Alessandro Valleggi

CHADS2 and CHA2DS2-VASc scores to predict morbidity and mortality in heart failure patients candidates to cardiac resynchronization therapy

AIMS CHADS2 and CHA2DS2-VASc scores are pivotal in assessing the risk of stroke in atrial fibrillation patients, and were recently proved to predict hospitalizations and mortality in specific clinical settings. Aim of this study was to evaluate whether these scores could predict clinical outcomes [first hospitalization for heart failure (HF) and a combined event of HF hospitalization and death for any cause] in patients candidates to cardiac resynchronization therapy and implantable defibrillator (CRT-D). METHODS AND RESULTS In a retrospective multicentre Italian study, we enrolled 559 consecutive HF patients candidates to CRT-D, and we grouped them in three pre-specified risk classes: low (CHADS2/CHA2DS2-VASc 1-2), moderate (CHADS2/CHA2DS2-VASc 3-4), and high (CHADS2 5-6/CHA2DS2-VASc 5-8). All patients underwent regular follow-up at implanting centres every 6 months; data collection was extended till the 72th month of follow-up. At a median FU of 30 months, 143 patients (25.4%) were hospitalized for HF and 110 (19.5%) died. Event-free survival analysis showed a significant difference according to baseline CHADS2 and CHA2DS2-VASc scores (Log-Rank for HF P < 0.001 for CHADS2 and CHA2DS2-VASc; Log-Rank for combined end-point P = 0.001 for CHADS2, P < 0.001 for CHA2DS2-VASc). At multivariate analysis, independent predictors of endpoints were: previous atrial fibrillation (AF) or AF at implant, NYHA class, QRS duration and the CHA2DS2-VASc score (for HF hospitalization P = 0.013; for the combined event, P = 0.007), while the CHADS2 score was not independently associated with either the end-points. CONCLUSION In CRT-D patients, pre-implant CHA2DS2-VASc score is an independent predictor of major clinical events at 30-month follow-up.

Concordant Versus Discordant Left Bundle Branch Block in Heart Failure Patients: Novel Clinical Value of an Old Electrocardiographic Diagnosis

BACKGROUND Over the last 50 years left bundle branch block (LBBB) has been defined as homophasic (concordant: cLBBB) or heterophasic (discordant: dLBBB) when associated with a positive or negative T wave in leads I and V5-V6, respectively. LBBB is recognized as an adverse prognostic factor in heart failure (HF). The prevalence and clinical significance of cLBBB and dLBBB in HF patients are unknown. METHODS AND RESULTS A total of 897 consecutive systolic HF patients (age 65 +/- 13 years, left ventricular ejection fraction [LVEF], 34 +/- 10%) underwent clinical characterization, electrocardiographic evaluation for LBBB diagnosis and classification, and follow-up for cardiac events (median 37 months, range 1-84). LBBB was diagnosed in 232 patients (26%), cLBBB in 71 (31%), and dLBBB in 161 (69%). The dLBBB patients were older than those with cLBBB, and presented with lower LVEF, greater left ventricular telediastolic diameter and left ventricular mass index, higher level of brain natriuretic peptide, N-terminal pro-brain natriuretic peptide, renin activity, and norepinephrine (all P < .05). At Kaplan-Meier analysis, LBBB (P = .003) and dLBBB (P = .036) were associated with a worse prognosis when the composite end point of sudden death and implantable cardioverter defibrillator shock was considered. CONCLUSIONS In systolic HF, dLBBB is associated with a worse clinical, neurohormonal, and prognostic profile. LBBB classification could represent a useful tool in routine clinical evaluation.

Statin intolerance in heterozygous familial hypercolesterolemia with cardiovascular disease: After PCSK-9 antibodies what else?

Background Familial hypercholesterolemia is the elective clinical condition that deserves the maximal personalisation in lipid-lowering therapy, especially in the presence of statin intolerance. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a promising approach to lower low-density lipoprotein (LDL) cholesterol. Methods We enrolled 18 patients (mean age 62 ± 8 years, 72% men) affected by heterozygous familial hypercholesterolemia and cardiovascular disease, with a history of statin intolerance assigned to PCSK9 inhibitors. Six patients were also on LDL apheresis. Associated Lp(a)-hyperlipoproteinemia (defined as >60 mg/dl) was observed in two out of 18 subjects. PCSK9 inhibitor injectable monoclonal antibodies were administered, every 2 weeks, on top of patient therapy for 12 ± 4 weeks (evolocumab in 15 subjects, alirocumab in three subjects). Results After 3 months (12 ± 4 weeks) of therapy, a decrease in total cholesterol (–35%), LDL cholesterol (–51%) and Lp(a) levels (–20%) was observed. Five out of 18 patients reached LDL cholesterol levels of <70 mg/dl, seven showed LDL cholesterol values between 71 and 100 mg/dl, and six out of 18 still had LDL cholesterol levels above 100 mg/dl. Among the six patients with LDL cholesterol levels >100 mg/dl, three were already on LDL apheresis before the PCSK9 inhibitor treatment, while three were referred to LDL apheresis treatment. Adverse events were reported in two out of 18 patients on evolocumab: one presented with flu-like syndrome and the other reported episodes of mild difficulty in maintaining concentration. Conclusions PCSK9 inhibitors represent a novel therapeutic tool for patients with familial hypercholesterolemia who are intolerant to statins. However, more data are needed before cleaning up the old therapeutic armamentarium, such as LDL apheresis, which is likely to preserve its valuable role also in the new lipid-lowering era.

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.

Glycosylated haemoglobin is associated with neurohormonal activation and poor outcome in chronic heart failure patients with mild left ventricular systolic dysfunction

Aims We aimed to evaluate the impact of glycometabolic imbalance as assessed by glycosylated haemoglobin [HbA(1c)] on neurohormonal activation and outcome in chronic heart failure (CHF). Methods and results Nine hundred and twenty CHF patients (65 ± 12 years, left ventricular ejection fraction 33 ± 10%, 29% diabetic patients) underwent a thorough humoral and clinical characterization, including HbA(1c), and were then followed up for the endpoint of cardiac death. In the whole population, diagnosis of diabetes resulted in no difference in neurohormonal or echocardiographic data, or in outcome. Conversely, the diabetic patients with HbA(1c) above 7% showed, in comparison to both diabetic patients with HbA(1c) below 7% and non-diabetic individuals, higher plasma renin activity (1.81, 0.48–5.68 vs. 1.23, 0.43–2.8 and 1.29, 0.44–5 ng/ml/h, respectively; P < 0.01 for both), N-terminal pro-brain natriuretic peptide (NT-pro-BNP) (1602, 826–3498 vs. 1022, 500–3543 and 1134, 455–3545 ng/l, respectively; P < 0.01 for both) and worse symptoms with a higher rate of cardiac mortality vs. both diabetic patients with HbA1(c) below 7% and non-diabetic individuals (P < 0.05 for both). In the left ventricular ejection fraction 38–50% tertile (mild left ventricular dysfunction), elevated HbA(1c) was associated with higher NT-pro-BNP and PRA (P < 0.01), and, alongside NT-pro-BNP, resulted the only independent predictor of outcome beyond diagnosis of diabetes. HbA(1c) failed to show up differences in neuroendocrine activation or in outcome in moderate and severe left ventricular dysfunction tertiles. Conclusion Glycometabolic imbalance, as represented by HbA(1c), is associated with neurohormonal activation and poor prognosis in CHF patients, beyond diabetes. The impact of metabolic derangement on prognosis appears greater at the early stages of CHF, when it might exacerbate neurohormonal activation.

NT-PROBNP PREDICTS MORTALITY IN ELDERLY AND VERY ELDERLY PATIENTS WITH CHRONIC SYSTOLIC HEART FAILURE

Heart failure (HF) prevalence among elderly will boost in the near future. NT-proBNP is a powerful diagnostic and prognostic biomarker in HF, despite its circulating concentrations are influenced by age and comorbidities (in particular renal dysfunction) which are more frequent with advanced age.

NT-proBNP prognostic value is maintained in elderly and very elderly patients with chronic systolic heart failure

BACKGROUND Circulating concentrations of N-terminal fragment of the prohormone of brain natriuretic peptide (NT-proBNP) are influenced by age and common age-related comorbidities, such as renal dysfunction. Therefore, utility of NT-proBNP for prediction of prognosis in the aged has been questioned. We aimed to investigate the prognostic value of NT-proBNP across age classes in a cohort of patients with chronic systolic HF. METHODS AND RESULTS We enrolled 2364 consecutive outpatients with HF and left ventricular ejection fraction ≤50%. Patients were classified according to age quartiles, and a very elderly subgroup was identified, aged ≥85 years. After baseline assessment (including NT-proBNP testing), patients were followed-up for the composite of cardiovascular death, heart transplantation or ventricular assistance device implantation (primary outcome) and for all-cause death (secondary outcome). Patients in the fourth quartile (Q4, age ≥ 77 years, n = 638) and in the very elderly subgroup (age ≥ 85 years, n = 153), had higher NT-proBNP (p < .001 vs Q1). NT-proBNP was independently associated with primary and secondary outcome at 1- and 5-years follow-up in the whole population, as well as in Q4 and in the very elderly subgroup (all p < .05). Compared to the whole population, Q4 and very elderly had higher NT-proBNP cut-off for prediction of 1-year primary (4188 and 9729 ng/l, respectively vs 3710 ng/l) and secondary outcome (4296 and 7634 ng/l, respectively vs 3056 ng/l). CONCLUSIONS NT-proBNP predicts mortality in elderly and very elderly patients with chronic systolic HF, both at mid- and long-term follow-up. Higher NT-proBNP prognostic cut-off should be considered in the aged HF population.

PROGNOSTIC IMPACT OF DISCORDANT VERSUS CONCORDANT LEFT BUNDLE BRANCH BLOCK IN HEART FAILURE PATIENTS UNDERGOING CARDIAC RESYNCHRONIZATION THERAPY

Background: Left bundle branch block (LBBB) is a frequent observation in heart failure (HF) patients, and is recognized as both an adverse prognostic factor and a key-element for referring patients to cardiac resynchronization therapy (CRT). It has been previously defined as concordant (cLBBB) or discordant (dLBBB) when associated with a positive or negative T wave in leads I and V5-V6, respectively. Recently, dLBBB has been shown to be associated with a worse clinical, neurohormonal, and prognostic profile in systolic HF patients. Our aim was to evaluate the impact of CRT on the prognostic value of LBBB morphology in a population of systolic HF.

Modern diagnostic and therapeutical approach to cardiac AL amyloidosis and neuroendocrine model of heart failure: lessons from a clinical case.

Although cardiac amyloidosis secondary to monoclonal light chain deposition (AL amyloidosis) is one common cause of diastolic heart failure, current therapeutical approach, including mostly diuretics, is outdated, referring to the old-fashioned cardiorenal model, and disregarding the more recent neurohormonal model of heart failure. However, being the body response to reduced cardiac output stereotyped, it is likely that the overall neurohormonal activation, including adrenergic, renin-angiotensin-aldosterone systems and cardiac endocrine response, would be present even in the setting of an amyloid heart. Although, on the one hand, the hematologic treatment is fundamental to achieve disease remission in cardiac amyloidosis, on the other hand a more modern and pathophysiologically based cardiologic strategy is needed, to reduce the risk of arrhythmias and progression to systolic heart failure. We will discuss this, analyzing the case of a patient with overt (diastolic) heart failure and cardiac AL amyloidosis developed after multiple myeloma, followed-up on a 16-month period. Introduction: Systemic AL amyloidosis is the most common form of amyloid disease in developed countries. The AL fibrils are derived from monoclonal immunoglobulin light chains produced by almost every type of B-cell dyscrasia, including myeloma, macroglobulinemia, lymphomas, and ‘benign’ monoclonal gammopathies [1,2]. The heart is affected in up to 60% of AL patients, and in 50% symptoms and physical signs of heart failure are a presenting feature, with initial involvement of left ventricular (LV) diastolic function, and subsequent impairment of LV systolic and right heart function [1]. Although diastolic heart failure is the main clinical feature of AL amyloidosis, the cardiologic treatment strategy currently applied, is mainly aimed to treatment of fluid overload causing dyspnea, edemas, pleural and pericardial effusions, through diuretics in accordance with the cardiorenal model [3]. Paradoxically, neither diastolic dysfunction nor the subsequent neurohormonal activation, obvious therapeutical targets in current Guidelines for the management of heart failure [4] are usually taken into account. Indeed, as recently stated, ‘the mainstay of the treatment of heart failure in AL amyloidosis is the use of diuretics’, while ‘there are no data on the use of beta-blockers’ and ‘vasoactive drugs, including angiotensin-converting enzyme inhibitors and angiotensin II inhibitors, should be used with caution in cardiac amyloidosis because even small doses may cause profound hypotension.’ [1] However, the low number of studies investigating the potentiality of a modern therapeutic approach based on neurohormonal antagonism in cardiac AL amyloidosis, limits the validity to this therapeutical behavior to common (and timorous) sense, without evidence-based indications, mirroring the approach in use for heart failure before the advent of the neurohormonal era, in which, for instance, a modern treatment cornerstone as beta-blockers were nothing short of contraindicated [5]. We will discuss the potential of a ‘pathophysiological’ neurohormonal approach to the evaluation of clinical status and therapeutical decision-making, analyzing the case of a patient with overt heart failure and cardiac AL amyloidosis developed after multiple myeloma, followed-up on a 16-month period in our institution. Case report: A 52-year-old male patient, who had been elsewhere previously diagnosed as ‘angina pectoris with normal coronary arteries’ after the onset of chest discomfort on effort in 2007, was then referred to our institution in 2008 because of dyspnea (NYHA class III) and edema, and finally diagnosed with cardiac AL amyloidosis. An echocardiographic pattern of pseudo-hypertrophy (left ventricular ejection fraction: 55%; restrictive diastolic pattern with E/E’ of 22; interventricular septum thickness: 15 mm, posterior wall thickness: 14 mm, LV mass index 130 g/m, date: August 2008) had been overlooked, because of history of border-line hypertension. Search for repeat elevation of troponin and NT-proBNP level, despite normal systolic function, as well as confirmation of ventricular hypertrophy and disclosure of diastolic LV dysfunction, led to magnetic resonance imaging, where a typical amyloidotic pattern was found (concentric wall thickening, pleural-pericardial effusion, and biventricular/biatrial gadolinium late enhancement at both subendocardium and subepicardium level) [6]. The suspicion of cardiac amyloidosis was confirmed by monoclonal lambda chains at urinary immunofixation and multiple myeloma histology at 124