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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. Summary 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.

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. Summary 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.

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 Ca 2+ uptake were determined in isolated mitochondria. Excitation-contraction coupling was integrated with mitochondrial redox state, ROS, and Ca 2+ 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 Ca 2+ affinity and slowed cross-bridge cycling caused diastolic dysfunction, in part, compensated by accelerated diastolic Ca 2+ decay through preactivated sarcoplasmic reticulum Ca 2 + -ATPase. Taz deficiency provoked heart-specific loss of mitochondrial Ca 2+ uniporter protein that prevented Ca 2+ -induced activation of the Krebs cycle during β-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 β-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca 2+ export through the mitochondrial Na + /Ca 2+ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo. Conclusions: Downregulation of mitochondrial Ca 2+ uniporter, increased myofilament Ca 2+ affinity, and preactivated sarcoplasmic reticulum Ca 2+ -ATPase provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca 2+ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.

Aims To compare the clinical characteristics and in-hospital outcomes of patients undergoing complex vs. non-complex percutaneous coronary intervention (PCI) with peri-procedural use of cangrelor. Methods Consecutive patients treated with cangrelor in 6 Italian institutions were retrospectively enrolled in the ICARUS (“Intravenous CAngrelor in high-bleeding Risk patients Undergoing percutaneouS coronary intervention”, NCT05505591) registry. Complex PCI was defined as any of the following: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion. The primary endpoint was net adverse clinical events (NACE), defined as a composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis and Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding, at 48 hours. Secondary endpoints were assessed at 48 hours and throughout the hospital stay. Results Among 551 patients enrolled in the ICARUS registry and undergoing PCI between January 2019 and August 2022, a total of 534 (97%) patients had complete information on PCI complexity, of whom 173 (32%) underwent complex PCI and 361 (68%) underwent non-complex PCI. In general, patients with complex PCI had similar clinical features compared with non-complex PCI patients, including comparable prevalence of high bleeding risk (HBR) status according to the ARC-HBR definition (35% vs. 30%, p=0.253), but complex PCI patients presented more often with cardiogenic shock (9% vs. 2%, p Conclusions Among patients receiving peri-procedural cangrelor, about 30% of cases underwent complex interventions. Notwithstanding higher procedural complexity, short-term clinical outcomes were similar between complex and non-complex PCI patients.

Aims To investigate the prevalence of high bleeding risk (HBR) criteria and compare clinical outcomes between HBR and non-HBR patients receiving cangrelor in the peri-percutaneous coronary intervention (PCI) phase. Methods Consecutive patients treated with cangrelor in 7 Italian institutions were retrospectively enrolled in the ICARUS (“Intravenous CAngrelor in high-bleeding Risk patients Undergoing percutaneouS coronary intervention”, NCT05505591) registry. HBR status was assessed according to the Academic Research Consortium (ARC-HBR) definition. The primary endpoint was net adverse clinical events (NACE), defined as a composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis and Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding, at 48 hours. Secondary endpoints were assessed at 48 hours and throughout the hospital stay. Results We enrolled 551 patients undergoing PCI with cangrelor between January 2019 and August 2022. HBR definition was met in 33% of cases. HBR patients were older (76±10 vs. 63±10 years, p Conclusions Among consecutive patients treated with cangrelor in the peri-PCI phase, about 30% fulfilled the ARC-HBR definition. In the HBR subpopulation, the incidence of 48-hour adverse events was higher than in the non-HBR subgroup, primarily driven by a higher rate of clinically relevant and major bleeding.

Background Recent studies have shown that the concentrations of growth differentiation factor 15 (GDF-15) increase after anthracycline administration and may be associated with cardiotoxicity during or shortly after treatment. The relation of GDF-15 with late-onset cardiotoxicity has far less been studied. Methods We examined GDF-15 levels across the spectrum of left ventricular (LV) function in a single-center cohort of adult patients who had received curative chemotherapy for Hodgkin lymphoma and underwent comprehensive cardiologic assessment including transthoracic echocardiography (TTE) as part of long-term follow-up. Plasma GDF-15 was measured by enzyme-linked immunosorbent assay, and the concentrations between TTE phenotypes were compared by unpaired Student's t test. The correlation between GDF-15 values and echocardiographic parameters was investigated by linear regression. Results 35 (18 males, 51%) patients were evaluated a median of 47 months (IQR 24-67) after doxorubicin-containing chemotherapy. The median age at the end of treatment and at the time of TTE was 35 years (IQR 28-50) and 40 years (IQR 32-56), respectively. All subjects had received ABVD with or without rituximab as a first-line treatment; 2 (6%) had also received mediastinal irradiation, 6 (17.4%) a second-line therapy, 2 (8.7%) a third-line treatment, and 8 (17.4%) had ultimately undergone bone marrow transplantation. None had a history of heart disease or atrial fibrillation, nor NYHA class ≥II. Body mass index was 24 ± 5 Kg/m2. Seven (20%) patients had hypertension, 9 dyslipidemia (26%), and 2 (6%) diabetes; 28 (80%) were prior or current smoker. Mean GDF-15 was 1132,9 ± 485,0 pg/mL. LV ejection fraction (LVEF) was always >50%; 3 (9%) subjects had global longitudinal strain (GLS) < -18%. Moreover, 7 (20%) had mild or moderate diastolic dysfunction, as defined by E/A ratio Conclusions Our results suggest that GDF-15 tracks with LV diastolic, rather than systolic, dysfunction years after anthracycline chemotherapy.

Aims To assess the clinical characteristics and compare in-hospital outcomes of elderly and non-elderly patients receiving cangrelor in the peri-percutaneous coronary intervention (PCI) phase. Methods Consecutive patients treated with cangrelor in 7 Italian institutions were retrospectively enrolled in the ICARUS (“Intravenous CAngrelor in high-bleeding Risk patients Undergoing percutaneouS coronary intervention”, NCT05505591) registry. Elderly patients were defined if age was ≥75 years at the time of PCI. The primary endpoint was net adverse clinical events (NACE), defined as a composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis and Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding, at 48 hours. Secondary endpoints were assessed at 48 hours and throughout the hospital stay. Independent predictors of the primary endpoint were also assessed. Results Out of 551 patients undergoing PCI with cangrelor between January 2019 and August 2022, 174 (32%) were elderly. Mean age was 81±5 vs. 61±8 years in elderly vs. non-elderly patients (p Conclusions Advanced age is a distinctive risk feature among patients receiving intravenous cangrelor in the peri-PCI phase. Elderly patients had higher rates of adverse events at 48 hours, with advanced age (≥75 years) being an independent predictor of NACE.

Aims To assess the frequency, clinical characteristics, and clinical outcomes of patients presenting with and without cardiogenic shock (CS) among those receiving cangrelor in the peri-percutaneous coronary intervention (PCI) phase. Methods Consecutive patients treated with cangrelor in 7 Italian institutions were retrospectively enrolled in the ICARUS (“Intravenous CAngrelor in high-bleeding Risk patients Undergoing percutaneouS coronary intervention”, NCT05505591) registry. Cardiogenic shock was defined as system hypotension (systolic blood pressure < 90 mmHg) despite adequate volume in presence of clinical or laboratory signs of hypoperfusion. The primary endpoint was net adverse clinical events (NACE), defined as a composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis and Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding, at 48 hours. Secondary endpoints were assessed at 48 hours. Major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, myocardial infarction, stroke, and definite or probable stent thrombosis were evaluated at discharge. Results Out of 551 patients undergoing PCI with cangrelor between January 2019 and August 2022, cardiogenic shock status was available in 550 (99.9%). Among those, 25 (4.5%) presented with CS. Median age was 67 (59-78) vs. 68 (59-77) years in CS vs. non-CS patients (p=0.767). Female sex (44% vs. 24%, p=0.038), presentation with ST-elevation myocardial infarction (84% vs. 42%, p Conclusions Approximately 5% of patients receiving cangrelor in real-world clinical practice presented with CS. These patients were at higher risk of both ischemic and bleeding events. CS independently predicted the occurrence of 48-hour NACE and major bleeding, as well as in-hospital MACE.

Background Genetic testing is one essential element in the diagnostic workup of patients with idiopathic dilated cardiomyopathy (DCM), and genotype-phenotype correlations are still poorly understood. We assessed the diagnostic yield of genetic testing in a selected DCM cohort including both familial and nonfamilial cases and evaluated phenotypic differences and the relationship of left ventricular reverse remodeling (LVRR) with the presence of pathogenic (P) or likely pathogenic (LP) variants of disease-associated DCM genes. Methods From 680 outpatients with heart with reduced ejection fraction followed at our Heart Failure Outpatient Clinic we selected subjects with a diagnosis of DCM before 65 years of age and without secondary causes of DCM including ischemic, valvular, hypertensive, or drug-induced heart disease or myocarditis. All patients underwent extensive clinical, laboratory, and imaging evaluation at the time of diagnosis and during regular follow-up visits and were offered genetic investigations with Next Generation Sequencing (NGS) of 42 disease-associated DCM genes. Results Of 680 DCM outpatients, 70 fulfilled the definition of idiopathic DCM and 66 gave consent to undergo genetic investigation (median age at diagnosis 57 years, 68% males). A total of 18 pathogenic/likely pathogenic (P/LP) variants were identified in 16 patients (diagnostic yield 24%), the most common (7, 39% of all variants) involving the TTN gene, followed by lamin A/C (n=3), cytoskeleton Z-disk (n=3), motor sarcomeric (n=2), desmosomal (n=1), and ion channel (n=1) gene variants. At the time of DCM diagnosis, patients with P/LP had a higher left ventricular (LV) ejection fraction (LVEF) compared with subjects (31±11% vs 28±8%, p=0.17). After a median follow-up of 53 (IQR 20-111) months, P/LP-positive patients had lower systolic and diastolic blood pressure and higher plasma natriuretic peptide levels than patients without P/LP variants. Patients without P/LP variants exhibited a larger extent of LVRR, as reflected by the increase in LVEF (+14% vs. +1%, p=0.0008) and decrease in LVEDDi (-3 vs. -1 mm/m2, p=0.03) compared with subjects carrying P/LP variants (Figure). 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 left ventricular reverse remodeling in response to guideline-directed medical therapy.

Background Hyperkalemia (HK) has been related to increased mortality in patients with heart failure (HF), at least in part because it leads to down-titration or interruption of renin angiotensin system inhibitors (RASi) and mineralocorticoid receptor antagonists (MRA). Methods We reviewed the records of the HF outpatients with ≥2 visits at our clinic between 2014 and 2021 and complete data on therapy, and identified those who had HK at any time after the first visit. The characteristics between these subjects and those without HK were compared by chi-square test, T-test, or Mann-Whitney test. The use of RASi, MRA and beta-blockers at multiple time points was examined by chi-square or Fisher exact test, and the mean dose for each drug class, expressed as percentage of the guideline-recommended dose, by Wilcoxon rank sum test. The trend of RASi dose over time in HK vs no-HK was assessed by two-way ordinal regression analysis, and the association of HK with all-cause death by Kaplan-Meier method and Cox regression analysis. Results 110 of 690 patients (15.9%) had HK, with the mean potassium concentration being 5.6 mEq/L. Subjects with HK were older [73 (66-79) vs 68 (58-78) years, p Conclusions The negative impact of HK on RASi and MRA prescription and on prognosis may be mitigated in tertiary centers with expertise in HF treatment.

Aims To assess the clinical characteristics and compare in-hospital outcomes of patients with and without anaemia receiving cangrelor in the peri-percutaneous coronary intervention (PCI) phase. Methods Consecutive patients treated with cangrelor in 7 Italian institutions were retrospectively enrolled in the ICARUS (“Intravenous CAngrelor in high-bleeding Risk patients Undergoing percutaneouS coronary intervention”, NCT05505591) registry. According to the World Health Organization, anaemia was defined as haemoglobin (Hb) levels < 13 g/dL in men and < 12 g/dL in women; severe anaemia as an Hb value < 11 g/dL irrespective of sex. The primary endpoint was net adverse clinical events (NACE), defined as a composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis and Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding, at 48 hours. Secondary endpoints were assessed at 48 hours. Major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, myocardial infarction, stroke and definite or probable stent thrombosis were also evaluated at discharge. Results Out of 551 patients undergoing PCI with cangrelor between January 2019 and August 2022, 125 (23%) were anaemic. Mean age was 74±10 vs. 65±11 years in anaemic vs. non-anaemic patients (p At 48 hours, anaemic patients had higher rates of NACE (14% vs. 7%, p=0.019) and BARC 2, 3 or 5 bleeding (12% vs. 5%, p=0.013), whereas the rates of other 48-hour endpoints did not differ. At multivariable analysis, severe anaemia (odds ratio [OR] 1.12, 95% CI 1.02-1.24, p=0.015), acute coronary syndrome at presentation (OR 1.06, 95% CI 1.01-1.12, p=0.013), femoral access (OR 1.12, 95% CI 1.04-1.20, p=0.001) and cardiogenic shock (OR 1.27, 95% CI 1.13-1.44, p Conclusions Anaemia is a distinctive risk feature among patients receiving intravenous cangrelor in the peri-PCI phase. Anaemic patients experience higher incidence of adverse events at 48 hours, with severe anaemia being an independent predictor of NACE.

Key points Mitochondrial Ca2+ uptake stimulates the Krebs cycle to regenerate the reduced forms of pyridine nucleotides (NADH, NADPH and FADH2 ) required for ATP production and reactive oxygen species (ROS) elimination. Ca2+ /calmodulin-dependent protein kinase II (CaMKII) has been proposed to regulate mitochondrial Ca2+ uptake via mitochondrial Ca2+ uniporter phosphorylation. We used two mouse models with either global deletion of CaMKIIδ (CaMKIIδ knockout) or cardiomyocyte-specific deletion of CaMKIIδ and γ (CaMKIIδ/γ double knockout) to interrogate whether CaMKII controls mitochondrial Ca2+ uptake in isolated mitochondria and during β-adrenergic stimulation in cardiac myocytes. CaMKIIδ/γ did not control Ca2+ uptake, respiration or ROS emission in isolated cardiac mitochondria, nor in isolated cardiac myocytes, during β-adrenergic stimulation and pacing. The results of the present study do not support a relevant role of CaMKII for mitochondrial Ca2+ uptake in cardiac myocytes under physiological conditions. Abstract Mitochondria are the main source of ATP and reactive oxygen species (ROS) in cardiac myocytes. Furthermore, activation of the mitochondrial permeability transition pore (mPTP) induces programmed cell death. These processes are essentially controlled by Ca2+ , which is taken up into mitochondria via the mitochondrial Ca2+ uniporter (MCU). It was recently proposed that Ca2+ /calmodulin-dependent protein kinase II (CaMKII) regulates Ca2+ uptake by interacting with the MCU, thereby affecting mPTP activation and programmed cell death. In the present study, we investigated the role of CaMKII under physiological conditions in which mitochondrial Ca2+ uptake matches energy supply to the demand of cardiac myocytes. Accordingly, we measured mitochondrial Ca2+ uptake in isolated mitochondria and cardiac myocytes harvested from cardiomyocyte-specific CaMKII δ and γ double knockout (KO) (CaMKIIδ/γ DKO) and global CaMKIIδ KO mice. To simulate a physiological workload increase, cardiac myocytes were subjected to β-adrenergic stimulation (by isoproterenol superfusion) and an increase in stimulation frequency (from 0.5 to 5 Hz). No differences in mitochondrial Ca2+ accumulation were detected in isolated mitochondria or cardiac myocytes from both CaMKII KO models compared to wild-type littermates. Mitochondrial redox state and ROS production were unchanged in CaMKIIδ/γ DKO, whereas we observed a mild oxidation of mitochondrial redox state and an increase in H2 O2 emission from CaMKIIδ KO cardiac myocytes exposed to an increase in workload. In conclusion, the results obtained in the present study do not support the regulation of mitochondrial Ca2+ uptake via the MCU or mPTP activation by CaMKII in cardiac myocytes under physiological conditions.

Aims Conflicting data exist regarding the risk of cancer in patients with heart failure (HF). It was first reported that incident cancer is more common among patients with than without HF, whereas more recent studies indicate that this association is primarily driven by comorbidities. HF, cancer, and comorbidities, such as chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), share numerous risk factors, including a state of chronic low-grade inflammation reflected by elevated circulating levels of pro-inflammatory cytokines. The objective of this analysis was to assess whether chronic low-grade inflammation, as measured by levels of high-sensitivity C-reactive protein (hsCRP), and comorbidities mediate the association of HF with incident cancer. Methods We used data from the 3rd wave of the Nord-Trøndelag Health Study (HUNT3), a population-based study that enrolled 50 803 individuals ≥18-year-old between October 2006 and June 2008 in the Nord-Trøndelag County (Norway), and from the administrative health care records of the same region. Associations between baseline characteristics and the development of cancer were assessed using Cox proportional hazards regression models, using time from HUNT3 enrolment as the time scale. Analyses were performed using R statistical software, version 4.0.2. Results In HUNT3, hsCRP was measured in 47 571 individuals at the time of enrolment. Of these, we excluded 2308 patients because of missing information, leaving a cohort of 45 263 subjects. The prevalence of cardiovascular disease, comorbidities, and obesity was progressively higher with increasing concentrations of hsCRP. During a median follow-up of 12 years, there were 66/408 cases of incident cancer in patients with HF at baseline and 5024/47 163 in subjects without HF, with a more than 2-fold (HR 2.30; 95% CI 1.80–2.93; P Conclusions The increased risk of cancer in HF patients compared with the general population is at least in part explained by concomitant inflammation and comorbidities.

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.We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin (Downregulation of mitochondrial Ca

Background Conflicting data exist regarding the risk of cancer in patients with heart failure (HF). It was first reported that incident cancer is more common among patients with than without HF, whereas more recent studies indicate that this association is primarily driven by comorbidities. HF, cancer, and comorbidities, such as chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), share numerous risk factors, including a state of chronic low-grade inflammation reflected by elevated circulating levels of pro-inflammatory cytokines. The objective of this analysis was to assess whether chronic low-grade inflammation, as measured by levels of high-sensitivity C-reactive protein (hsCRP), and comorbidities mediate the association of HF with incident cancer. Methods We used data from the 3rd wave of the Nord-Trøndelag Health Study (HUNT3), a population-based study that enrolled 50,803 individuals ≥18-year-old between October 2006 and June 2008 in the Nord-Trøndelag County (Norway), from the Cancer Registry of Norway and from the administrative health care records of the same region. Associations between baseline characteristics and the development of cancer were assessed using Cox proportional hazards regression models, using time from HUNT3 enrollment as the time scale. Analyses were performed using R statistical software, version 4.0.2. Results In HUNT3, hsCRP was measured in 47,571 individuals at the time of enrollment. Of these, we excluded 2,308 patients because of missing information, leaving a cohort of 45,263 subjects. Figure 1 shows the characteristics of the study population at baseline stratified by hsCRP tertiles. The prevalence of cardiovascular disease, comorbidities, and obesity was progressively higher with increasing concentrations of hsCRP. During a median follow-up of 12 years, there were 66/408 cases of incident cancer in patients with HF at baseline and 5,024/47,163 in subjects without HF, with a more than 2-fold (HR 2.30; 95% CI 1.80–2.93; p Conclusions The increased risk of cancer in HF patients compared with the general population is at least in part explained by concomitant inflammation and comorbidities. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Background Studies assessing whether heart failure (HF) is associated with an excess risk of cancer and cancer-related mortality yielded conflicting results. Here, we assessed the incidence and mortality of cancer according to the presence of HF in a community-based cohort. Methods By reviewing the health care records of the Puglia region in Italy, we first selected individuals ≥50-year-old, with no history of cancer within 3 years before the baseline evaluation and ≥5 years of follow-up, during the period from January 1st, 2005 to December 31st, 2013. Next, we matched 1:1 104,020 subjects with HF at baseline and 104,020 controls based on age, sex, Charlson Comorbidity Index, Drug-Derived Complexity Index, and follow-up duration. Cancer incidence and mortality were analyzed by Kaplan-Meier method and Cox regression models. Fine and Grey's regression model was also used to compare cancer-specific mortality while taking into account the competing risk of non-cancer death. Results Overall, the mean age of the study population was 76±10 years and the mean follow-up was 5.7 years. The incidence rate of cancer in HF patients and controls was 21.36 (95% CI, 20.98–21.74) and 12.42 (95% CI, 12.14–12.72) per 1000 person/years, respectively, corresponding to a 76% higher risk of incident cancer in HF patients (HR, 1.76; 95% CI, 1.71–1.81). HF patients also died from cancer more frequently than controls (HR 4.11; 95% CI, 3.86–4.38; Figure 1). This excess mortality was highest when age was The HF-related risk applied to the majority of cancer types, with the exception of neoplasm of the male reproductive system. Interestingly, among HF patients a high consumption of loop diuretic (>37.5 mg/d of furosemide) was associated with a higher mortality for cancer (HR 1.34, 95% CI 1.26–1.42 vs. ≤37.5 mg/d). Conclusions The analysis of this large community-based sample suggests that HF does portend an increased risk of cancer and cancer-related mortality, which is blunted, yet remains substantial, with increasing age and competing risk of dying from other causes. The risk of cancer may be heightened when HF is poorly compensated. Funding Acknowledgement Type of funding sources: None. Figure 1. Cancer mortality in HF patient

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy and is mainly caused by mutations of genes encoding cardiac sarcomeric proteins. HCM is characterized by hypertrophy of the left ventricle, frequently involving the septum, that is not explained solely by loading conditions. HCM has a heterogeneous clinical profile, but diastolic dysfunction and ventricular arrhythmias represent two dominant features of the disease. Preclinical evidence indicates that the enhanced Calcium (Ca2+ ) sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric mutations, but can also result from secondary mutation-driven alterations. Here, we review experimental and clinical evidence indicating that increased myofilament Ca2+ sensitivity lies upstream of numerous cellular derangements which potentially contribute to the progression of HCM toward heart failure and sudden cardiac death.

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.

Recent trials have shown the efficacy of new drugs for the medical therapy of heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduced hospitalizations for heart failure (HF), HF events, and cardiovascular death in patients with HFrEF or hospitalized for HF. Iron repletion with ferric carboxymaltose (FCM) improved symptoms, functional capacity, and quality of life in chronic HFrEF patients, and decreased the risk of subsequent HF hospitalizations in subjects with acutely decompensated HF. New-generation potassium binders may allow initiation and up-titration of renin–angiotensin–aldosterone system inhibitors (RASis). Lastly, the guanylate cyclase stimulator vericiguat and the myosin activator omecamtiv mecarbil reduced the primary endpoint in two major controlled trials. These results open novel pathways for the treatment of HFrEF. This review discusses new opportunities of an individualized approach to HFrEF pharmacotherapy, where new compounds expand a spectrum of drugs that target primarily neuroendocrine activation. SGLT2i can be safely applied once daily at a fixed dose to the vast majority of patients with HFrEF, including those with moderate renal dysfunction and/or systolic blood pressure as low as 95–100 mmHg. Additional medications are suitable for more specific phenotypes, with ivabradine providing benefit in patients with sinus rhythm and heart rates ≥70 b.p.m., FCM in the presence of iron deficiency, and potassium-lowering agents to implement RASi when hyperkalaemia occurs. Vericiguat and omecamtiv mecarbil also have potential for tailored approaches towards the haemodynamic status. Thus, a new era is starting for a more personalized medical treatment of HFrEF.

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.

The co‐occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre‐clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time., We describe the co‐occurrence of cancer and heart failure (HF), their potential shared risk factors, and their pathophysiological mechanisms. We advocate intense interaction between cardiologists and oncologists to achieve unifying hypotheses and collaborative pre‐clinical and clinical studies.

In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H2O2 by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H2O2 elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, α-ketoglutarate dehydrogenase (α-KGDH) is a major source of superoxide in skeletal muscle mitochondria with low NNT activity. Here, we analyzed how α-KGDH and NNT control H2O2 emission in cardiac mitochondria. In cardiac mitochondria from NNT-competent BL/6N mice, H2O2 emission is equally low with pyruvate/malate (P/M) or α-ketoglutarate (α-KG) as substrates. Complex I inhibition with rotenone increases H2O2 emission from P/M, but not α-KG respiring mitochondria, which is potentiated by depleting H2O2-eliminating capacity. Conversely, in NNT-deficient BL/6J mitochondria, H2O2 emission is higher with α-KG than with P/M as substrate, and further potentiated by complex I blockade. Prior depletion of H2O2-eliminating capacity increases H2O2 emission from P/M, but not α-KG respiring mitochondria. In cardiac myocytes, downregulation of α-KGDH activity impaired dynamic mitochondrial redox adaptation during workload transitions, without increasing H2O2 emission. In conclusion, NADH from α-KGDH selectively shuttles to NNT for NADPH formation rather than to complex I of the respiratory chain for ATP production. Therefore, α-KGDH plays a key role for H2O2 elimination, but is not a relevant source of superoxide in heart. In heart failure, α-KGDH/NNT-dependent NADPH formation ameliorates oxidative stress imposed by complex I blockade. Downregulation of α-KGDH may, therefore, predispose to oxidative stress in heart failure.

Recent epidemiological analyses suggest that incident cancer may be more common among patients with preexisting heart failure (HF) than in patients without HF. Arguments against this notion have been the increased chance of co-occurrence of 2 high-prevalence conditions and increased tumor detection in patients with HF because of intensified medical observation. However, biological data lend support to the hypothesis that HF is an oncogenic condition. Neurohormonal activation has been related to cancer initiation, progression, and dissemination by studies not specifically focusing on HF, which are now reappraised in the light of the emerging evidence that tumors are diagnosed more often in HF than control cohorts. Furthermore, a thought-provoking scenario to be considered is that a systemically perturbed milieu, where low-grade inflammation plays a primary role, leads to both HF and malignancy, thus connecting 1 disease to another. Postischemic HF has been shown to promote tumor growth in an animal model. Exploring these and other pathways potentially linking HF to malignancy is a new and exciting field of research, with the ultimate goal of answering the question of whether HF does promote cancer.

In heart failure, alterations of Na + and Ca 2+ handling, energetic deficit, and oxidative stress in cardiac myocytes are important pathophysiological hallmarks. Mitochondria are central to these processes because they are the main source for ATP, but also reactive oxygen species (ROS), and their function is critically controlled by Ca 2+ . During physiological variations of workload, mitochondrial Ca 2+ uptake is required to match energy supply to demand but also to keep the antioxidative capacity in a reduced state to prevent excessive emission of ROS. Mitochondria take up Ca 2+ via the mitochondrial Ca 2+ uniporter, which exists in a multiprotein complex whose molecular components were identified only recently. In heart failure, deterioration of cytosolic Ca 2+ and Na + handling hampers mitochondrial Ca 2+ uptake and the ensuing Krebs cycle–induced regeneration of the reduced forms of NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate), giving rise to energetic deficit and oxidative stress. ROS emission from mitochondria can trigger further ROS release from neighboring mitochondria termed ROS-induced ROS release, and cross talk between different ROS sources provides a spatially confined cellular network of redox signaling. Although low levels of ROS may serve physiological roles, higher levels interfere with excitation–contraction coupling, induce maladaptive cardiac remodeling through redox-sensitive kinases, and cell death through mitochondrial permeability transition. Targeting the dysregulated interplay between excitation–contraction coupling and mitochondrial energetics may ameliorate the progression of heart failure.

Mitochondria play a prominent role in cardiac energy metabolism, and their function is critically dependent on the integrity of mitochondrial membranes. Disorders characterized by mitochondrial dysfunction are commonly associated with cardiac disease. The mitochondrial phospholipid cardiolipin directly interacts with a number of essential protein complexes in the mitochondrial membranes including the respiratory chain, mitochondrial metabolite carriers, and proteins critical for mitochondrial morphology. Barth syndrome is an X-linked disorder caused by an inherited defect in the biogenesis of the mitochondrial phospholipid cardiolipin. How cardiolipin deficiency impacts on mitochondrial function and how mitochondrial dysfunction causes cardiomyopathy has been intensively studied in cellular and animal models of Barth syndrome. These findings may also have implications for the molecular mechanisms underlying other inherited disorders associated with defects in cardiolipin, such as Sengers syndrome and dilated cardiomyopathy with ataxia (DCMA).

The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. These genetic diseases are characterized by cardiac structural and functional anomalies in the absence of abnormal conditions that can explain the observed myocardial abnormality, and are frequently associated with heart failure. Since their original description, major advances have been achieved in the genetic and phenotype knowledge, highlighting the involvement of metabolic abnormalities in their pathogenesis. This review provides a brief overview of the role of mitochondria in the energy metabolism in the heart and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.

Despite important advances in diagnosis and treatment, heart failure (HF) remains a syndrome with substantial morbidity and dismal prognosis. Although implementation and optimization of existing technologies and drugs may lead to better management of HF, new or alternative strategies are desirable. In this regard, basic science is expected to give fundamental inputs, by expanding the knowledge of the pathways underlying HF development and progression, identifying approaches that may improve HF detection and prognostic stratification, and finding novel treatments. Here, we discuss recent basic science insights that encompass major areas of translational research in HF and have high potential clinical impact.

Type-2 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose is central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy/redox balance under excess glucose, rescuing β-adrenergic-stimulated cardiac excitation–contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodelling associated with cardiac function in diabetic db/db mice subjected to stress given by β-adrenergic stimulation with isoproterenol and high glucose compared to their non-diabetic controls (+/+, WT) under euglycaemic conditions. When perfused with Palm, T2DM hearts exhibited improved contractility/relaxation compared to WT, accompanied by extensive metabolic remodelling as demonstrated by metabolomics–fluxomics combined with bioinformatics and computational modelling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids and redox metabolism. Using a validated computational model of heart’s central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are ~2-fold lower in heart from T2DM vs. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced β-oxidation and decreased glucose uptake, leading to flux-redirection away from redox-consuming pathways (e.g. polyol) while maintaining the flux through redox-generating pathways together with glucose–FA ‘shared fuelling’ of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycaemia and increased workload.

Mitochondrial CaMitochondria are the main source of ATP and reactive oxygen species (ROS) in cardiac myocytes. Furthermore, activation of the mitochondrial permeability transition pore (mPTP) induces programmed cell death. These processes are essentially controlled by Ca

The effects of intense glycaemic control on macrovascular complications in patients with type 2 diabetes are incompletely resolved, and many glucose-lowering medications negatively affect cardiovascular outcomes. Recently, the EMPA-REG OUTCOME trial revealed that empagliflozin, an inhibitor of the sodium-glucose cotransporter 2 (SGLT2), substantially reduced the risk of hospitalization for heart failure, death from cardiovascular causes, and all-cause mortality in patients with type 2 diabetes mellitus at high cardiovascular risk. Although several mechanisms may explain this benefit, plasma volume contraction and a metabolic switch favouring cardiac ketone bodies oxidation have recently been proposed as the major drivers. Recent experimental work has prompted a novel and intriguing hypothesis, according to which empagliflozin may reduce intracellular sodium (Na+) load observed in failing cardiac myocytes by inhibiting the sarcolemmal Na+/H+ exchanger. Since elevated intracellular Na+ hampers mitochondrial Ca2+ handling and thereby, deteriorates energy supply and demand matching and the mitochondrial antioxidative defence systems, empagliflozin may positively affect cardiac function by restoring mitochondrial function, and redox state in the failing heart. Here, we review the current evidence for such a third mechanistic hypothesis, which may foster heart failure and diabetes research into a new direction which harbours several potential targets for therapeutic intervention.