ANMCO position paper on vericiguat use in heart failure: from evidence to place in therapy.

In the growing therapeutic armamentarium for heart failure (HF) management, vericiguat represents an innovative therapeutic option. The biological target of this drug is different from that of other drugs for HF. Indeed, vericiguat does not inhibit neuro-hormonal systems overactivated in HF or sodium-glucose co-transporter 2 but stimulates the biological pathway of nitric oxide and cyclic guanosine monophosphate, which is impaired in patients with HF. Vericiguat has recently been approved by international and national regulatory authorities for the treatment of patients with HF and reduced ejection fraction who are symptomatic despite optimal medical therapy and have worsening HF. This ANMCO position paper summarises key aspects of vericiguat mechanism of action and provides a review of available clinical evidence. Furthermore, this document reports use indications based on international guideline recommendations and local regulatory authority approval at the time of writing.

Tako-Tsubo syndrome in patients with COVID-19: a single centre retrospective case series.

Growing evidence shows that COVID-19 is associated with an increase in Tako-Tsubo syndrome (TTS) incidence. We collected data from patients hospitalized in our multidisciplinary COVID-19 department who had a diagnosis of TTS during the second and third wave of the pandemic in Italy. We reported four cases of TTS associated with COVID-19. No patient had any classical trigger for TTS except for COVID-19. Mean age was 72 years (67-81) and all patients had a SARS-CoV-2-related interstitial pneumonia confirmed by computed tomography. Typical apical ballooning and transitory reduction in left ventricle (LV) systolic function with a complete recovery before discharge were observed in all patients. The mean LV ejection fraction (LVEF) at TTS onset was 42% (40-48%). ECG showed ST-segment elevation in two cases, while an evolution with negative T waves and QTc prolongation was observed in all patients. Three patients underwent coronary angiography. Two patients had Alzheimer's disease. The time interval from hospital admission to TTS onset was 4 (2-6) days, and the time interval from COVID-19 symptom onset to TTS diagnosis was 10 (8-12) days.  COVID-19 may be a trigger for TTS, though TTS pathophysiology in COVID-19 patients remains unclear, likely due to its multifactorial nature.

Transfemoral approach with systematic use of FemoSeal™ closure device compared to transradial approach in primary angioplasty.

OBJECTIVES: To compare the incidence of major adverse cardiac and cerebrovascular events (MACCE) and thrombolysis in myocardial infarction (TIMI) bleedings in primary percutaneous coronary intervention (pPCI) performed through transradial approach (TRA) or transfemoral approach (TFA) with systematic closure by FemoSeal™. BACKGROUND: Although the risk of bleeding can be reduced using vascular closure devices (VCD), there are few data comparing TRA and TFA with VCD, particularly in the setting of pPCI. METHODS: we included in this retrospective registry 777 patients who underwent pPCI at two centers from years 2010 to 2013. Exclusion criteria were implantation of intra-aortic balloon pump and achievement of femoral hemostasis by other means than FemoSeal™. We performed propensity-score matching and multivariate analysis to adjust for clinical and procedural confounders. RESULTS: We enrolled 511 patients in TRA group and 266 in TFA group. Both in the general population and in the propensity-matched population, the incidence of MACCE was comparable in TRA vs. TFA patients (3.5 vs. 3.4% and 4.4 vs. 2.6%, respectively; P = ns). On the contrary, we observed a higher incidence of TIMI bleedings in TFA vs. TRA patients (5.6 vs. 2.2% in the general population and 6.6 vs. 1.3% in the propensity-matched population; P < 0.05); this difference was mainly driven by TIMI major bleedings. TFA was an independent predictor of bleeding at multivariate analysis. CONCLUSIONS: In pPCI the rate of TIMI major bleedings was higher in TFA with closure by FemoSeal™ as compared to TRA, whereas the rates of minor bleedings and of MACCE were similar.

[Dual pathway inhibition in peripheral arterial disease]. / "Dual pathway inhibition" nell'arteriopatia periferica.

Despite its high worldwide prevalence and the intuitable negative prognostic connotation, for a long time peripheral artery disease (PAD) has not been the subject of particular interest by the cardiac scientific community. The availability of a new therapeutic strategy (low-dose rivaroxaban associated with acetylsalicylic acid) has reignited interest in PAD. The clear evidence derived from the COMPASS and VOYAGER PAD trials, with the possibility of using dual pathway inhibition, has given new energy to the therapeutic front against symptomatic PAD also associated with coronary artery disease. This review article aims to revisit the pathophysiological concepts underlying PAD and the path of the various clinical trials that have led to new scientific evidence.

The direct renin inhibitor aliskiren improves vascular remodelling in transgenic rats harbouring human renin and angiotensinogen genes.

In the present study, we tested the hypothesis that chronic treatment with the direct rennin inhibitor aliskiren improves the remodelling of resistance arteries in dTGR (double-transgenic rats). dTGR (5 weeks) were treated with aliskiren (3 mg/kg of body mass per day) or ramipril (1 mg/kg of body mass per day) for 14 days and compared with age-matched vehicle-treated dTGR. BP (blood pressure) was similarly reduced in both aliskiren-treated and ramipril-treated rats compared with control dTGR (167±1 and 169±2 mmHg compared with 197±4 mmHg respectively; P<0.05). The M/L (media-to-lumen) ratio assessed on pressurized preparations was equally reduced in aliskiren-treated and ramipril-treated rats compared with controls (6.3±0.5 and 6.4±0.2% compared with 9.8±0.4% respectively; P<0.05). Endothelium-dependent and -independent relaxations were similar among the groups. L-NAME (N(G)-nitro-L-arginine methyl ester) significantly reduced acetylcholine-induced dilation in drug-treated dTGR. This effect was significantly more prominent in aliskiren-treated rats. eNOS (endothelial NO synthase) expression showed a 2-fold increase only in aliskiren-treated dTGR as compared with controls (P<0.01) and ramipril-treated dTGR (P<0.05). Plasma nitrite, as an index of NO production, was significantly increased in dTGR treated with either aliskiren or ramipril compared with controls. Only aliskiren induced a 2-fold increase in plasma nitrite, which was significantly greater than that induced by ramipril (P<0.05). gp91(phox) expression and ROS (reactive oxygen species) production in aorta were significantly and similarly reduced by both drugs. In conclusion, equieffective hypotensive doses of aliskiren or ramipril reduced the M/L ratio of mesenteric arteries and improved oxidative stress in dTGR. However, only aliskiren increased further NO production in the vasculature. Hence, in dTGR, direct renin inhibition induces favourable effects similar to that induced by ACE (angiotensin-converting enzyme) inhibition in improving vascular remodelling through different mechanisms.

The polypill strategy in cardiovascular disease prevention: It's time for its implementation.

A polypill strategy has been demonstrated to improve treatment adherence in several cardiovascular disease (CVD) settings. However, data on the prognostic impact in the secondary prevention setting have been scarce. The Secondary Prevention of Cardiovascular Disease in the Elderly trial, the results of which have been recently published, has demonstrated a benefit in terms of major adverse CVD event reduction. This finding, in addition to previous evidence, should lead to a broader polypill implementation in CVD prevention.

[ANMCO Position paper: Vericiguat use in heart failure: from evidence to place in therapy]. / Position paper ANMCO: Impiego di vericiguat nello scompenso cardiaco: dalle evidenze al posizionamento terapeutico.

In the growing therapeutic armamentarium for heart failure management, vericiguat represents an innovative therapeutic option. The biological target of this drug is different from that of other drugs for heart failure. Indeed, vericiguat does not inhibit neurohormonal systems overactivated in heart failure or sodium-glucose cotransporter 2 but stimulates the biological pathway of nitric oxide and cyclic guanosine monophosphate, which is impaired in patients with heart failure. Vericiguat has recently been approved by international and national regulatory authorities for the treatment of patients with heart failure and reduced ejection fraction who are symptomatic despite optimal medical therapy and have worsening heart failure. This ANMCO position paper summarizes key aspects of vericiguat mechanism of action and provides a review of available clinical evidence. Furthermore, this document reports use indications based on international guideline recommendations and local regulatory authority approval at the time of writing.

[ANMCO Expert opinion: Bempedoic acid place in therapy for hypercholesterolemia management]. / ANMCO Expert opinion: Posizionamento terapeutico dell'acido bempedoico nel trattamento dell'ipercolesterolemia.

Growing evidence supporting the central role of hypercholesterolemia in atherosclerotic disease pathogenesis and progression has led to the development of new therapeutic approaches. Bempedoic acid has recently been approved for marketing following several studies that demonstrated its efficacy and safety. This drug represents a new therapeutic option that, like statins, acts on the enzymatic cascade that is involved in cholesterol synthesis. However, its hepatic selectivity of action reduces the risk of muscle adverse effects. This ANMCO document highlights clinical settings in which bempedoic acid represents a particularly useful therapeutic option. Furthermore, the document discusses the possibilities of use based on both international recommendations and current national regulations. Finally, we report practical guidance on hypercholesterolemia management in light of the available therapeutic armamentarium.

Bridging the gap in the symptomatic heart failure patient journey: insights from the Italian scenario.

BACKGROUND: The prognosis for heart failure (HF) patients remains poor, with a high mortality rate, and a marked reduction in quality of life (QOL) and functional status. This study aims to explore the ongoing needs of HF management and the epidemiology of patients followed by Italian HF clinics, with a specific focus on cardiac contractility modulation (CCM). RESEARCH DESIGN AND METHODS: Data from patients admitted to 14 HF outpatients clinics over 4 weeks were collected and compared to the results of a survey open to physicians involved in HF management operating in Italian centers. RESULTS: One hundred and five physicians took part in the survey. Despite 94% of patients receive a regular follow-up every 3-6 months, available therapies are considered insufficient in 30% of cases. Physicians reported a lack of treatment options for 23% of symptomatic patients with reduced ejection fraction (EF) and for 66% of those without reduced EF. Approximately 3% of HF population (two patients per month per HF clinic) meets the criteria for immediate CCM treatment, which is considered a useful option by 15% of survey respondents. CONCLUSIONS: Despite this relatively small percentage, considering total HF population, CCM could potentially benefit numerous HF patients, particularly the elderly, by reducing hospitalizations, improving functional capacity and QOL.

Lipoprotein(a): a risk factor for atherosclerosis and an emerging therapeutic target.

Lipoprotein(a) (Lp(a)) is a complex circulating lipoprotein, and increasing evidence has demonstrated its role as a risk factor for atherosclerotic cardiovascular disease (ASCVD) and as a possible therapeutic target. Lp(a) atherogenic effects are attributed to several potential mechanisms in addition to cholesterol accumulation in the arterial wall, including proinflammatory effects mainly mediated by oxidised phospholipids. Several studies have found a causal and independent relationship between Lp(a) levels and cardiovascular risk. Furthermore, several studies also suggest a causal association between Lp(a) levels and calcific aortic valve stenosis. Available lipid-lowering agents have at best moderate impact on Lp(a) levels. Among available therapies, antibody proprotein convertase subtilisin/kexin type 9 inhibitors are the most effective in reducing Lp(a). Potent Lp(a)-lowering treatments that target LPA expression are under development. Lp(a) level measurement poses some challenges due to the absence of a definitive reference method and the reporting of Lp(a) values as molar (nanomoles per litre (nmol/L)) or mass concentrations (milligrams per decilitre (mg/dL)) by different assays. Currently, Lp(a) measurement is recommended to refine cardiovascular risk in specific clinical settings, that is, in individuals with a family history of premature ASCVD, in patients with ASCVD not explained by standard risk factors or in those with recurrent events despite optimal management of traditional risk factors. Patients with high Lp(a) levels should be managed with more intensive approaches to treat other modifiable cardiovascular risk factors. Overall, this review focuses on Lp(a) as an ASCVD risk factor and therapeutic target. Furthermore, it reports practical recommendations for Lp(a) measurement and interpretation and updated evidence on Lp(a)-lowering approaches.

Potential pathophysiologic mechanisms underlying the inherent risk of cancer in patients with atherosclerotic cardiovascular disease.

Emerging evidence demonstrates an intimate interplay between cardiovascular disease and cancer pathophysiology. The aim of this review is to shed light on the common biological pathways underlying cardiovascular disease and cancer. These common pathways form the basis of "reverse cardio-oncology". We focus on the role of inflammation, stress response, cell proliferation, angiogenesis and tissue remodeling, neurohormonal system activation, and genomic instability as pathogenic pathways shared by cardiovascular disease and cancer. We also discuss shared mediators that may have a potential role as biomarkers for risk prediction in both diseases. Furthermore, we highlight current knowledge on biological pathways and mediators that are upregulated in diabetes and myocardial infarction and may be involved in tumorigenesis. On the basis of the shared pathophysiologic mechanisms, we also suggest an integrated approach to reduce the global burden of both cardiovascular disease and cancer.

Natriuretic peptides and cardiovascular damage in the metabolic syndrome: molecular mechanisms and clinical implications.

Natriuretic peptides are endogenous antagonists of vasoconstrictor and salt- and water-retaining systems in the body's defence against blood pressure elevation and plasma volume expansion, through direct vasodilator, diuretic and natriuretic properties. In addition, natriuretic peptides may play a role in the modulation of the molecular mechanisms involved in metabolic regulation and cardiovascular remodelling. The metabolic syndrome is characterized by visceral obesity, hyperlipidaemia, vascular inflammation and hypertension, which are linked by peripheral insulin resistance. Increased visceral adiposity may contribute to the reduction in the circulating levels of natriuretic peptides. The dysregulation of neurohormonal systems, including the renin-angiotensin and the natriuretic peptide systems, may in turn contribute to the development of insulin resistance in dysmetabolic patients. In obese subjects with the metabolic syndrome, reduced levels of natriuretic peptides may be involved in the development of hypertension, vascular inflammation and cardio vascular remodelling, and this may predispose to the development of cardiovascular disease. The present review summarizes the regulation and function of the natriuretic peptide system in obese patients with the metabolic syndrome and the involvement of altered bioactive levels of natriuretic peptides in the pathophysiology of cardiovascular disease in patients with metabolic abnormalities.

Tortuosity, Recurrent Segments, and Bridging of the Epicardial Coronary Arteries in Patients With the Takotsubo Syndrome.

Myocardial bridging (MB) and a long recurrent wraparound left anterior descending artery (wrap-LAD) are coronary anatomic variants that have been recently suggested to be associated with takotsubo syndrome (TS). Until now, coronary artery tortuosity (CAT) has never been investigated in this setting. Our study sought to evaluate the prevalence of the aforementioned anatomic variants in a large population with TS. In this retrospective angiographic study, 109 patients with TS were compared with 109 age- and gender-matched subjects without coronary artery disease, valve heart disease, or cardiomyopathy. CAT was identified by ≥3 consecutive curvatures ≥90° (criteria 1) or by ≥2 consecutive curvatures ≥180° (criteria 2). Wrap-LAD was defined if any part of the vessel outreached the apex of the left ventricle and MB as the presence of a milking effect or a step-up and step-down phenomenon. An anatomic variant was found in 79 patients with TS (72%) and in 48 controls (44%) (p <0.001). CAT in at least 1 vessel (criteria 1: 49% vs 20%, p <0.001; criteria 2: 38% vs 13%, p <0.001), ≥2 vessels (criteria 2: 14% vs 3%, p = 0.005), and wrap-LAD (41% vs 27%, p = 0.02) were significantly more frequent in patients with TS than in controls. The prevalence of MB (9% vs 5%, p = 0.18) did not differ between groups. In conclusion, CAT and wrap-LAD have higher prevalence in patients with TS than in matched controls. These findings could support the hypothesis that anatomic variants might act as potential pathogenic substrates in TS.

Comparison Between Radial Approach and Femoral Approach With Vascular Closure Devices on the Occurrence of Access-Site Complications and Periprocedural Bleeding After Percutaneous Coronary Procedures: A Systematic Review and Meta-Analysis.

OBJECTIVES: Periprocedural bleedings, often related to vascular access site, represent an important drawback of percutaneous coronary procedures and are associated with worse outcomes. Radial access (RA) and, potentially, femoral access (FA) with vascular closure device (VCD) are useful strategies in order to mitigate periprocedural bleedings; nevertheless, their relative efficacy is largely undetermined. We aimed to perform a systematic review and meta-analysis of available studies comparing the efficacy of RA and FA with hemostasis by VCD (FA + VCD) on the reduction of access-site complications and/or periprocedural bleedings. METHODS: Published studies reporting outcomes on access-site complications and periprocedural bleedings were included in the analysis. Data were extracted by two independent reviewers; odds ratio (OR) and 95% confidence interval (CI) were calculated by random-effects model and were used as summary statistics. RESULTS: We included in the analysis 13 studies, of which 5 were randomized. Access-site complications were reported by 11 studies, amounting to 157,031 patients (77,713 in the RA group and 79,318 in the FA + VCD group), whereas periprocedural bleedings were reported by 12 studies, amounting to 600,196 patients (137,277 in the RA group and 462,919 in the FA + VCD group). RA was associated with a significant reduction in access-site complications (OR, 0.25; 95% CI ,0.21-0.31; P<.001) and periprocedural bleedings (OR, 0.40; 95% CI, 0.34-0.48; P<.001) as compared with FA + VCD; the results were consistent among randomized and observational studies. CONCLUSIONS: This meta-analysis shows that RA is superior to FA + VCD in the reduction of access-site complications and periprocedural bleedings.

Comparison of risk of acute kidney injury after primary percutaneous coronary interventions with the transradial approach versus the transfemoral approach (from the PRIPITENA urban registry).

The risk of acute kidney injury (AKI) is a major issue after percutaneous coronary interventions (PCIs), especially in the setting of ST-elevation myocardial infarction. Preliminary data from large retrospective registries seem to show a reduction of AKI when a transradial (TR) approach for PCI is adopted. Little is known about the relation between vascular access and AKI after emergent PCI. We here report the results of the Primary PCI from Tevere to Navigli (PRIPITENA), a retrospective database of primary PCI performed at high-volume centers in the urban areas of Rome and Milan. Primary end point of this study was the occurrence of AKI in the TR and transfemoral (TF) access site groups. Secondary end points were major adverse cardiovascular events, stent thrombosis, and Thrombolysis in Myocardial Infarction major and minor bleedings. The database included 1,330 patients, 836 treated with a TR and 494 with a TF approach. After a propensity-matched analysis performed to exclude possible confounders, we identified 450 matched patients (225 TR and 225 TF). The incidence of AKI in the 2 matched groups was lower in patients treated with TR primary PCI (8.4% vs 16.9%, p = 0.007). Major adverse cardiovascular events and stent thrombosis were not different among study groups, whereas major bleedings were more often seen in the TF group. At multivariate analysis, femoral access was an independent predictor of AKI (odds ratio 1.654, 95% confidence interval 1.084 to 2.524, p = 0.042). In conclusion, in this database of primary PCI, the risk of AKI was lower with a TR approach, and the TF approach was an independent predictor for the occurrence of this complication.

Effects of a long-term treatment with aliskiren or ramipril on structural alterations of subcutaneous small-resistance arteries of diabetic hypertensive patients.

Structural alterations of subcutaneous small-resistance arteries are associated with a worse clinical prognosis in hypertension and non-insulin-dependent diabetes mellitus. The effects of the direct renin inhibitor aliskiren on microvascular structure were never previously evaluated. Therefore, we investigated the effects of aliskiren in comparison with those of an extensively used angiotensin-converting enzyme inhibitor, ramipril, on peripheral subcutaneous small-resistance artery morphology, retinal arteriolar structure, and capillary density in a population of patients with non-insulin-dependent diabetes mellitus. Sixteen patients with mild essential hypertension and with a previous diagnosis of non-insulin-dependent diabetes mellitus were included in the study. Patients were then randomized to 1 of the 2 active treatments (aliskiren 150 mg once daily, n=9; or ramipril 5 mg once daily, n=7). Each patient underwent a biopsy of the subcutaneous fat from the gluteal region, an evaluation of retinal artery morphology (scanning laser Doppler flowmetry), and capillary density (capillaroscopy), at baseline and after 1 year of treatment. Subcutaneous small arteries were dissected and mounted on a pressurized micromyograph, and the media-to-lumen ratio was evaluated. A similar office blood pressure-lowering effect and a similar reduction of the wall-to-lumen ratio of retinal arterioles were observed with the 2 drugs. Aliskiren significantly reduced media-to-lumen ratio of subcutaneous small-resistance arteries, whereas ramipril-induced reduction of media to lumen ratio was not statistically significant. No relevant effect on capillary density was observed. In conclusion, treatment with aliskiren or ramipril was associated with a correction of microvascular structural alterations in patients with non-insulin-dependent diabetes mellitus.

Vascular inflammation and endothelial dysfunction in experimental hypertension.

Essential hypertension is characterized by increased peripheral vascular resistance to blood flow. The endothelium is a crucial regulator of vascular tone. Its function is impaired in patients with hypertension, with reduced vasodilation, increased vascular tone associated with a proinflammatory and prothrombotic state. Low-grade inflammation localized in vascular tissue is therefore recognized as an important contributor to the pathophysiology of hypertension, to the initiation and progression of atherosclerosis as well as to the development of cardiovascular diseases.