Gianluca Mirizzi

Measurement of myocardial amyloid deposition in systemic amyloidosis: insights from cardiovascular magnetic resonance imaging

Cardiac involvement in systemic amyloidosis is caused by the extracellular deposition of misfolded proteins, mainly immunoglobulin light chains (AL) or transthyretin (ATTR), and may be detected by cardiovascular magnetic resonance (CMR). The aim of this study was to measure myocardial extracellular volume (ECV) in amyloid patients with a novel T1 mapping CMR technique and to determine the correlation between ECV and disease severity.

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.

Biomarkers of activation of renin-angiotensin-aldosterone system in heart failure: how useful, how feasible?

Renin-angiotensin-aldosterone system (RAAS), participated by kidney, liver, vascular endothelium, and adrenal cortex, and counter-regulated by cardiac endocrine function, is a complex endocrine system regulating systemic functions, such as body salt and water homeostasis and vasomotion, in order to allow the accomplishment of physiological tasks, such as orthostasis, physical and emotional stimuli, and to react towards the hemorrhagic insult, in tight conjunction with other neurohormonal axes, namely the sympathetic nervous system, the endothelin and vasopressin systems. The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction. RAAS activation is a fingerprint of systemic arterial hypertension, kidney dysfunction, vascular atherosclerotic disease, and is definitely an hallmark of heart failure, which rapidly shifts from organ disease to a disorder of neurohormonal regulatory systems. Chronic RAAS activation is an indirect or direct target of most effective pharmacological treatments in heart failure, such as beta-blockers, inhibitors of angiotensin converting enzyme, angiotensin receptor blockers, direct renin inhibitors, and mineralocorticoid receptor blockers. Biomarkers of RAAS activation are available, with different feasibility and accuracy, such as plasma renin activity, renin, angiotensin II, and aldosterone, which all accompany the increasing clinical severity of heart failure disease, and are well recognized prognostic factors, even in patients with optimal therapy. Polymorphisms influencing the expression and activity of RAAS pathways have been recognized as clinically relevant biomarkers, likely influencing either the individual clinical phenotype, or the response to drugs. This solid, growing evidence strongly suggests the rationale for the use of biomarkers of the RAAS activation, as a guide to tailor individual therapy in the current practice, and their implementation as a rule-in marker for future trials on novel drugs in the heart failure setting.

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.

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.

Leiomyosarcoma of the inferior vena cava in a patient with Budd-Chiari syndrome.

A 65-year-old man with no history of cardiovascular disease was admitted because of abdominal pain, nausea and lower limb edema. At clinical examination he presented hepatomegaly, ascites and laboratory evidence of liver failure. The echocardiogram (Figure 1A) showed preserved biventricular function, but a large irregular mass was visible in the right atrium (arrow; Supplementary data, Movie 1 and 2). Computed tomography (Figure 1B) showed patchy contrast uptake and positron emission tomography (Figure 1C) showed pathological uptake of 18-fluoro-deoxyglucose in the mass (arrow), extending along the inferior vena cava (arrowheads), suggesting a neoplastic nature. At cardiovascular magnetic resonance (Figure 1D and E; Supplementary data, Movie 3 and 4) the mass involved the right atrium (arrow) and extended into the inferior vena cava (arrowheads); moreover, it presented irregular contours and signal characteristics typical of a neoplastic mass,

How to take arms against central apneas in heart failure

ABSTRACT Introduction Despite being a risk mediator in several observational studies, central apneas are currently orphan of treatment in heart failure. After the neutral effects on survival of two randomized controlled trials (RCTs) based on the use of positive airway pressure (the CANPAP and SERVE-HF trials), two alternative hypotheses have been formulated: 1) Periodic breathing/Cheyne-Stokes respiration (PB/CSR) in HF is protective. Indeed, the Naughton’s hypothesis assumes that hyperventilation leads to increased cardiac output, lung volume, oxygen storage and reduced muscle sympathetic nerve activity, while central apnea to respiratory muscle rest and hypoxia-induced erythropoiesis. 2) The use of positive airway pressure is just a wrong treatment for PB/CSR. If this is the case, the search for novel potential alternative treatment approaches is mandatory in HF. Areas covered This review will focus on the crucial issue of whether PB/CSR should be treated or not in HF, first by outlining the ideal design of pathophysiological studies to test the Naughton’s hypothesis and second by summarizing the treatment strategies so far proposed for PB/CSR in HF and identifying the most promising options to be tested in future RCTs. Expert commentary It is likely that PB/CSR may be compensatory in some cases, but after a certain threshold (to be defined) it becomes maladaptive with negative prognostic meaning in HF. The development of a pathophysiologically based treatment targeting feedback resetting and neurohormonal activation underlying PB/CSR is likely to be the best option to obtain survival benefits in HF.

Peripheral reflex feedbacks in chronic heart failure: Is it time for a direct treatment?

Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure (HF), no single conceptual paradigm for HF has withstood the test of time. The last model that has been developed, the neurohormonal model, has the great virtue of highlighting the role of the heart as an endocrine organ, as well as to shed some light on the key role on HF progression of neurohormones and peripheral organs and tissues beyond the heart itself. However, while survival in clinical trials based on neurohormonal antagonist drugs has improved, HF currently remains a lethal condition. At the borders of the neurohormonal model of HF, a partially unexplored path trough the maze of HF pathophysiology is represented by the feedback systems. There are several evidences, from both animal studies and humans reports, that the deregulation of baro-, ergo- and chemo-reflexes in HF patients elicits autonomic imbalance associated with parasympathetic withdrawal and increased adrenergic drive to the heart, thus fundamentally contributing to the evolution of the disease. Hence, on top of guideline-recommended medical therapy, mainly based on neurohormonal antagonisms, all visceral feedbacks have been recently considered in HF patients as additional potential therapeutic targets.

Targeting and Treating Apneas

The way central apneas can be treated in heart failure will be addressed in this chapter, enumerating pro and contra of all treatment tools proposed up-to-date. First, the use of different kinds of noninvasive mechanical ventilation (continuous positive airway pressure, bi-level positive airway pressure, adaptive servo-assisted ventilation) will be described, addressing the apnea phenomenon directly, without an effect on triggers. Further, therapeutic strategies acting on hemodynamics and circulatory time (in particular current guideline-recommended drug/device therapy of heart failure), on apneic threshold (gas administration, acetazolamide), or respiratory centers (e.g., xanthine derivatives) will be discussed. We will finally focus on novel treatments acting straight on the chemoreflex system (carotid body denervation).

To Breathe, or Not to Breathe: That Is the Question

Central apnea and specifically Cheyne-Stokes respiration represents a very common phenomenon in the context of systolic heart failure (HF) and has been associated with several neurohormonal and hemodynamic alterations that connote a negative clinical profile that ultimately leads to adverse prognosis. However, the negative consequences of the treatments proposed so far to tackle this phenomenon have raised concerns about the real connotation of central apnea in the context of systolic HF, specifically, whether CSR represent a neutral phenomenon or even a compensatory one.