[ANMCO Position paper: Amyloidosis for the clinical cardiologist. A "clinical primer" from the ANMCO Rare Disease Working Group]. / Position paper ANMCO: L'amiloidosi per il cardiologo clinico. Un "clinical primer" dell'Area Malattie Rare ANMCO.

Cardiac amyloidosis, in the three forms of immunoglobulin light chain (AL), transthyretin (ATTR) wild type (ATTRwt) and mutated (ATTRv) amyloidosis, is an increasingly known and recognized disease in the cardiovascular setting. The first stage of the patient's journey is the clinical suspicion of the disease, which is placed, in presence of a hypertrophic phenotype, by the identification of red flags, both extracardiac and cardiac clues whose presence increase the probability of being faced with a patient with this disease. The second stage is represented by diagnosis, which occurs with certainty through the identification of amyloid substance in cardiac tissue. This stage is spotted in wo parts, i.e. disease confirmation and disease etiology definition (AL vs ATTRwt vs ATTRv). However, it is possible in some selected cases to make a diagnosis of ATTR without the need for tissue assessment, in presence of a positive grade 2-3 bisphosphonate scintigraphy and absence of monoclonal component. Once the diagnosis has been made, the third stage is the assessment of prognosis, the fourth is the patient therapy pathway and fifth is the follow-up plan. Prognosis evaluation is based on different staging systems at the onset of the disease, whose applicability in the era of new effective therapies is still to be defined. To date, the transthyretin tetramer stabilizer tafamidis is the only approved treatment for both wild-type and mutant ATTR cardiomyopathy without polyneuropathy, while ATTRv with associated neuropathy can benefit from treatment with patisiran, an inhibitor of hepatic protein synthesis. Therapies for complications and comorbidities, must be addressed individually, due to the lack of specific clinical trials on this category of patients. In fact, it is important to take into consideration the risks linked to the use of some drugs due to the infiltration of the conduction tissue by the amyloid substance, which increases the risk of bradycardia and heart blocks, the tendency towards hypotension and the increased thromboembolic risk. It is also essential to follow the course of the disease and the efficacy of the treatment in affected patients with a standardized follow-up, and to identify early the signs/symptoms of the disease in asymptomatic TTR mutation carriers.This ANMCO position paper on amyloidosis aims to provide the clinical cardiologist with a practical summary of the disease, to accompany the patient with amyloidosis in the various stages of his journey.

Reduction in heart failure hospitalization rate during coronavirus disease 19 pandemic outbreak.

AIMS: The recent coronavirus disease 19 (COVID-19) pandemic outbreak forced the adoption of restraint measures, which modified the hospital admission patterns for several diseases. The aim of the study is to investigate the rate of hospital admissions for heart failure (HF) during the early days of the COVID-19 outbreak in Italy, compared with a corresponding period during the previous year and an earlier period during the same year. METHODS AND RESULTS: We performed a retrospective analysis on HF admissions number at eight hospitals in Italy throughout the study period (21 February to 31 March 2020), compared with an inter-year period (21 February to 31 March 2019) and an intra-year period (1 January to 20 February 2020). The primary outcome was the overall rate of hospital admissions for HF. A total of 505 HF patients were included in this survey: 112 during the case period, 201 during intra-year period, and 192 during inter-year period. The mean admission rate during the case period was 2.80 admissions per day, significantly lower compared with intra-year period (3.94 admissions per day; incidence rate ratio, 0.71; 95% confidence interval [CI], 0.56-0.89; P = 0.0037), or with inter-year (4.92 admissions per day; incidence rate ratio, 0.57; 95% confidence interval, 0.45-0.72; P < 0.001). Patients admitted during study period were less frequently admitted in New York Heart Association (NYHA) Class II compared with inter-year period (P = 0.019). At covariance analysis NYHA class was significantly lower in patients admitted during inter-year control period, compared with patients admitted during case period (P = 0.014). CONCLUSIONS: Admissions for HF were significantly reduced during the lockdown due to the COVID-19 pandemic in Italy.

Prevalence and predictors of long corrected QT interval in HIV-positive patients: a multicenter study.

AIMS: HIV and highly active antiretroviral therapy (HAART) may affect cardiac conduction, and a higher incidence of sudden death has been recognized in HIV-positive patients. Nevertheless, predictors of prolonged corrected QT interval (cQT) have been poorly described. The aim of the study was to investigate the prevalence and predictors of long cQT in a cohort of HIV-positive patients. METHODS: Consecutive HIV-positive patients followed in a primary prevention clinic at two Italian institutions were retrospectively enrolled. A 12-lead ECG was recorded in all patients; main clinical features were collected. Prevalence of long cQT (defined as cQT >470 ms in women and >450 ms in men) was the primary end-point. Secondary end-points were the identification of predictors of cQT prolongation, and the association between HAART and HIV-related features with long cQT. RESULTS: Three hundred and fifty-one HIV-positive patients were included, 26 (7.4%) with long cQT. Mean age was higher among those with long cQT (51.6 vs. 57.6 years; P = 0.007). A higher prevalence of long cQT was reported for patients with a CD4+ cell count below 200 cells/µl at the moment of ECG (60 vs. 24.2%; P = 0.002) and with a nadir of CD4+ cell count below 200 cells/µl (91.3 vs. 58.6%; P = 0.001). At multivariate analysis, only the nadir of CD4+ cell count below 200 cells/µl consistently related to the presence of long cQT (odds ratio 5.8, 95% confidence interval 1.3-26.4). CONCLUSION: A low CD4+ cell count is associated with long cQT independently from HAART in HIV-positive patients and may be useful to correctly stratify arrhythmic risk in these patients.

HIV Infection and Primary Prevention of Cardiovascular Disease: Lights and Shadows in the HAART Era.

With the progressive increase in life-expectancy of human immunodeficiency virus (HIV)-positive patients in the "highly active antiretroviral therapy" (HAART) era, co-morbidities, particularly cardiovascular (CV) diseases (CVD) are emerging as an important concern. The pathophysiology of CVD in this population is complex, due to the interaction of classical CV risk factors, viral infection and the effects of antiretroviral therapy (ARV). The role of ARV drugs in HIV is double edged. While these drugs reduce systemic inflammation, an important factor in CV development, they may at the same time be proatherogenic by inducing dyslipidemia, body fat redistribution and insulin resistance. In these patients primary prevention is challenging, considering the lower median age at which acute coronary syndromes occur. Furthermore prevention is still limited by the lack of robust evidence-based, HIV-specific recommendations. Therefore we performed a comprehensive evaluation of the literature to analyze current knowledge on CVD prevalence in HIV-infected patients, traditional and HIV-specific risk factors and risk stratification, and to summarize the recommendations for primary prevention of CVD in this HIV population.

Comparative safety and efficacy of statins for primary prevention in human immunodeficiency virus-positive patients: a systematic review and meta-analysis.

The efficacy and safety of different statins for human immunodeficiency virus (HIV)-positive patients in the primary prevention setting remain to be established. In the present meta-analysis, 18 studies with 736 HIV-positive patients receiving combination antiretroviral therapy (cART) and treated with statins in the primary prevention setting were included (21.0% women, median age 44.1 years old). The primary endpoint was the effect of statin therapy on total cholesterol (TC) levels. Rosuvastatin 10 mg and atorvastatin 10 mg provided the largest reduction in TC levels [mean -1.67, 95% confidence interval (CI) (-1.99, -1.35) mmol/L; and mean -1.44, 95% CI (-1.85, -1.02) mmol/L, respectively]. Atorvastatin 80 mg and simvastatin 20 mg provided the largest reduction in low-density lipoprotein (LDL) [mean -2.10, 95% CI (-3.39, -0.81) mmol/L; and mean -1.57, 95% CI (-2.67, -0.47) mmol/L, respectively]. Pravastatin 10-20 mg [mean 0.24, 95% CI (0.10, 0.38) mmol/L] and atorvastatin 10 mg [mean 0.15, 95% CI (0.007, 0.23) mmol/L] had the largest increase in high-density lipoprotein, whereas atorvastatin 80 mg [mean -0.60, 95% CI (-1.09, -0.11) mmol/L] and simvastatin 20 mg [mean -0.61, 95% CI (-1.14, -0.08) mmol/L] had the largest reduction in triglycerides. The mean discontinuation rate was 0.12 per 100 person-years [95% CI (0.05, 0.20)], and was higher with atorvastatin 10 mg [26.5 per 100 person-years, 95% CI (-13.4, 64.7)]. Meta-regression revealed that nucleoside reverse transcriptase inhibitors-sparing regimens were associated with reduced efficacy for statin's ability to lower TC. Statin therapy significantly lowers plasma TC and LDL levels in HIV-positive patients and is associated with low rates of adverse events. Statins are effective and safe when dose-adjusted for drug-drug interactions with cART.

Supraventricular Arrhythmias in Patients With Pulmonary Arterial Hypertension.

The onset of supraventricular arrhythmias (SVA) may be associated with clinical worsening in patients with pulmonary arterial hypertension (PAH). However, limited data have been reported, especially at long-term follow-up. Aim of this study was to investigate the incidence of SVA in our patients with PAH, the risk factors correlated to their onset and the prognostic impact. All consecutive patients with PAH without history of SVA were enrolled. Incidence of new SVA was investigated and also the risk factors for SVA. Primary end point of the study was the impact of SVA on a composite of all-cause mortality and re-hospitalization, whereas mortality was the secondary end point. Seventy-seven patients were enrolled. No significant differences in the clinical or instrumental baseline characteristics between the 2 study groups were reported. During a median follow-up of 35 months (interquartile range 21.5 to 53.5), 17 (22%) patients experienced SVA. Development of SVA was associated with worsening of prognostic parameters at the follow-up: increasing of World Health Organization (WHO) functional class (p = 0.005) and N-terminal-pro-brain natriuretic peptide (NT-proBNP) (p = 0.018) and reduction of 6-minute walking distance (p = 0.048), tricuspid annular plane systolic excursion (TAPSE) (p = 0.041), and diffusing capacity of the lung for carbon monoxide (p = 0.025). The primary end point occurred in 13 patients (76%) in the SVA group and in 22 patients (37%) in the group without SVA (p = 0.004), whereas 9 patients (53%) among those with SVA died during the follow-up compared with 8 (13%) among those without (p = 0.001). At multivariate analysis, development of SVA was independently associated with an increased risk to meet the both primary (hazard ratio 2.13; 95% confidence interval 1.07 to 4.34; p = 0.031) and secondary (hazard ratio 4.1; 95% confidence interval 1.6 to 10.6; p = 0.004) end points. In conclusion, during the 3-year follow-up period, 1/3 of patients with PAH developed SVA, which was related to worsening of hemodynamic and functional parameter and independently predicted adverse prognosis.

High prevalence at computed coronary tomography of non-calcified plaques in asymptomatic HIV patients treated with HAART: a meta-analysis.

INTRODUCTION: Asymptomatic patients with human immunodeficiency virus (HIV) infection are at increased risk of vascular disease. Whether asymptomatic HIV patients have increased prevalence or structural differences in coronary artery plaques is not clear. METHODS: Pubmed, Cochrane and Google Scholar were searched for articles evaluating asymptomatic HIV patients evaluated with coronary computed tomography. The prevalence of coronary stenosis (defined as >30% and >50%), of calcified coronary plaques (CCP) viewed as more 'stable' plaques, and of non-calcified coronary plaques (NCP) viewed as more 'vulnerable' plaques were the end points of interest. RESULTS: 9 studies with 1229 HIV patients and 1029 controls were included. No significant differences were detected about baseline cardiovascular risk profile. The prevalence of significant coronary stenosis>30% or >50% did not differ between HIV+ and HIV- patients (42% [37-44] and 46% [35-52] with an Odds Ratio [OR] of 1.38 [0.86-2.20] for >30% stenosis) and (15% [9-21] and 14% [7-22] with an OR of 1.11 [0.81-1.52]), respectively. The prevalence of calcified coronary plaques (CCP) (31% [24-32] and 21% [14-30] with an OR of 1.17 [0.63-2.16]) also did not differ among HIV+ and HIV- patients. On the contrary rates of NCP were >3-fold higher in HIV-positive patients [58% (48-60) and 17% (14-27) with an OR of 3.26 (1-30-8.18)], with an inverse relationship with CD4 cell count at meta-regression (Beta -0.20 [-0.35-0.18], p 0.04). CONCLUSION: Asymptomatic HIV patients present a similar burden of coronary stenosis and calcified coronary artery plaques but significantly higher rates of non-calcific coronary plaques at computed tomography. The association between HIV infection, reduced CD4 cell counts and higher prevalence on non-calcific coronary artery plaques may shed light into the pathogenesis in HIV-associated coronary artery disease, stressing the importance of primary prevention in this population.

Heart failure in patients with human immunodeficiency virus: a review of the literature.

Coronary artery disease represents the leading cause of death for HIV patients treated with highly active antiretroviral treatment. Besides this, an extensive amount of data related to the risk of overt heart failure and consequently of atrial fibrillation and sudden cardiac death (SCD) in this population has been reported. It seems that persistent deregulation of immunity in HIV-infected patients is a common pathway related to both of these adverse clinical outcomes. Despite the fact that atrial fibrillation and heart failure are relatively common in HIV, few data are reported about screening, diagnosis, and potential treatment of these conditions.

Berberine behind the thriller of marked symptomatic bradycardia.

Patients with chronic aortic dissections are at high risk of catheter-induced complications. We report a Berberine is used in traditional Chinese medicine for the treatment of congestive heart failure, hypertension, diabetes, and dyslipidaemia and has a good safety profile. We report a case of a 53-year-old sportsman referred to our hospital for the onset of fatigue and dyspnoea upon exertion after he started berberine to treat hypercholesterolaemia. An electrocardiogram showed sinus bradycardia (45 bpm), first-degree atrioventricular block, and competitive junctional rhythm. An ergometric stress test showed slightly reduced chronotropic competence and the presence of runs of competitive junctional rhythm, atrial tachycardia, and sinus pauses in the recovery. After 10 d of wash-out from berberine, the patient experienced a complete resolution of symptoms, and an ergometric stress test showed good chronotropic competence. An electrocardiogram Holter showed a latent hypervagotonic state. This is the first case report that shows that berberine could present certain side effects in hypervagotonic people, even in the absence of a situation that could cause drug accumulation. Therefore, berberine's use should be carefully weighed in hypervagotonic people due to the drug's bradycardic and antiarrhythmic properties, which could became proarrhythmic, exposing patients to potential health risks.

Echo Doppler predictors of pulmonary artery hypertension in patients with systemic sclerosis.

OBJECTIVES: Evaluate echocardiographic predictors of pulmonary artery hypertension (PAH) in a prospective cohort of patients with systemic sclerosis (SSc). METHODS: 38 patients with SSc who did not have PAH and significant left heart disease, with peak tricuspid regurgitant velocity (TRV) ≤ 2.8 m/sec and systolic pulmonary artery pressure (sPAP) < 40 mmHg on echo Doppler were enrolled. Patients underwent: clinical assessment, NT-proBNP, and DLco measurements. Echo Doppler evaluation included right ventricular (RV) dimensions, tricuspid annular plan systolic excursion, fractional area change, tricuspid DTI systolic velocity, Tei index, pulmonary flow acceleration time (AcT), ratio of TRV to RV outflow tract time-velocity integral (TVI) and a parameter of disturbed RV ejection (TRV/AcT). After a planned 12-month follow-up we evaluated the predictive value of these parameters for the development of PAH, as demonstrated by right heart catheterization (RHC). Criteria for RHC were TRV ≥ 3 m/sec or sPAP ≥ 40 mmHg. RESULTS: Four patients developed PAH. Only TRV/TVI and TRV/AcT ratios significantly predicted PAH development (TRV/TVI ratio ≥ 0.16 [predefined and ROC confirmed]: OR 99, CI 95%: 4.865-2015, P = 0.004; TRV/AcT ratio ≥ 0.022 [predefined and ROC confirmed]: OR 12.68, CI 95% 1.163-379.3, P = 0.036). Both parameters showed a good diagnostic power (TRV/TVI ratio: ROC area 79%, sensitivity 75%, specificity 97% and diagnostic accuracy 94.74% for cutoff value of 0.16; TRV/AcT ratio: ROC area 75%, sensitivity 75%, specificity 71% and diagnostic accuracy 72% for cutoff value of 0.022). CONCLUSIONS: This prospective study identified increased values of the two ratios TRV/TVI and TRV/AcT as predictors of PAH in SSc.