Sacubitril/valsartan effects on arrhythmias and left ventricular remodelling in heart failure: An observational study.

AIMS: Conflicting results have been reported in the literature on the potential antiarrhythmic effect of sacubitril/valsartan in heart failure patients with reduced ejection fraction (HFrEF). The objectives of this study were: 1- to evaluate the long term effects of sacubitril/valsartan on arrhythmic burden in HFrEF patients; 2- to evaluate the correlation between the reduction of premature ventricular complexes during f-up and reverse remodelling. METHODS: We identified 255 consecutive HFrEF patients treated with sacubitril/valsartan between March 2017 and May 2020 and followed by the Heart Failure and Cardiac Transplant Unit of IRCCS San Matteo Hospital in Pavia (Italy). Within this subgroup, 153 patients underwent 24 h-Holter-ECG or implantable cardioverter defibrillators (ICD) interrogation at baseline, at 12 months (t1) and at 24 months (t2) and transthoracic echocardiography at baseline and after 12 months after the beginning of sacubitril/valsartan. Cardiac-related hospitalizations were analyzed in the 12 months preceding and during 24 months following the drug starting date. RESULTS: Global burden of 24-h premature ventricular complexes (PVC) was significantly reduced at 12 months (t1) and at 24 months (t2) as compared to the same period before treatment (1043 [304-3360] vs 768 [82-2784] at t1 vs 114 [9-333] at t2, P = 0.000). In the subgroup of patients implanted with biventricular ICD (n = 30), the percentage of biventricular pacing increased significantly (96% [94-99] vs 98% [96-99] at t1 vs 98%[97-100] at t2; P = 0.027). The burden of non-sustained ventricular tachycardia and sustained ventricular tachycardia did not change from baseline to t1 and t2, but a reduction of patients with at least one ICD appropriate shock was reported. The correlations between reduction in 24 h PVC and reduction in LV-ESVi or improvement in LVEF were not statistically significant (respectively R = 0.144, P = 0.197 and R = -0.190, P = 0.074). Heart failure related hospitalizations decreased during follow up (11.1% in the year before treatment vs 4.6% at t1 and 4.6% at t2; P = 0.040). CONCLUSION: Sacubitril/valsartan reduced the number of premature ventricular complexes and increased the percentage of biventricular pacing in a cohort of HFrEF patients already on optimal medical therapy. PVC reduction did not correlate with reverse left ventricular remodelling. Whether sacubitril/valsartan has any direct antiarrhythmic effects is an issue to be better explored in future studies.

Hypertrophic Cardiomyopathy and Atrial Fibrillation: A Systematic Review and Meta-analysis of Anticoagulation Strategy.

BACKGROUND: Atrial fibrillation (AF) frequently complicates hypertrophic cardiomyopathy (HCM), and anticoagulation significantly decreases the risk of stroke in this population. To date, no randomized controlled trials (RCTs) have compared direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs). The present study aimed to systematically compare the two anticoagulation strategies in terms of effectiveness and safety. METHOD: We performed a systematic literature search and meta-analysis in the PubMed, MEDLINE, and EMBASE databases for studies reporting all-cause mortality, major bleeding, or thromboembolic events (TEs). Since no RCTs were available, we included observational studies only. The overall hazard ratio (HR) and 95% confidence interval (CI) for each analyzed parameter were pooled using a random-effects model. RESULTS: Five observational studies including 6919 patients were eligible for inclusion. Compared with VKAs, DOACs were associated with statistically significant lower rates of all-cause mortality (HR 0.64, 95% CI 0.35-0.54; p < 0.00001), comparable major bleeding events (HR 0.64, 95% CI 0.40-1.03; p = 0.07), and TEs (HR 0.94, 95% CI 0.73-1.22; p = 0.65). CONCLUSIONS: Compared with VKAs, a DOAC-based strategy might represent an effective and safe strategy regarding all-cause mortality, major/life-threatening bleeding complications, and TEs in HCM patients with concomitant AF. However, further prospective studies are necessary to reinforce a DOAC-based anticoagulation strategy in this population.

Role of cardiac magnetic resonance in the differential diagnosis between arrhythmogenic cardiomyopathy with left ventricular involvement and previous infectious myocarditis.

AIMS: Arrhythmogenic cardiomyopathy with left ventricular involvement (ACM-LV), particularly in case of isolated left ventricular involvement (i.e. left dominant arrhythmogenic cardiomyopathy, LDAC) and previous infectious myocarditis (pIM) may have overlapping clinical and cardiac magnetic resonance (CMR) features. To date, there are no validated CMR criteria for the differential diagnosis between these conditions. The present study aimed to identify CMR characteristics to distinguish ACM-LV from pIM. METHODS AND RESULTS: This observational, retrospective, single-centre study included 30 pIM patients and 30 ACM-LV patients. In ACM-LV patients CMR was performed at diagnosis; in patients with pIM, CMR was performed six months after acute infection. CMR analysis included quantitative assessment of left ventricle (LV) volumes, systolic function and wall thicknesses, qualitative and quantitative assessment of late gadolinium enhancement (LGE) sequences. Compared with pIM, ACM-LV patients showed slightly larger LV volumes, more frequent regional wall motion anomalies and reduced wall thicknesses. ACM-LV patients had higher amounts of LV LGE and extension. Notably, the LDAC subgroup had the highest amount of LV LGE. LV LGE amount > 15 g and a LV LGE percentage > 30% of LV mass discriminated ACM-LV from pIM with a 100% specificity. LGE segmental distribution was superimposable among the groups, except for septal segments that were more frequently involved in ACM-LV and LDAC patients. CONCLUSIONS: A great extension of LV LGE (a cut-off of LGE >15 g and a percentage above 30% of LV LGE in relation to total myocardial mass) discriminates ACM-LV from pIM with extremely high specificity.

Prognostic value of TAPSE after therapy optimisation in patients with pulmonary arterial hypertension is independent of the haemodynamic effects of therapy.

OBJECTIVE: To evaluate the prognostic significance of right ventricular function assessed by echocardiography after start or escalation of targeted therapy in patients with pulmonary arterial hypertension. STUDY DESIGN: longitudinal study. SETTING: tertiary referral centre for pulmonary hypertension. PATIENTS: 81 consecutive patients with pulmonary arterial hypertension (33 naive and 48 prevalent). INTERVENTIONS: right heart catheterisation and echocardiography performed prior to starting or escalating targeted therapy and repeated in 55 patients after 4-12 months of therapy. MAIN OUTCOME MEASURE: survival after follow-up examinations. RESULTS: 11 patients died and 7 were lost to follow-up during the first year; 8 patients underwent first follow-up evaluation beyond 1 year. 55 patients were re-evaluated after therapy; during the subsequent follow-up period of 25 months, 9 patients died, 7 worsened from WHO I/II to III/IV and 15 remained in WHO III/IV despite therapy. A baseline tricuspid annular plane systolic excursion (TAPSE) ≥15 mm was associated with a lower risk of death (HR=0.32; 95% CI 0.12 to 0.83, p=0.012). Attaining a TAPSE≥15 mm after therapy was associated with a significantly lower risk of death or clinical worsening (HR=0.2; 95% CI 0.1 to 0.6, p=0.002) and a lower risk of death which approached statistical significance (HR=0.3; 95% CI 0.2 to 1.1, p=0.075). Per cent changes in TAPSE were loosely related to changes in pulmonary vascular resistances after therapy (R=0.37). CONCLUSIONS: In patients with pulmonary arterial hypertension, the evaluation of right ventricular function by TAPSE after targeted therapy is useful to predict subsequent prognosis, regardless of the haemodynamic effects of therapy.

Pulmonary arterial compliance: How and why should we measure it?

The pulmonary circulation is a high-flow/low-pressure system, coupled with a flow generator chamber-the right ventricle-, which is relatively unable to tolerate increases in afterload. A right heart catheterization, using a fluid-filled, balloon-tipped Swan-Ganz catheter allows the measurement of all hemodynamic parameters characterizing the pulmonary circulation: the inflow pressure, an acceptable estimate the outflow pressure, and the pulmonary blood flow. However, the study of the pulmonary circulation as a continuous flow system is an oversimplification and a thorough evaluation of the pulmonary circulation requires a correct understanding of the load that the pulmonary vascular bed imposes on the right ventricle, which includes static and dynamic components. This is critical to assess the prognosis of patients with pulmonary hypertension or with heart failure. Pulmonary compliance is a measure of arterial distensibility and, either alone or in combination with pulmonary vascular resistance, gives clinicians the possibility of a good prognostic stratification of patients with heart failure or with pulmonary hypertension. The measurement of pulmonary arterial compliance should be included in the routine clinical evaluation of such patients.

Relationship between sRAGE and eotaxin-3 with CRP in hypertensive patients at high cardiovascular risk.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in Western countries and is highly prevalent in patients with kidney disease. Traditional risk factors for CVD often accompany kidney dysfunction, and chronic kidney disease per se is considered an additional risk factor. Risk stratification for CVD remains suboptimal even after the introduction of global risk assessment by various scores. This has prompted the search for novel markers of cardiovascular risk, and several biomarkers have been suggested as candidates, together with C-reactive protein (CRP). The objective of the present study was to investigate the relationship between novel biomarkers of vascular inflammation (soluble form of the receptor for advanced glycation end products [sRAGE] and eotaxin-3) with CRP in a population of hypertensive patients at high cardiovascular risk. METHODS: Plasma sRAGE, high-sensitivity CRP (hs-CRP) and eotaxin-3 were measured in 399 hypertensive patients (265 men, mean age 58 ± 8 years)with diabetes mellitus, metabolic syndrome or organ damage. RESULTS: Plasma concentrations of sRAGE, eotaxin-3 and hs-CRP were not different between diabetic and nondiabetic subjects. Univariate analysis showed that plasma levels of sRAGE and eotaxin-3 were not associated with hs-CRP in either subgroup. CONCLUSION: Our study confirms the robust and widely studied role of CRP as an important marker of vascular inflammation. We also postulate the possible involvement of sRAGE and eotaxin, 2 novel biomarkers, in CVDs. On the basis of our results, we can put forward the hypotheses that hs-CRP, s-RAGE and eotaxin are reliable but unrelated cardiovascular risk markers.

Microalbuminuria and sRAGE in high-risk hypertensive patients treated with nifedipine/telmisartan combination treatment: a substudy of TALENT.

Some antihypertensive drugs have also renoprotective and anti-inflammatory properties that go beyond their effect on blood pressure. It has been suggested that microalbuminuria and glomerular filtration rate (GFR) are associated with circulating levels of the soluble form of the receptor, sRAGE (soluble receptor for advanced glycation ends-products). In the present analysis, we used data from the TALENT study to evaluate soluble receptor for advanced glycation end-products (sRAGE) plasma levels in patients with hypertension and high-cardiovascular risk-treated nifedipine and telmisartan in combination. Treatment with nifedipine-telmisartan significantly decreased mean systolic and diastolic ambulatory blood pressure and resulted in a significant increase in sRAGE plasma concentrations after 24 weeks of therapy. We concluded that in hypertensive patients with early-stage renal disease, sRAGE concentrations are not influenced by either microalbuminuria or GFR. Long-term treatment with a combination of nifedipine-telmisartan may have a beneficial effect increasing sRAGE plasma levels, thus exerting an atheroprotective and anti-inflammatory activity.

APJ polymorphisms in coronary artery disease patients with and without hypertension.

Apelin is an endogenous peptide that increases cardiac inotropism through its APJ receptor. Certain findings indicate that the apelinergic system may have a pathophysiological role in cardiovascular disease and there is evidence showing the role of the apelinergic system in blood pressure regulation in vitro and in animal models. The role of the apelin-APJ system in cardiovascular physiology and its interaction with other neuroendocrine pathways has not been fully elucidated. However, the small number of reported studies indicates that apelin signaling may be involved in the regulation of blood pressure, cardiac contractile function, fluid balance, angiogenesis and inhibition of apoptosis. We evaluated the possible relationship between the G212A and A445C APJ polymorphisms and coronary artery disease (CAD) in Italian patients and in healthy controls by RFLP-PCR. We analyzed the allelic and genotypic frequencies of APJ polymorphisms in 664 patients (378 with hypertension) and 143 controls. There were no differences between allelic and genotypic frequencies in patients in respect to the controls for both polymorphisms analyzed. In the CAD population, there was an increased frequency of the G212 allele in patients with hypertension in respect to patients without hypertension. No differences were present in the two subgroups for the A445C polymorphism. Although the functional role of the G212A polymorphism has not yet been identified, it is possible to hypothesize that the presence of the A allele may cause a gain in function of the apelin/APJ system associated with a lower risk of hypertension.

Age of onset of myocardial infarction: is promoter polymorphism of the RAGE gene implicated?

Receptor for advanced glycation endproducts (RAGE) is a cell-surface molecule member of the immunoglobulin superfamily and engages differing ligands relevant to distinct processes. A growing body of evidence has suggested that RAGE may promote vascular inflammation through several mechanisms. The objective of this study was to identify the possible relationship between the -374 T/A polymorphism of the RAGE gene, myocardial infarction (MI), and its age of onset. A total of 691 MI patients and 234 matched controls were investigated. In this study, the frequency of the A allele and AA genotype of the -374 T/A promoter polymorphism is significantly lower in patients with MI respect to the control group (p < 0.01). Our results showed a significant role of the AA genotype on age of onset of MI. In particular, the mean age of the first MI was higher in patients with the AA genotype as compared to those that were AT or TT genotype carriers (p = 0.002). The relationship between -374 T/A RAGE polymorphism and age for the appearance of MI was independently related to common risk factors of disease (p < 0.01). Kaplan-Meier curves confirmed that subjects with the AA genotype have a later development of MI (p = 0.0022). This study is the first to investigate the role of RAGE polymorphisms on the susceptibility to develop the acute coronary events in the Italian population and identified this polymorphism as an age-related factor for MI development. The homozygous AA genotype may exert a protective role against the early development of MI.

Coronary artery disease and depression: possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms.

Cardiovascular disease (CVD) and depression are two of the most common human health problems. Patients with depression have an increased risk of developing cardiovascular disease and mortality after experiencing a cardiac event. Both diseases are complex disorders that are influenced by genetic and environmental factors. Brain-derived neuro-trophic factor (BDNF) plays a critical role in regulating both vascular development and response to injury, and promotes survival, differentiation, and maintenance of neurons in the peripheral and nervous system. Evidence suggests that BDNF can enhance serotoninergic transmission. Serotonin modulates different brain functions and is known to regulate sleep, appetite, pain and inflammation. The aims of the present case-control study were to investigate the possible role of BDNF Val66Met, 5-HTTLPR and -1438 G/A polymorphisms in the development of coronary artery disease (CAD) in patients with and without depression. Regarding BDNF, our data suggest an involvement of the AA genotype in the pathogenesis of CAD in females and in the predisposition to CAD associated with depression. Furthermore, it could be argued that the GG genotype is protective against CAD in the female population and against CAD associated with depression. In our CAD population we also observed a significant increase in the L/L genotype and a decrease in the S/L genotype with respect to the controls. A higher frequency of the L allele, responsible for enhancing the efficiency of transcription, was found in CAD patients. These findings may be responsible for the increased capacity of platelet serotonin uptake previously observed in patients with CAD. Although no differences were found for genotype and allelic frequencies of the -1438 G/A polymorphism between the CAD patients and controls, we cannot exclude the possible role of this receptor in coronary artery disease.

CR1 genotype and haplotype involvement in coronary artery disease: the pivotal role of hypertension and dyslipidemia.

Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and coronary syndromes. Atherosclerosis is a complex multifactorial disorder. Data indicate that the complement proteins play a crucial role in the link between inflammation and atherogenesis. Thus, there is evidence supporting the role of complement activation in atherogenesis. Complement receptor 1 (CR1) is a membrane protein found on different cells involved in various activities of the complement system. We demonstrated the possible involvement of CR1 in atherosclerosis studying the allele and genotype frequencies of the CR1 Pro1827Arg, CR1 His1208Arg exon 22 and int27 HindIII polymorphisms in a sample of patients with angiographically documented coronary artery disease (CAD) (n=550) and in healthy controls (n=380) matched for age, gender and ethnicity. Our data showed no significant deviations between the two groups with regard to either allele or genotype frequencies. After stratification according to risk factors, our analysis revealed a reduced frequency of the GG genotype of the Pro1827Arg polymorphism in patients with CAD and dyslipidemia vs the controls (p=0.031) and of the GG and LL genotypes in CAD patients with dyslipidemia vs CAD patients without dyslipidemia regarding the Pro1827Arg and CR1 HindIII intron 27 polymorphisms (GG, p=0.019; LL, p=0.184). We analyzed the haplotype frequencies of CR1. A decrease in CAD patients carrying the CAC haplotype compared to controls (p=0.043) and a decrease in the CAC haplotype in CAD patients with hypertension vs healthy controls (p=0.029) were demonstrated. Our data showed a possible involvement of CR1 gene polymorphisms in the predisposition to the development of this disease.