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.

Association of inflammatory markers with incident heart failure or cancer in the HUNT3 and Health ABC population studies.

AIMS: To investigate the relationship between chronic low-grade inflammation, as measured by high-sensitivity C-reactive protein (hsCRP) levels, and incident heart failure (HF) or cancer. METHODS: We assessed the relationship between baseline hsCRP concentrations and subsequent HF or cancer in two community-based cohorts, the Trøndelag Health Study (HUNT3) and the Health, Aging and Body Composition (ABC) study. In the latter, the analysis was replicated with interleukin (IL)-1, IL-6, or tumour necrosis factor (TNF)-α instead of hsCRP. RESULTS: In HUNT3, hsCRP was measured in 47,163 subjects (mean age 52.3 ± 15.8 years). During a median follow-up of 12.1 years, 2,034 (4.3%) individuals developed HF and 5,024 (10.7%) cancer, with 442 (0.9%) being diagnosed with both. After adjusting for age, male sex, diabetes, obesity, previous or current smoking, and comorbidities, elevated baseline hsCRP was associated with a higher risk of HF or cancer (HR 1.09; 95%CI, 1.07-1.10). In the Health ABC study, hsCRP levels were assessed in 2,803 participants, who had a mean age of 72.6 ± 2.9 years and a higher burden of comorbidities than in HUNT3. During a median follow-up of 8.2 years, HF and cancer were diagnosed in 346 (12.3%) and 776 (27.7%) subjects, respectively, with 77 (2.7%) having both conditions. After adjusting for the same variables used for the HUNT3 cohort, hsCRP remained significantly associated with incident HF or cancer (HR 1.11; 95%CI, 1.05-1.18), as were IL-1 (HR 1.15; 1.07-1.24), IL-6 (HR 1.09; 1.02-1.17), and TNF-α (HR 1.15; 1.07-1.24). CONCLUSIONS: A state of chronic, low-grade inflammation captured by an increase in hsCRP levels is associated with an increased risk of developing HF or cancer, with potential implications for clinical trials with anti-inflammatory therapies.

There is an increasing recognition that cardiovascular (CV) risk factors portend an increased risk of both heart failure (HF) and cancer. Chronic, low-grade inflammation might represent a shared pathogenic pathway underlying the association between these risk factors, HF, and malignancy. The biomarker high-sensitivity C-reactive protein (hsCRP) might add prognostic information on CV and cancer risk by capturing this inflammatory state. In this study we analysed the association of inflammation, as assessed by baseline measurement of hsCRP, and the risk of developing HF and cancer in two community-based prospective studies, the Trøndelag Health Study (HUNT3) and the Health, Aging and Body Composition (Health ABC) study.In these cohorts, comprising more than 50,000 individuals, inflammation at baseline was associated with an increased risk of incident HF or cancer during a median follow-up of 8-12 years, after adjusting for traditional risk factors and comorbidities.In the Health ABC study sample, three inflammatory markers other than hsCRP, namely interleukin (IL)-1, IL-6, or tumour necrosis factor α, performed similarly to hsCRP in predicting the risk of incident HF or cancer. These results provide insights into the interconnection between HF and cancer and reinforce the concept that low-grade, chronic inflammation promotes the development of both HF and cancer and, thereby, might be targeted for prevention of either condition. Furthermore, our findings confirm the reliability of hsCRP as a biomarker to select individuals who may benefit from anti-inflammatory treatments to reduce CV and cancer events.

Ischaemic heart disease in patients with cancer.

Cardiologists are encountering a growing number of cancer patients with ischaemic heart disease (IHD). Several factors account for the interrelationship between these two conditions, in addition to improving survival rates in the cancer population. Established cardiovascular (CV) risk factors, such as hypercholesterolaemia and obesity, predispose to both IHD and cancer, through specific mechanisms and via low-grade, systemic inflammation. This latter is also fuelled by clonal haematopoiesis of indeterminate potential. Furthermore, experimental work indicates that IHD and cancer can promote one another, and the CV or metabolic toxicity of anticancer therapies can lead to IHD. The connections between IHD and cancer are reinforced by social determinants of health, non-medical factors that modify health outcomes and comprise individual and societal domains, including economic stability, educational and healthcare access and quality, neighbourhood and built environment, and social and community context. Management of IHD in cancer patients is often challenging, due to atypical presentation, increased bleeding and ischaemic risk, and worse outcomes as compared to patients without cancer. The decision to proceed with coronary revascularization and the choice of antithrombotic therapy can be difficult, particularly in patients with chronic coronary syndromes, necessitating multidisciplinary discussion that considers both general guidelines and specific features on a case by case basis. Randomized controlled trial evidence in cancer patients is very limited and there is urgent need for more data to inform clinical practice. Therefore, coexistence of IHD and cancer raises important scientific and practical questions that call for collaborative efforts from the cardio-oncology, cardiology, and oncology communities.

Real-world candidacy to mavacamten in a contemporary hypertrophic obstructive cardiomyopathy population.

AIMS: In the EXPLORER-HCM trial, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved functional capacity of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients. We sought to define the potential use of mavacamten by comparing real-world HOCM patients with those enrolled in EXPLORER-HCM and assessing their eligibility to treatment. METHODS AND RESULTS: We collected information on HOCM patients followed up at 25 Italian HCM outpatient clinics and with significant LVOTO (i.e. gradient ≥30 mmHg at rest or ≥50 mmHg after Valsalva manoeuvre or exercise) despite pharmacological or non-pharmacological therapy. Pharmacological or non-pharmacological therapy resolved LVOTO in 1044 (61.2%) of the 1706 HOCM patients under active follow-up, whereas 662 patients (38.8%) had persistent LVOTO. Compared to the EXPLORER-HCM trial population, these real-world HOCM patients were older (62.1 ± 14.3 vs. 58.5 ± 12.2 years, p = 0.02), had a lower body mass index (26.8 ± 5.3 vs. 29.7 ± 4.9 kg/m2 , p < 0.0001) and a more frequent history of atrial fibrillation (21.5% vs. 9.8%, p = 0.027). At echocardiography, they had lower left ventricular ejection fraction (LVEF, 66 ± 7% vs. 74 ± 6%, p < 0.0001), higher left ventricular outflow tract gradients at rest (60 ± 27 vs. 52 ± 29 mmHg, p = 0.003), and larger left atrial volume index (49 ± 16 vs. 40 ± 12 ml/m2 , p < 0.0001). Overall, 324 (48.9%) would have been eligible for enrolment in the EXPLORER-HCM trial and 339 (51.2%) for treatment with mavacamten according to European guidelines. CONCLUSIONS: Real-world HOCM patients differ from the EXPLORER-HCM population for their older age, lower LVEF and larger atrial volume, potentially reflecting a more advanced stage of the disease. About half of real-world HOCM patients were found eligible to mavacamten.

Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.

Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.

Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection.

The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal.

An arrhythmogenic metabolite in atrial fibrillation.

BACKGROUND: Long-chain acyl-carnitines (ACs) are potential arrhythmogenic metabolites. Their role in atrial fibrillation (AF) remains incompletely understood. Using a systems medicine approach, we assessed the contribution of C18:1AC to AF by analysing its in vitro effects on cardiac electrophysiology and metabolism, and translated our findings into the human setting. METHODS AND RESULTS: Human iPSC-derived engineered heart tissue was exposed to C18:1AC. A biphasic effect on contractile force was observed: short exposure enhanced contractile force, but elicited spontaneous contractions and impaired Ca2+ handling. Continuous exposure provoked an impairment of contractile force. In human atrial mitochondria from AF individuals, C18:1AC inhibited respiration. In a population-based cohort as well as a cohort of patients, high C18:1AC serum concentrations were associated with the incidence and prevalence of AF. CONCLUSION: Our data provide evidence for an arrhythmogenic potential of the metabolite C18:1AC. The metabolite interferes with mitochondrial metabolism, thereby contributing to contractile dysfunction and shows predictive potential as novel circulating biomarker for risk of AF.

Diagnostic yield and predictive value on left ventricular remodelling of genetic testing in dilated cardiomyopathy.

AIMS: We assessed the diagnostic yield of genetic testing and the relationship of left ventricular (LV) reverse remodelling (LVRR) with the presence of DNA pathogenic (P) or likely pathogenic (LP) variants in patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: From 680 outpatients followed at the Heart Failure Outpatient Clinic of our institution, we selected subjects with a diagnosis of DCM as defined by LV ejection fraction (LVEF) ≤40% and LV dilatation not explained by coronary artery disease or other causes. All patients were offered genetic investigation of 42 disease-associated DCM genes with next-generation sequencing. Seventy patients fulfilled the definition of DCM and 66 underwent genetic investigation. We identified 18 P/LP variants in 16 patients, with a diagnostic yield of 24%. The most common variants were truncating TTN variants (n = 7), followed by LMNA (n = 3), cytoskeleton Z-disc (n = 3), ion channel (n = 2), motor sarcomeric (n = 2), and desmosomal (n = 1) genes. After a median follow-up of 53 months (inter-quartile range 20-111), patients without P/LP variants exhibited higher systolic and diastolic blood pressure, lower plasma brain natriuretic peptide levels, and a larger extent of LVRR, as reflected by the increase in LVEF (+14% vs. +1%, P = 0.0008) and decrease in indexed LV end-diastolic diameter (-6.5 vs. -2 mm/m2 , P = 0.03) compared with patients with P/LP variants. CONCLUSIONS: Our results confirm the high diagnostic yield of genetic testing in selected DCM patients and suggest that identification of P/LP variants in DCM portends poorer LVRR in response to guideline-directed medical therapy.

Cardiac Involvement in Mitochondrial Disorders.

PURPOSE OF REVIEW: We review pathophysiology and clinical features of mitochondrial disorders manifesting with cardiomyopathy. RECENT FINDINGS: Mechanistic studies have shed light into the underpinnings of mitochondrial disorders, providing novel insights into mitochondrial physiology and identifying new therapeutic targets. Mitochondrial disorders are a group of rare genetic diseases that are caused by mutations in mitochondrial DNA (mtDNA) or in nuclear genes that are essential to mitochondrial function. The clinical picture is extremely heterogeneous, the onset can occur at any age, and virtually, any organ or tissue can be involved. Since the heart relies primarily on mitochondrial oxidative metabolism to fuel contraction and relaxation, cardiac involvement is common in mitochondrial disorders and often represents a major determinant of their prognosis.

Cancer Incidence and Mortality According to Pre-Existing Heart Failure in a Community-Based Cohort.

Background: Studies assessing whether heart failure (HF) is associated with cancer and cancer-related mortality have yielded conflicting results. Objectives: This study assessed cancer incidence and mortality according to pre-existing HF in a community-based cohort. Methods: Among individuals ≥50 years of age from the Puglia region in Italy with administrative health data from 2002 to 2018, no cancer within 3 years before the baseline evaluation, and ≥5-year follow-up, the study matched 104,020 subjects with HF at baseline with 104,020 control subjects according to age, sex, drug-derived complexity index, Charlson comorbidity index, and follow-up duration. Cancer incidence and mortality were defined based on International Classification of Diseases-Ninth Revision codes in hospitalization records or death certificates. Results: The incidence rate of cancer in HF patients and control subjects was 21.36 (95% CI: 20.98-21.74) and 12.42 (95% CI: 12.14-12.72) per 1000 person-years, respectively, with the HR being 1.76 (95% CI: 1.71-1.81). Cancer mortality was also higher in HF patients than control subjects (HR: 4.11; 95% CI: 3.86-4.38), especially in those <70 years of age (HR: 7.54; 95% CI: 6.33-8.98 vs HR: 3.80; 95% CI: 3.44-4.19 for 70-79 years of age; and HR: 3.10; 95% CI: 2.81-3.43 for ≥80 years of age). The association between HF and cancer mortality was confirmed in a competing risk analysis (subdistribution HR: 3.48; 95% CI: 3.27-3.72). The HF-related excess risk applied to the majority of cancer types. Among HF patients, prescription of high-dose loop diuretic was associated with higher cancer incidence (HR: 1.11; 95% CI: 1.03-1.21) and mortality (HR: 1.35; 95% CI: 1.19-1.53). Conclusions: HF is associated with an increased risk of cancer and cancer-related mortality, which may be heightened in decompensated states.

Mitochondria as Therapeutic Targets in Heart Failure.

PURPOSE OF REVIEW: We review therapeutic approaches aimed at restoring function of the failing heart by targeting mitochondrial reactive oxygen species (ROS), ion handling, and substrate utilization for adenosine triphosphate (ATP) production. RECENT FINDINGS: Mitochondria-targeted therapies have been tested in animal models of and humans with heart failure (HF). Cardiac benefits of sodium/glucose cotransporter 2 inhibitors might be partly explained by their effects on ion handling and metabolism of cardiac myocytes. The large energy requirements of the heart are met by oxidative phosphorylation in mitochondria, which is tightly regulated by the turnover of ATP that fuels cardiac contraction and relaxation. In heart failure (HF), this mechano-energetic coupling is disrupted, leading to bioenergetic mismatch and production of ROS that drive the progression of cardiac dysfunction. Furthermore, HF is accompanied by changes in substrate uptake and oxidation that are considered detrimental for mitochondrial oxidative metabolism and negatively affect cardiac efficiency. Mitochondria lie at the crossroads of metabolic and energetic dysfunction in HF and represent ideal therapeutic targets.

Immuno-metabolic interfaces in cardiac disease and failure.

The interplay between the cardiovascular system, metabolism, and inflammation plays a central role in the pathophysiology of a wide spectrum of cardiovascular diseases, including heart failure. Here, we provide an overview of the fundamental aspects of the interrelation between inflammation and metabolism, ranging from the role of metabolism in immune cell function to the processes how inflammation modulates systemic and cardiac metabolism. Furthermore, we discuss how disruption of this immuno-metabolic interface is involved in the development and progression of cardiovascular disease, with a special focus on heart failure. Finally, we present new technologies and therapeutic approaches that have recently emerged and hold promise for the future of cardiovascular medicine.

Loss of Mitochondrial Ca2+ Uniporter Limits Inotropic Reserve and Provides Trigger and Substrate for Arrhythmias in Barth Syndrome Cardiomyopathy.

BACKGROUND: Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise, and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Because mitochondrial function and ROS formation are regulated by excitation-contraction coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy. METHODS: We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin (Taz-KD) compared with wild-type littermates. Respiratory chain assembly and function, ROS emission, and Ca2+ uptake were determined in isolated mitochondria. Excitation-contraction coupling was integrated with mitochondrial redox state, ROS, and Ca2+ uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzed in vivo. RESULTS: Taz-KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca2+ affinity and slowed cross-bridge cycling caused diastolic dysfunction, in part, compensated by accelerated diastolic Ca2+ decay through preactivated sarcoplasmic reticulum Ca2+-ATPase. Taz deficiency provoked heart-specific loss of mitochondrial Ca2+ uniporter protein that prevented Ca2+-induced activation of the Krebs cycle during ß-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes. In vivo, Taz-KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to ß-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca2+ export through the mitochondrial Na+/Ca2+ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo. CONCLUSIONS: Downregulation of mitochondrial Ca2+ uniporter, increased myofilament Ca2+ affinity, and preactivated sarcoplasmic reticulum Ca2+-ATPase provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca2+ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.

A pathophysiological compass to personalize antianginal drug treatment.

Myocardial ischaemia results from coronary macrovascular or microvascular dysfunction compromising the supply of oxygen and nutrients to the myocardium. The underlying pathophysiological processes are manifold and encompass atherosclerosis of epicardial coronary arteries, vasospasm of large or small vessels and microvascular dysfunction - the clinical relevance of which is increasingly being appreciated. Myocardial ischaemia can have a broad spectrum of clinical manifestations, together denoted as chronic coronary syndromes. The most common antianginal medications relieve symptoms by eliciting coronary vasodilatation and modulating the determinants of myocardial oxygen consumption, that is, heart rate, myocardial wall stress and ventricular contractility. In addition, cardiac substrate metabolism can be altered to alleviate ischaemia by modulating the efficiency of myocardial oxygen use. Although a universal agreement exists on the prognostic importance of lifestyle interventions and event prevention with aspirin and statin therapy, the optimal antianginal treatment for patients with chronic coronary syndromes is less well defined. The 2019 guidelines of the ESC recommend a personalized approach, in which antianginal medications are tailored towards an individual patient's comorbidities and haemodynamic profile. Although no antianginal medication improves survival, their efficacy for reducing symptoms profoundly depends on the underlying mechanism of the angina. In this Review, we provide clinicians with a rationale for when to use which compound or combination of drugs on the basis of the pathophysiology of the angina and the mode of action of antianginal medications.