Mitophagy modulation for the treatment of cardiovascular diseases.

BACKGROUND: Defects of mitophagy, the selective form of autophagy for mitochondria, are commonly observed in several cardiovascular diseases and represent the main cause of mitochondrial dysfunction. For this reason, mitophagy has emerged as a novel and potential therapeutic target. METHODS: In this review, we discuss current evidence about the biological significance of mitophagy in relevant preclinical models of cardiac and vascular diseases, such as heart failure, ischemia/reperfusion injury, metabolic cardiomyopathy and atherosclerosis. RESULTS: Multiple studies have shown that cardiac and vascular mitophagy is an adaptive mechanism in response to stress, contributing to cardiovascular homeostasis. Mitophagy defects lead to cell death, ultimately impairing cardiac and vascular function, whereas restoration of mitophagy by specific compounds delays disease progression. CONCLUSIONS: Despite previous efforts, the molecular mechanisms underlying mitophagy activation in response to stress are not fully characterized. A comprehensive understanding of different forms of mitophagy active in the cardiovascular system is extremely important for the development of new drugs targeting this process. Human studies evaluating mitophagy abnormalities in patients at high cardiovascular risk also represent a future challenge.

Hereditary Transthyretin Amyloidosis: How to Differentiate Carriers and Patients Using Speckle-Tracking Echocardiography.

BACKGROUND: Hereditary transthyretin amyloidosis is a rare disease caused by transthyretin (TTR) gene mutations. The aim of our study was to identify early signs of cardiac involvement in patients with a TTR gene mutation in order to differentiate carriers from patients with neurological or cardiac disease. METHODS: A case-control study was carried out on 31 subjects with the TTR mutation. Patients were divided into three groups: 23% with cardiac amyloidosis and polyneuropathy (group A), 42% with only polyneuropathy (group B) and 35% carriers (group C). Speckle-tracking echocardiography (left-ventricular global longitudinal strain-GLS, atrial stiffness) was performed in all patients. The apical/basal longitudinal strain ratio (SAB) and relative apical sparing (RAS) were assessed in all subjects. RESULTS: Analyzing groups C and B, we only found a significant difference in the SAB (p-value 0.001) and RAS (p-value 0.039). These parameters were significantly more impaired in group A compared to group B (SAB p-value 0.008; RAS p-value 0.002). Also, atrial stiffness was significantly impaired in groups A and B compared to group C. CONCLUSIONS: Our study suggests the diagnostic role of the SAB and RAS in cardiac amyloidosis. The SAB and RAS showed a gradual increase from carriers to patients with neurological and cardiac diseases. Thus, these parameters, in addition to atrial stiffness, could be used to monitor carriers. More extensive data are needed.

Chemotherapy-related cardiac dysfunction: the usefulness of myocardial work indices.

AIMS: The role of left ventricular global longitudinal strain (GLS) in the diagnosis of subclinical cardiac damage induced by anticancer drugs is now consolidated. Considering some strain disadvantages such as the dependence on the haemodynamic loading conditions, the aim of our study was to investigate the usefulness of non-invasive myocardial work indices (MWI) derived from pressure-strain analysis, in the early diagnosis of cardiotoxicity. METHODS AND RESULTS: We enrolled 61 consecutive patients with breast cancer undergoing adjuvant treatment with anthracycline-containing chemotherapy followed by taxane + trastuzumab. Patients underwent a cardiological evaluation with 2D echocardiography including measurement of the left ventricular ejection fraction (LVEF) and other conventional parameters of systolic and diastolic function, GLS and MWI at baseline (T0), 3 months (T1) and 6 months (T2) after starting chemotherapy. At T1 and T2, we did not find a significant reduction in LVEF but we found a significant reduction in GLS and MWI (p value < 0.05). In addition, at T2, 31% of patients developed subclinical cardiac dysfunction defined as a relative decrease ≥ 12% of GLS from baseline. Global work index (GWI), global constructive work (GCW) and global work efficiency (GWE) decreased significantly in both patients with subclinical dysfunction and in those without subclinical dysfunction (p value < 0.05). Patients with subclinical dysfunction at T2 showed lower values of GCW at T0. CONCLUSION: MWI changed significantly during chemotherapy and appeared to alter precociously compared to GLS. Therefore, a multiparametric approach including left ventricular GLS and MWI measurements should be used in the evaluation of patients undergoing cardiotoxic antineoplastic treatment.

Coronary Artery Disease in South Asian Patients: Cardiovascular Risk Factors, Pathogenesis and Treatments.

In the last decades a significant increase of the migratory phenomenon from South Asian countries to the Western World has occurred for social, economic and geopolitical reasons. The aim of this review is to describe cardiovascular risk factors, pathogenesis and treatments of coronary artery disease in South Asian patients. It is well established that South Asian populations have a higher prevalence of coronary artery disease and premature onset of myocardial infarction episodes than other populations. This higher predisposition might be caused by genetic factors, common in both South Asian patients residing in their birth country and in those residing abroad, but it may also be due to the new spatial environment in which they live. It will be important to examine the leading cardiovascular risk factors determining increasing incidence of coronary artery disease in the South Asian population. These include: insulin resistance, hypertension, dyslipidaemia and abdominal obesity caused by a diet rich in refined carbohydrates and saturated fats. Furthermore, it is important to examine emerging cardiovascular risk factors strictly related to this particular ethnic group. The evidence of higher levels of prothrombotic and proinflammatory factors, for example lipoprotein(a) and proinflammatory adipokines, as well as the influence of air pollution and psychosocial stress, may have consequences on the risk, treatment and outcomes of the coronary artery disease in this population. Migrants from South Asia deserve to be addressed and framed with particular care in terms of cardiovascular risk and especially in the management of acute coronary events.

Contractile Reserve in Heart Failure with Preserved Ejection Fraction.

Background: Diastolic stress echocardiography (SE) is useful for confirming the diagnosis of heart failure with preserved left ventricular ejection fraction (HFpEF) when it is uncertain. The aim of this study was to assess the value of new echocardiographic parameters during diastolic SE in patients with dyspnea and suspected HFpEF. Methods: Sixty-two patients with exertional dyspnea and inconclusive rest echocardiography for a diagnosis of HFpEF were enrolled. Exercise SE was performed in all patients. Contractile reserve (LVCR) was assessed by measuring: 1. changes in the left ventricular ejection fraction (LVEF) between rest and peak stress; 2. stress-to-rest ratio of force (force was defined as the ratio between systolic arterial pressure and left ventricular end-systolic volume); and 3. mechanical reserve, defined as the change in systolic strain (GLS) between rest and peak stress. Results: Diagnosis of HFpEF was performed by SE in 26 patients. Comparing patients with a diagnosis of HFpEF (group A) to patients with other causes of dyspnea (group B), we found a significant increase in the E/e' ratio in group A at peak stress. LV GLS was significantly reduced in group A compared to group B at rest and stress (p value 0.01 at rest; p value 0.04 at stress). At peak stress, GLS did not significantly increase in group A, while it increased in group B (p value 0.04). LVEF increased significantly in both groups. Conclusion: Patients with HFpEF have impaired LVCR when assessed using GLS. Thus, the assessment of mechanical reserve could give additional diagnostic information during stress tests in patients with HFpEF.

Right Ventricle Function in Patients With Anterior Myocardial Infarction: Are We Sure it Is Not Involved?

The right and left ventricle of heart are intimately connected by anatomical and functional links. Hence, acute changes in cardiac geometry and function can modify the performance and physiology of both sides of the heart, influencing each other. After a brief overview of the anatomy and related imaging techniques for the study of right ventricular function, we report a review-on the interesting correlation of acute anterior myocardial infarction and right ventricular function, very often underestimated.

Biomarkers of Coronary Microvascular Dysfunction in Patients With Microvascular Angina: A Narrative Review.

The current gold standard for diagnosis of coronary microvascular dysfunction (CMD) in the absence of myocardial diseases, whose clinical manifestation is microvascular angina (MVA), is reactivity testing using adenosine or acetylcholine during coronary angiography. This invasive test can be difficult to perform, expensive, and harmful. The identification of easily obtainable blood biomarkers which reflect the pathophysiology of CMD, characterized by high reliability, precision, accuracy, and accessibility may reduce risks and costs related to invasive procedures and even facilitate the screening and diagnosis of CMD. In this review, we summarized the results of several studies that have investigated the possible relationships between blood biomarkers involved with CMD and MVA. More specifically, we have divided the analyzed biomarkers into 3 different groups, according to the main mechanisms underlying CMD: biomarkers of "endothelial dysfunction," "vascular inflammation," and "oxidative stress." Finally, in the last section of the review, we consider mixed mechanisms and biomarkers which are not included in the 3 major categories mentioned above, but could be involved in the pathogenesis of CMD.

Arterial Stiffness: Effects of Anticancer Drugs Used for Breast Cancer Women.

Purpose: It is well known that anticancer drugs used for treating breast cancer can cause cardiac toxicity, and less is known about vascular toxicity. The aim of this study was to assess subclinical vascular effects of anthracyclines and trastuzumab (TRZ) in women treated for breast cancer. Methods: We enrolled 133 female patients with breast cancer undergoing adjuvant treatment with anthracycline-containing chemotherapy (CT) followed by taxane (paclitaxel/docetaxel) + TRZ. Patients underwent a standard echocardiography including measurement of left ventricular ejection fraction and global longitudinal strain at baseline and at follow-up. Vascular toxicity was evaluated by measuring brachial blood pressure (BP) and arterial stiffness indices (pulse wave velocity and Beta stiffness index) at T0 (baseline), T1 (3 months), T2 (6 months), and T3 (12 months). Results: Arterial stiffness indices were significantly increased at T1 in patients treated with anthracycline-containing CT (PWV 5.5 m/s IQR 5.15-6.4 at T0 vs. PWV 6.7 m/s IQR 5.6-7.2 at T1, p < 0.05; Beta index PWV 6.7 IQR 5.25-6.65 at T0, PWV 8.35 IQR 6.5-10.15 at T1, p < 0.05) but not at T2 and T3, when treatment with anthracyclines was stopped and patients were under treatment with taxane and TRZ. Blood pressure values did not significantly change during follow-up. Conclusion: Changes in arterial stiffness parameters occur early after starting treatment with anthracyclines, and they seem to be reversible if anthracycline treatment is stopped. These changes are not influenced by blood pressure values modifications. Therefore, in breast cancer women, anthracyclines seem to cause early reversible subclinical vascular injury.

Subclinical Cardiotoxicity: The Emerging Role of Myocardial Work and Other Imaging Techniques.

In recent years, the cancer survival of patients has improved thanks to advances in the pharmacological field. In many guidelines, cardiotoxicity induced by anticancer drugs was defined as a reduction from baseline in the left ventricular ejection fraction (LVEF) assessed by echocardiography. It is known that LVEF is not a sensible parameter in the detection of cardiotoxicity. Therefore, a decrease from baseline in the global longitudinal strain (GLS) or troponins elevation is used to detect subclinical cardiotoxicity. LVEF and GLS as well as the increase in some biomarkers are influenced by loading conditions that are frequent during chemotherapy. Other parameters not influenced by loading conditions should be used in the early diagnosis of cardiotoxicity. The aim of this review is to delineate the role of current strategies used in the early diagnosis of cardiotoxicity and to identify new strategies that could have greater application in the future in cardioncology.

[Cardiovascular health in Asian immigrants to Italy: risk factors, pathogenesis and pharmacological treatment]. / Malattie cardiovascolari nei pazienti provenienti dal Sud dell'Asia e 'residenti in Italia: fattori di rischio, patogenesi e trattamento farmacologico.

In the last decades a significant increase of the migratory phenomenon from South Asian countries to the western world has occurred due to several factors, such as economic crisis, political instabilities, persecutions and wars. It is well established that South Asians (SA) have a higher prevalence of coronary artery disease (CAD) and premature onset of myocardial infarction episodes than other populations. This higher predisposition might be caused by genetic factors, common in both SA residing in their birth country and in those residing abroad, but it may also be due to the new spatial environment in which they live. We have found a higher prevalence of traditional cardiovascular risk factors in SA compared with other populations; in particular abdominal obesity, caused by an unhealthy diet rich in refined carbohydrates and saturated fats, plays a key role in the development of insulin-resistance, diabetes, dyslipidemia and hypertension, leading to the increase risk of CAD in SA. Even emerging risk factors were found to be higher in this ethnic group; indeed, the evidence of higher levels of pro-thrombotic and pro-inflammatory factors, such as lipoprotein(a) and pro-inflammatory adipokines, as well as the influence of air pollution and psychosocial stress, may have consequences on the risk, treatment and outcomes of CAD in this population.

Role of the HIPPO pathway as potential key player in the cross talk between oncology and cardiology.

The HIPPO pathway (HP) is a highly conserved kinase cascade that affects organ size by regulating proliferation, cell survival and differentiation. Discovered in Drosophila melanogaster to early 2000, it immediately opened wide frontiers in the field of research. Over the last years the field of knowledge on HP is quickly expanding and it is thought will offer many answers on complex pathologies. Here, we summarized the results of several studies that have investigated HP signaling both in oncology than in cardiology field, with an overview on future perspectives in cardiology research.

Direct Oral Anticoagulants in the Setting of Catheter Ablation of Atrial Fibrillation: State of art.

Atrial fibrillation (AF) represents the arrhythmia of greatest clinical impact and catheter ablation of AF (CAAF) has become the most effective strategy for rhythm control in selected patients. Therefore, appropriate anticoagulation strategies are of paramount importance for patients undergoing CAAF, especially those at high risk, such those with high CHA2DS2VASc scores. Optimal management of anticoagulation before, during, and after CAAF is crucial. Several studies have evaluated the use of different anticoagulation strategies in the periprocedural period. Randomized controlled trial seem to suggest that in patients undergoing CAAF, uninterrupted (or minimally interrupted) direct oral anticoagulants (DOACs) provides an alternative to continuous vitamin K antagonists strategy, with low thromboembolic and bleeding risk.

Physiopathology and Diagnosis of Congestive Heart Failure: Consolidated Certainties and New Perspectives.

Volume overload and fluid congestion are a fundamental issue in the assessment and management of patients with heart failure (HF). Recent studies have found that in acute decompensated heart failure (ADHF), right and left-sided pressures generally start to increase before any notable weight changes take place preceding an admission. ADHF may be a problem of volume redistribution among different vascular compartments instead of, or in addition to, fluid shift from the interstitial compartment. Thus, identifying heterogeneity of volume overload would allow guidance of tailored therapy. A comprehensive evaluation of congestive HF needs to take into account myriad parameters, including physical examination, echocardiographic values, and biomarker serum changes. Furthermore, potentially useful diagnostic tools include bioimpedance to measure intercompartmental fluid shifts, and evaluation of ultrasound lung comets to detect extravascular lung water.

Usefulness of Stress Echocardiography in the Management of Patients Treated with Anticancer Drugs.

In recent years, the survival of patients with cancer has improved thanks to advances in antineoplastic therapeutic protocols. This has led to an increasing burden of cardiovascular complications related to cancer treatment. Therefore, a new branch of cardiology has been created, "cardio-oncology," with the aims of preventing cardiovascular complications related to antineoplastic treatment, achieving early diagnosis and treatment of any complications, and allowing completion of the expected antineoplastic treatment. Stress echocardiography has a pivotal role in achieving a timely diagnosis of coronary artery disease and thus is the best management approach in this clinical setting. Atherosclerotic processes can be exacerbated by both chemotherapy and chest irradiation in patients with cancer, even several years after anticancer treatment completion. Moreover, stress echocardiography has many other potential applications, such as in the evaluation of subclinical left ventricular dysfunction and contractile reserve in patients treated with anticancer drugs that have the potential to induce myocardial damage, as well as evaluating valve disease. The objective of this review is to delineate the role of stress echocardiography in cardio-oncology.

[Ischemia with no obstructive coronary artery disease: microvascular angina and vasospastic angina]. / L'ischemia in assenza di malattia coronarica ostruttiva (INOCA): l'angina microvascolare e l'angina vasospastica.

About 40% of patients undergoing coronary angiography for chest pain with anginal features have angiographically normal or near-normal coronary arteries. It was necessary to standardize all myocardial ischemia scenarios in stable patients in the absence of coronary artery disease, therefore the term INOCA (ischemia with non-obstructive coronary artery disease) was coined. The aim of this article is to summarize and to clarify the vast and controversial chapter of INOCA, in order to better understand the pathophysiological, nosographic, diagnostic and therapeutic aspects.

Fatal Heart Failure Induced by Pazopanib in a Sarcoma Patient Previously Treated with Gemcitabine.

Gemcitabine is commonly used for various solid organ malignancies with rarely reported cardiac side effects such as cardiomyopathy. Pazopanib usually can cause arterial hypertension but cases of heart failure have recently been reported. We describe a case of fatal heart failure after treatment with gemcitabine and pazopanib in a 55-year-old female with sarcoma. Patient developed left ventricular dysfunction after gemcitabine treatment and acute heart failure after 22 days of pazopanib treatment which led to death. Physicians should be aware of the cardiotoxicity risk when managing the use of pazopanib especially in patients previously treated with other cardiotoxic drugs.

Management of Direct Oral Anticoagulants in Patients with Atrial Fibrillation Undergoing Cardioversion.

Atrial fibrillation the most common cardiac arrhythmia. Its incidence rises steadily with each decade, becoming a real "epidemic phenomenon". Cardioversion is defined as a rhythm control strategy which, if successful, restores normal sinus rhythm. This, whether obtained with synchronized shock or with drugs, involves a periprocedural risk of stroke and systemic embolism which is reduced by adequate anticoagulant therapy in the weeks before or by the exclusion of left atrial thrombi. Direct oral anticoagulants are safe, manageable, and provide rapid onset of oral anticoagulation; they are an important alternative to heparin/warfarin from all points of view, with a considerable reduction in bleedings and increase in the safety and quality of life of patients.