline has markedly deteriorated, with ever more frenetic lives: we spend our time stressing to meet needs created by others. Psychological stress is among the main triggers that unleash inflammation: it is the body’s response to danger, but when it becomes chronic, beyond 72 hours, the body pays a biological price. Another reason is that we eat very poorly. A few multinational corporations dominate the agro-food sector and have interests that extend into the pharmaceutical industry. And the therapies we sometimes pursue for various conditions can actually worsen the situation. If I have gastritis due to intestinal inflammation and chronically use a proton-pump inhibitor, without other supportive therapies, I simply worsen the condition: I disrupt the gut microbiota, reduce immune system function, and chronify the disease.”
Acting on the Microbiota
The microbiota remains one of the potential keys to a comprehensive approach. “I’m optimistic about a growing openness at recent traditional cardiology congresses: we have been talking about the microbiota for more than 20 years. We had evidence that when gut permeability is altered, filling pressures in the heart change. And we knew that when the gut is dysfunctional, all cardiovascular diseases worsen, even from a mechanical, hemodynamic standpoint. No treatment today can be separated from the view of the gut microbiota as a regulatory cornerstone of our immune system: when we use a proton-pump inhibitor or an antibiotic, these chemicals can damage the microbiota.”
One of the major problems tied to cardiovascular disease is obesity, and among the most interesting strains is Akkermansia muciniphila, but there is still a lot of research to do to modulate the gut flora and provide more appropriate answers. It isn’t simple and is not limited to supplementation with probiotics, prebiotics, or postbiotics. Integrated cardiology, according to Fioranelli, can, in the vast majority of cases, bring substantial improvements in patients’ quality of life. “There aren’t only chemical substances, but also more natural, complementary therapies. As a general anti-inflammatory, which may target joints, we could very well use turmeric, while also addressing nutritional and non-pharmacologic approaches.”
Stress Diagnostics
Antonio Sacco is a general practitioner with the Verona Local Health Authority (ASL Verona). A specialist in Medical Hydrology, he has earned multiple university masters, including oxygen-ozone therapy, homeotoxicology, neuropsychophysiological optimization, and CRM therapy for stress-related conditions. For 25 years he has integrated Knowledge of Functional Medicine into cardiovascular care.
“Today we focus heavily on lifestyle risk factors that predispose to inflammation, such as stress management, physical activity, sedentary behavior, sleep quality, inefficient breathing, quality of food, and altered circadian rhythms. And there is the possibility to monitor and correct them in a personalized way using innovative, non-invasive technologies.
Among these are peripheral photoplethysmography (PPG), body bioimpedance analysis with intracellular analysis, and extracellular electrolyte tomography for recognizing and localizing chronic low-grade inflammatory processes, enabling primary and secondary prevention predictions for both cardiovascular patients and healthy individuals or athletes. The innovation lies in stress diagnostics and heart-rate variability using tools that leverage traditional technologies like very low-frequency bioelectric fields, supported by research and scientific publications. We assess innovative parameters such as intramuscular adipose tissue (IMAT), a predictive risk factor for insulin resistance, hepatic steatosis, and fat infiltration in skeletal and cardiac muscle, followed by evaluation of the extracellular matrix. We also analyze coherence and heart rate variability, respiratory sinus arrhythmia, indicators of good health and cardiovascular risk prediction. All this allows real-time insight into a patient’s vascular condition in response to stressors. The platform can integrate hundreds of data points and enable, for example, the estimation of biological age, disease risk, and health reserve. We monitor individuals with telemedicine equipment and at-distance AI, based on respiratory biofeedback.”
Constant Monitoring
Today inflammaging is a common term, with stress as a growing trigger. “If I discuss metabolic cardiology, I cannot focus only on the cardiovascular aspect. The heart is tightly linked with the brain and the gut. It is a single system where stress dominates. The vagus nerve is the main anti-inflammatory nerve, but under stress it loses this capability and its afferent fibers cannot inform the brain about what is happening in the periphery. The same happens in endothelial inflammation, which we cannot detect through symptoms but only through predictive instrumental and laboratory tests. Low-grade, silent inflammation involves the extracellular matrix, which can be tested and treated with new technologies. For dietary habits I use an app powered by AI where the patient records for seven days what they eat, how much, and when. I use this to assess glycemic load, whether it is high in the morning or elevated in the evening when it should be near zero, indicating a cortisol and insulin curve that is inverted. I also look at PRAL, the potential renal acid load of foods, and the Food Insulin Index.”
Beware of Cholesterol
As a major driver of most cardiovascular diseases, this is also emphasized by Massimo Fioranelli, co-editor, together with Luca Speciani, of Integrated Cardiology: A New Approach to Therapeutic Strategies in Cardiovascular Disease, Tecnic Nuove. A volume that offers a critical appraisal of the mechanistic approach of today’s cardiology, opening up to systemic perspectives for new treatment horizons. “Cholesterol itself is not a killer the way it has been portrayed—it’s not simply a risky villain. It is the only fat in our body that the body does not metabolize away; it stores it in parts where it is needed. It is an antioxidant that protects membranes; about 30% of our brain is made of cholesterol; it forms the basic chemical structure of the main steroid hormones and vitamin D, and it is extremely important for the immune system, regulation of cell proliferation, modulation of inflammation, and metabolism.”
“It nourishes the immune system, which primarily works at night; and that is why cholesterol production is highest at night. The induction of a hepatic enzyme, HMG-CoA reductase, by certain hormones—especially insulin—drives cholesterol production, so cholesterol can be a protective component of immune function. Today we must be mindful of the serious issue of electromagnetic pollution, which the mainstream view would have us believe has no biological impact.”
“We have instead seen in extensive literature that it can alter the parameters of the immune system, including the blockade of calcineurin, a phosphatase involved in a wide range of biological responses, including lymphocyte activation, neural activity, muscle development, dendrite growth, and the morphogenesis of heart valves. Calcineurin blockade inhibits lymphocyte function, essential cells in the immune response.”
Functional Mycotherapy
As a cardiovascular support therapy, Dr. Sacco uses supplements to correct imbalances identified in tests that allow for precision therapy, but also Functional Mycotherapy, one of the first to be pioneered 26 years ago. “It differs from classic mycotherapy that focuses only on the organ tropism of each medicinal mushroom: before prescribing them, predictive tests are used to identify the patient’s neurovegetative state at that moment. I use mushrooms such as Reishi, Cordyceps, Agaricus, Shiitake, Maitake, Pleurotus, Chaga, paired with specific phytotherapeutics. They support the heart, lipid and glucose control. They regulate blood sugar, LDL cholesterol, inflammation; detoxify the liver, modulate the stress response. They address many causal factors of heart disease long before signs and symptoms appear that lead to atherosclerosis, type 2 diabetes, and metabolic syndrome. They can be combined with conventional drugs, paying attention to potential interactions. This makes possible true preventive and precision medicine that is necessary in cardiovascular care today.”
Obesity Under the Microscope
The intertwining of overweight, obesity, and cardiovascular disease was a central topic at the Change in Cardiology 2025 conference. Over the three days at the Lingotto Conference Center in Turin, attention focused on new obesity drugs, namely semaglutide and tirzepatide. Patients treated with these medications can lose between 10% and 20% of body weight, with a significant reduction in cardiovascular event risk. According to the data shared, obesity increases the risk of atrial fibrillation by nearly 50% compared with normal weight; risk of heart attack and stroke rises by 64%, and heart failure decompensation by 30%. Overweight and obesity affect more than 60% of Europe’s population. According to ISTAT data (2021), 11.5% of adults in our country are obese, with higher prevalence among men (12.3%) than women (10.8%). This translates to about 4 million obese adults in Italy, of which roughly 400,000 live with heart failure.
From the June 2025 issue of Karla Miller
References
Insulin Resistance with Associated Hyperinsulinemia as a Cause of the Development and Worsening of Heart Failure, Umberto Attanasio, Valentina Mercurio, Serafino Fazio, Biomedicina, 2024
https://pubmed.ncbi.nlm.nih.gov/39767796
Chronically Increased Levels of Circulating Insulin Secondary to Insulin Resistance: A Silent Killer, Serafino Fazio, Paolo Bellavite , Flora Affuso, Biomedicina, 2024
https://pubmed.ncbi.nlm.nih.gov/39457728
Insulin Resistance/Hyperinsulinemia, Neglected Risk Factor for the Development and Worsening of Heart Failure with Preserved Ejection Fraction, Serafino Fazio, Valentina Mercurio, Valeria Fazio, Antonio Ruvolo , Flora Affuso, Biomedicina, 2024
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