Alberto Aimo

Cardioprotection by remote ischemic conditioning: Mechanisms and clinical evidences.

In remote ischemic conditioning (RIC), several cycles of ischemia and reperfusion render distant organ and tissues more resistant to the ischemia-reperfusion injury. The intermittent ischemia can be applied before the ischemic insult in the target site (remote ischemic preconditioning), during the ischemic insult (remote ischemic perconditioning) or at the onset of reperfusion (remote ischemic postconditioning). The mechanisms of RIC have not been completely defined yet; however, these mechanisms must be represented by the release of humoral mediators and/or the activation of a neural reflex. RIC has been discovered in the heart, and has been arising great enthusiasm in the cardiovascular field. Its efficacy has been evaluated in many clinical trials, which provided controversial results. Our incomplete comprehension of the mechanisms underlying the RIC could be impairing the design of clinical trials and the interpretation of their results. In the present review we summarize current knowledge about RIC pathophysiology and the data about its cardioprotective efficacy.

Influence of central apneas and chemoreflex activation on pulmonary artery pressure in chronic heart failure

BACKGROUND Pulmonary artery hypertension (PH), associated with increased left ventricular (LV) diastolic pressure and pulmonary vasoconstriction, is frequently observed in heart failure (HF), where it holds prognostic significance. We hypothesized that Cheyne-Stokes respiration (CSR) may contribute to increased pulmonary arterartery pressure (PAP) and right ventricular (RV) remodeling in HF, via hypoxia/hypercapnia cycles and adrenergic activation by the chemoreflex stimulation. METHODS Seventy-two HF patients (57 males, aged 65.1 SD 12.3 years, LV ejection fraction<50%, 33.2 SD 7.5%), on guideline recommended pharmacological/device treatment underwent thorough clinical, echocardiographic and neurohormonal assessment, 24-hour cardiorespiratory screening for arrhythmias and CSR, and chemoreflex test for hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses. RESULTS Twenty patients (28%) showed significant CSR (24-hour apnea-hypopnea index, AHI≥15). Patients with CSR presented with: a) higher systolic pulmonary artery pressure (sPAP: 42.8 standard deviation-SD 10.1 vs 32.3 SD 5.7 mmHg, p<0.001), despite similar LV systolic and diastolic function; b) indexes of right chamber remodeling (all p<0.05); c) enhanced HVR (median 0.78, interquartile range-IR 0.46-1.22 vs 0.42, IR 0.18-0.67 L/min/%, p=0.01) and HCVR (1.17, IR 0.97-1.29 vs 0.72, IR 0.47-0.93 L/min/mmHg, p=0.02); d) increased plasma norepinephrine levels (690, IR 477-868 vs 366, IR 226-508 ng/L, p<0.001). Univariate predictors of sPAP>35 mmHg were AHI, HVR, HCVR; only AHI maintained its predictive value at multivariate analysis (p=0.017). CONCLUSIONS CSR may contribute to increased pulmonary artery pressure and right chamber remodeling in HF, independently of the severity of LV systolic and diastolic dysfunction, likely via recurrent hypoxia/hypercapnia cycles and chemoreflex mediated adrenergic discharge.

Autonomic, functional, skeletal muscle, and cardiac abnormalities are associated with increased ergoreflex sensitivity in mitochondrial disease: Ergoreflex sensitivity in mitochondrial disease

Mitochondrial disease (MD) is a genetic disorder affecting skeletal muscles, with possible myocardial disease. The ergoreflex, sensitive to skeletal muscle work, regulates ventilatory and autonomic responses to exercise. We hypothesized the presence of an increased ergoreflex sensitivity in MD patients, its association with abnormal ventilatory and autonomic responses, and possibly with subclinical cardiac involvement.

Prognostic Value of High-Sensitivity Troponin T in Chronic Heart Failure: An Individual Patient Data Meta-Analysis

Background: Most patients with chronic heart failure have detectable troponin concentrations when evaluated by high-sensitivity assays. The prognostic relevance of this finding has not been clearly established so far. We aimed to assess high-sensitivity troponin assay for risk stratification in chronic heart failure through a meta-analysis approach. Methods: Medline, EMBASE, Cochrane Library, and Scopus were searched in April 2017 by 2 independent authors. The terms were “troponin” AND “heart failure” OR “cardiac failure” OR “cardiac dysfunction” OR “cardiac insufficiency” OR “left ventricular dysfunction.” Inclusion criteria were English language, clinical stability, use of a high-sensitivity troponin assay, follow-up studies, and availability of individual patient data after request to authors. Data retrieved from articles and provided by authors were used in agreement with the PRISMA statement. The end points were all-cause death, cardiovascular death, and hospitalization for cardiovascular cause. Results: Ten studies were included, reporting data on 11 cohorts and 9289 patients (age 66±12 years, 77% men, 60% ischemic heart failure, 85% with left ventricular ejection fraction <40%). High-sensitivity troponin T data were available for all patients, whereas only 209 patients also had high-sensitivity troponin I assayed. When added to a prognostic model including established risk markers (sex, age, ischemic versus nonischemic etiology, left ventricular ejection fraction, estimated glomerular filtration rate, and N-terminal fraction of pro-B-type natriuretic peptide), high-sensitivity troponin T remained independently associated with all-cause mortality (hazard ratio, 1.48; 95% confidence interval, 1.41–1.55), cardiovascular mortality (hazard ratio, 1.40; 95% confidence interval, 1.33–1.48), and cardiovascular hospitalization (hazard ratio, 1.42; 95% confidence interval, 1.36–1.49), over a median 2.4-year follow-up (all P<0.001). High-sensitivity troponin T significantly improved risk prediction when added to a prognostic model including the variables above. It also displayed an independent prognostic value for all outcomes in almost all population subgroups. The area under the curve–derived 18 ng/L cutoff yielded independent prognostic value for the 3 end points in both men and women, patients with either ischemic or nonischemic etiology, and across categories of renal dysfunction. Conclusions: In chronic heart failure, high-sensitivity troponin T is a strong and independent predictor of all-cause and cardiovascular mortality, and of hospitalization for cardiovascular causes, as well. This biomarker then represents an additional tool for prognostic stratification.

ANMCO/ELAS/SIBioC Consensus Document: biomarkers in heart failure

Abstract Biomarkers have dramatically impacted the way heart failure (HF) patients are evaluated and managed. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological or pathogenic processes, or pharmacological responses to a therapeutic intervention. Natriuretic peptides [B-type natriuretic peptide (BNP) and N-terminal proBNP] are the gold standard biomarkers in determining the diagnosis and prognosis of HF, and a natriuretic peptide-guided HF management looks promising. In the last few years, an array of additional biomarkers has emerged, each reflecting different pathophysiological processes in the development and progression of HF: myocardial insult, inflammation, fibrosis, and remodelling, but their role in the clinical care of the patient is still partially defined and more studies are needed before to be well validated. Moreover, several new biomarkers have the potential to identify patients with early renal dysfunction and appear to have promise to help the management cardio-renal syndrome. With different biomarkers reflecting HF presence, the various pathways involved in its progression, as well as identifying unique treatment options for HF management, a closer cardiologist-laboratory link, with a multi-biomarker approach to the HF patient, is not far ahead, allowing the unique opportunity for specifically tailoring care to the individual pathological phenotype.

Documento di consenso ANMCO/ELAS/SIBioC: Raccomandazioni sull'impiego dei biomarcatori cardiaci nello scompenso cardiaco

Biomarkers have dramatically impacted the way heart failure (HF) patients are evaluated and managed. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological or pathogenic processes, or pharmacological responses to a therapeutic intervention. Natriuretic peptides (B-type natriuretic peptide [BNP] and N-terminal proBNP) are the gold standard biomarkers in determining the diagnosis and prognosis of HF, and a natriuretic peptide-guided HF management looks promising. In the last few years, an array of additional biomarkers has emerged, each reflecting different pathophysiological processes in the development and progression of HF: myocardial insult, inflammation, fibrosis and remodeling, but their role in the clinical care of the patient is still partially defined and more studies are needed before to be well validated. Moreover, several new biomarkers have the potential to identify patients with early renal dysfunction and appear to have promise to help the management cardio-renal syndrome.With different biomarkers reflecting HF presence, the various pathways involved in its progression, as well as identifying unique treatment options for HF management, a closer cardiologist-laboratory link, with a multi-biomarker approach to the HF patient, is not far ahead, allowing the unique opportunity for specifically tailoring care to the individual pathological phenotype.

Targeting Mitochondrial Dysfunction in Chronic Heart Failure: Current Evidence and Potential Approaches

BACKGROUND Mitochondria are cellular organelles responsible for energy production, calcium handling, controlled synthesis of reactive oxygen species (ROS), and regulation of apoptosis. All these functions are crucial for cardiac homeostasis, and may be impaired in chronic heart failure (CHF). Therefore, mitochondrial dysfunction might represent a crucial element in the onset and progression of CHF and, as such, a promising therapeutic target. METHODS Original articles and review on the treatment of mitochondrial dysfunction in CHF were searched on Medline and Scopus. RESULTS The present review summarizes the current knowledge about mitochondrial modulation as a therapeutic strategy for CHF, and proposes some perspectives for future studies. Mitochondrial dysfunction can be ascribed to neuro-humoral activation and cardiac remodeling associated with CHF. Conceptually, the correction of mitochondrial dysfunction could provide an additive benefit to optimal CHF treatment. Increasing glucose metabolism and reducing oxidative stress within mitochondria are the two most promising approaches, even though further studies are required before implementing new treatments in the setting of CHF. On the other hand, inhibition of apoptosis, and normalization of calcium and mitochondrial dynamics have been assessed almost exclusively in ex vivo models, and mostly in settings other than CHF. CONCLUSION Mitochondrial modulation in CHF is an intriguing example of translational research and a potentially rewarding field.

Myocardial damage in a mitochondrial myopathy patient with increased ergoreceptor sensitivity and sympatho-vagal imbalance

Abbreviations: CMR, cardiac magnetic resonance; CPK electrocardiogram; hs-cTnT, high sensitivity cardiac tropo nase; pNN50, percentage of successive normal sinus RR O2 saturation. ⁎ Corresponding author at: Cardiovascular Medicine Gabriele Monasterio, National Research Council, CNR-R Moruzzi 1, 56124 Pisa, Italy. Tel.: +39 050 3153521, + +39 050 3152109. E-mail address: alberto.giannoni@gmail.com (A. Giann

Sex-related differences in chronic heart failure

The prevalence of chronic heart failure (CHF) is steadily increasing. Both sexes are affected, with significant differences in etiology, epidemiology and clinical presentation, prognosis, comorbidities, and response to treatment. Women tend to develop CHF at a more advanced age, present more often with HF with preserved ejection fraction, are more symptomatic, and have a worse quality of life than men, but also a better prognosis. In women, CHF has more frequently a non-ischemic etiology, and arterial hypertension and diabetes mellitus are leading comorbidities. Furthermore, many sex-related differences have been detected in the response to treatment, for example a greater prognostic benefit from angiotensin-receptor blockers in women, a higher incidence of complications after defibrillator implantation, and a greater response to cardiac resynchronization therapy. Furthermore, women are less likely to receive defibrillator therapy or heart transplantation. The significant underrepresentation of women in clinical trials limits our capacity to evaluate the extent of sex-related differences in CHF, although their characterization seems crucial in order to achieve the ultimate goal of a tailored therapy for this condition.

The bottleneck of cardiac rehabilitation for patients with coronary artery disease: How to overcome

Cardiovascular prevention has largely developed as secondary prevention in the setting of coronary artery disease (CAD). Indeed, the control of cardiovascular risk factors may slow down the progression of CAD and reduce the risk of future coronary events, as well as improving patient wellbeing. The definition of ‘cardiac rehabilitation’ (CR) encompasses both risk reduction, achieved through lifestyle modification and the use of disease-modifying drugs, and a structured programme of physical exercise. Exercise-based CR has proved effective in reducing total and cardiovascular mortality, hospital admissions, and improving health-related quality of life, while the effects on myocardial infarction (MI) rates or revascularisation are less clear especially in the long term. Patients are usually referred to CR after coronary revascularisation (either surgical or percutaneous) performed in the setting of acute coronary syndromes (ACSs) or, less often, for stable CAD. Nevertheless, the European Society of Cardiology (ESC) guidelines state that CR ‘should be considered in all patients with CAD, including those with chronic angina’, although only the generic recommendation to ‘educate patients about the disease, risk factors and treatment strategy’ (class I, level of evidence C) is issued for stable CAD, while the corresponding recommendations have class I, level of evidence A for both ST-segment elevation MI and non-ST-segment elevation ACS. The commitment of the ESC to CR also emerges from the guidelines dedicated to cardiovascular disease prevention and rehabilitation, and from the crosssectional surveys to assess guideline implementation in clinical practice. Overall, the European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) study has showed a largely unsatisfactory control of cardiovascular risk factors and no evidence of improvement over time. For example, the first three versions of the survey have shown adverse lifestyle trends, a substantial increase in obesity and a high prevalence of persistent smoking in younger patients. Despite a substantial increase in the use of antihypertensive drugs, almost half of the patients did not reach blood pressure targets. Similarly, the prescription rates of lipid-lowering drugs, principally statins, increased markedly, but most patients still remained above the low-density lipoprotein (LDL) cholesterol target. Finally, nearly one third of patients in EUROASPIRE III had a history of diabetes mellitus with poor glycaemic control. The fourth EUROASPIRE study included 7998 patients and was far larger than previous surveys (e.g. 2392 participants in EUROASPIRE III). Seventy-eight hospital centres in 24 European countries were involved. Patients aged 18–80 years who underwent either elective or emergency coronary artery bypass graft surgery or percutaneous coronary intervention were interviewed and examined after 6 months to 3 years. The results of this survey, first published in 2016, confirmed that a large majority of European patients with CAD failed to achieve the lifestyle change, risk factor control and therapeutic targets set by ESC guidelines. Furthermore, a large geographical variability exists in both lifestyle and risk factor management, the use of cardioprotective medications, the provision of cardiac prevention and rehabilitation and other preventive services. The characterisation of the wealth of data from EUROASPIRE IV is still underway. In the present issue of the journal, Kotseva and colleagues focus on the referral to CR programmes and their impact on