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Introduction PCSK9 inhibitors (PCSK9i) significantly decrease LDL cholesterol (LDL-C), either as monotherapy or in addition to the maximally tolerated dose of statin and/or ezetimibe. Yet, few data are available on efficacy and background lipid-lowering therapy (LLT) adjustment in patients treated with PCSK9i in real-world observations. Purpose AT-TARGET-IT is an Italian multicenter registry involving 9 Italian centers, designed to assess efficacy, adherence, and persistence of PCSK9i, as well as prescribing doctors' behavior in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH). The aim of the present analysis was to assess efficacy and changes in background LLT therapy in patients on PCSK9i in a real-world single country observation. Methods From June through November 2021, we enrolled patients with PCSK9i first prescription from 6 months before inclusion through starting of PCSK9i use. Clinical and demographic characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and at the latest observation preceding inclusion in the study. Background therapy was assessed at baseline and during follow-up, evaluating treatment withdrawal, reduction of doses, or changes from statin-ezetimibe association to single drug therapy. Results We enrolled 798 patients (27% with FH) receiving either alirocumab or evolocumab and followed for a median time of 19.3 months. At the time of PCSK9i first prescription LDL-C was 147.6 mg/dl and reached 51.5 mg/dl at the time of latest observation (64% reduction), and 129 patients (16%) were not receiving any LLT, 669 patients received background LLT, of them 246 (31%) were taking ezetimibe alone and 423 (53%) were taking statins with or without ezetimibe. At the end of the observation period, 785 patients (98%) were still receiving PCSK9i and 550 (69%) did not change background LLT. Of 248 patients changing background LLT, 116 (47%) withdrew therapy, 132 (53%) changed dose or type of LLT. After stratification by achievement of LDL-C target according CV risk class, 483 patients achieved the target (60%). Target was achieved at the end of the observation period in 63% of patients taking triple therapy, 65% patients receiving PCSK9i plus statins, 62% of patients receiving PCSK9i plus ezetimibe and 55% receiving PCSK9i alone (Figure 1). No significant differences in terms of percentage of patients changing background LLT during PCSK9i treatment were found between patients at target for LDL-C and those not at target. Conclusion AT-TARGET-IT study shows that PCSK9i therapy is effective in reaching LDL-C target in the majority of patients, yet a sizable number of them (40%) remains undertreated. LLT background therapy is either reduced or withdrawn in 31% of patients, being responsible for not reaching target. Reasons for inappropriate LLT changes in patients receiving PCSK9i should be identified and removed to optimize lipid control. Funding Acknowledgement Type of funding sources: None.

Background The association between sleep apnea (SA) and atrial fibrillation (AF) has been well described. However, it remains unclear whether the association is causative or primarily dependent on shared comorbidities such as obesity. The Respiratory Disturbance Index (RDI) computed by an implantable cardioverter defibrillator (ICD) algorithm accurately identifies severe SA, whether central or obstructive in origin. Purpose In the present analysis we studied in patients with heart failure the contribution of obesity in the relationship between SA, measured by RDI, and AF. Methods Patients with ejection fraction ≤35% implanted with an ICD endowed with an algorithm (ApneaScan) that calculates the RDI each night, were enrolled and followed-up for 24 months. The weekly mean RDI value was considered, as calculated during the entire follow-up period. The endpoint was daily AF burden of ≥6 hours. Results 164 patients (age 67±10 years, 75% male, ejection fraction 29±5%) had usable RDI values during the entire follow-up period. Body mass index (BMI) was Conclusions In heart failure patients, we confirmed the association between ICD-detected SA and AF, an association that persisted independent of patient body habitus. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The study is supported by a research grant from Boston Scientific

Background Heart Failure (HF) is a relevant issue for public health issue: it affects more than 64 million people worldwide1, and its burden is anticipated to increase as the population ages. Dapagliflozin is an inhibitor of the sodium–glucose cotransporter–2 (SGLT2i). In the DAPA–HF trial, dapagliflozin reduced the risk of hospitalisation for HF and death in patients with HFrEF (with or without Type 2 Diabetes) compared to placebo2,3,4. Currently, there is a lack of data on characteristics, treatment profiles, and patient reported outcomes (PROs) of patients initiated on dapagliflozin for HFrEF in clinical practice: the EVOLUTION–HF programme is aimed at answering those questions by collecting real–world data in 13 European Countries, including Italy. The primary objective is to characterise patients initiated on dapagliflozin for the treatment of HFrEF and to estimate occurrence of treatment discontinuations. Secondary objectives include an assessment of Health–related Quality of Life (HR–QoL) by means of the Kansas City Cardiomyopathy Questionnaire (KCCQ), patient–reported adherence to prescriptions of pharmacological treatments for HF (Medication Adherence Report Scale – 5 Item), performance on 6–Minutes Walking Test. Methods The study has an observational, longitudinal, descriptive design. To be enrolled, patients must be 18 years old or older and have initiated treatment with dapagliflozin according to the approved HFrEF label. Patients with a diagnosis of Type 1 Diabetes or previously treated with any SGLT2i are excluded from the study. Follow–up lasts one year from start of treatment. Sample size has been estimated in 250 patients, that will be enrolled in 11 centres. Results The study is currently ongoing, and it will generate evidences on the use and tolerability of dapagliflozin, as well as on treatment patterns of other pharmacological therapies for HF and diabetes. Also, the study will generate data from PROs regarding change of KCCQ across time, adherence to HF therapies in clinical practice, and 6–Minutes Walking Tesst. Multivariate analyses will evaluate association between patients’ characteristics and interruption of treatment, adherence and HR–QoL. The interim analysis will be available in the first months of 2023. Conclusions The EVOLUTION–HF Italy study Il programma di studio EVOLUTION–HF supporterà la pratica clinica con dati originali sull‘uso nel mondo reale delle nuove terapie farmacologiche per l‘HFrEF.

Bronchial asthma is a chronic inflammatory disease characterized by bronchial obstruction, usually reversible spontaneously or after therapy, bronchial hyperreactivity and accelerated decrease of lung function that may possibly evolve into irreversible obstruction of the respiratory tract. Bronchial provocation tests can be used in order to assess the presence and degree of bronchial hyper reactivity. The recently introduced mannitol powder inhalation indirect test seems to have an interesting and promising role, especially in childhood, because of its high diagnostic specificity, easiness of execution and best standardization. In this study the authors focused on the significance and clinical use of mannitol bronchial challenge test in asthmatic children.

The study aims to analyze retrospective results of extensive endovascular repair of the descending thoracic aorta with special attention to spinal cord malperfusion.From April 2002 through November 2011, 21 patients underwent stent-graft coverage of the thoracic aorta from the aortic arch at the origin of the left subclavian artery to the celiac trunk, 6 (mean age =72.3±8.1) for aneurysm disease, 13 (mean age =74.3±8.4) for type B aortic dissection and 2 (mean age =52.1±6.5) for aortic rupture. The mean of aortic diameter in cases with aneurysm disease was 7.1±1.6 cm and the causes of aortic rupture were post-traumatic and aneurysm pathology respectively. In all cases needing coverage of the left subclavian artery duplex ultrasonography and flowmetry were performed to evaluate patency and flow of both the vertebral arteries.Technical success was 100% with 0% in-hospital mortality. The left subclavian artery was crossed with the uncovered portion of the stent-graft in 11 cases (52.4%) and the covered segment in the other 10 patients (47.6%) without subclavian revascularization because no pre-operative hemodynamic alterations of vertebral arteries were revealed by duplex ultrasonography. The incidence of paraplegia was 9.5% in 2 patients who had prior abdominal aortic aneurysm repair: the first case with preoperative type B aortic dissection presented significant lower extremity paresis within 24 hours after the procedure and in the second patient with a large thoracic aneurysm the signs of paraplegia were evident 3 weeks after discharge from Hospital probably due to delayed occlusion of a major medullary artery. The cumulative survival rate after 1, 3 and 9 years was 91%, 81%, and 71%.The coverage of the entire thoracic aorta is an effective procedure with high probability of success. Spinal cord malperfusion remains a serious complication especially in patients with prior aortic surgery but if collateral blood supply is maintained the occlusion of intercostal arteries do not determine paraplegia or paraparesis. In order to consider acute or chronic occlusion of subclavian, lumbar or hypogastric arteries so preventing spinal cord ischemia, strong preoperative evaluation including analysis of previous surgery for abdominal aortic aneurysm repair and avoidance of T12 aortic segment coverage if feasible is mandatory.

Angioplasty is a principal treatment for occlusive vascular disease but 30-50% of patients show a restenosis of the vessel. There is no clinical effective therapy for this disease. It has been demonstrated, in animal models, that various drugs such as NO-donor, plasminogen inhibitor tranexamic acid and MMP (matrix metalloproteinases) reduce the rate of restenosis. Other therapeutic approaches are cytotoxic therapy, and strategies to inhibit cell cycle progression. Systemic administration of conventional pharmacologic agents inhibit cell cycle kinases and vascular lesion formation in animal models. As cell cycle progression is accompanied by fluctuations in the concentration of adenosine 3',5-monophospate (cAMP) and in the activity of the cAMP dependent protein kinase (PKA), local administration of cAMP and phospodiesterase-inhibitor drugs (aminophylline or amrinone) markedly inhibit neointima formation. The successful use of local radiation therapy to inhibit neointima formation after vascular injury may reflect a similar combination of cell-cycle arrest and vascular cell apoptosis. The most effective therapy for occlusive vascular disease will likely combine intravascular stenting with an antiproliferative therapy.

Accumulation and proliferation of vascular smooth muscle cells are associated with atherosclerosis and hypertension. Proliferation of smooth muscle cells constitutes a major pathological event responsible for long-term failure of coronary and peripheral arterial bypass graft as well as the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA). The incidence of restenosis after PTCA has been reported to be as high as 40-45% within 3-6 months. Major advantages in recombinant deoxyribonucleic acid (DNA) technology and eukaryotic gene regulation allow to hypothesize gene therapy as a potential treatment for inherited and acquired diseases. Gene therapy is the introduction of genes into somatic cells to correct an inherited or acquired disorder through the synthesis of missing or defective protein. Although no disease has yet been treated by gene therapy, several gene transfer protocols have recently been undertaken. We have studied the expression of foreign DNA that has been introduced into smooth muscle cells after balloon carotid injury in a rat model of angioplasty. The effects of different degree of balloon injury on neointima formation and c-fos expression was also assessed. Our data demonstrate that site-specific gene expression can be achieved by direct gene transfer in vivo and could be applied to the treatment of restenosis after PTCA.

Eighteen patients with isolated stenosis of left anterior descending artery, were randomly given 0.2 mg of nifedipine (Group II) or its solvent (Group I) via balloon catheter positioned across the lesion immediately prior balloon occlusion. Peak velocity of early (E peak) and late (A peak) filling, velocity flow integral at early (E area) and late (A area) filling and their ratios (by echo-Doppler) and heart rate, mean aortic and wedge (W) pressures were measured at baseline, 15 and 30 s during balloon occlusion and 10 min after balloon deflation. In Group I we observed a significant decrease in either E peak at 15 and 30 s (-24.7%, -29.3% respectively) and E area (-32.8%, -40.0% respectively) with a non significant increase in both A peak and A area. Accordingly, either E/A peak ratio and E/A area ratio decreased significantly. In Group II no significant changes were observed in the echo-Doppler parameters of left ventricular filling. Wedge pressure also significantly increased in Group I at 15 and 30 s (68.7% and 97.9% respectively), while a significant increase in Group II occurred only at 30 s (32.5%). Heart rate significantly increased only in Group I at 15 and 30 s (10.3% and 11% respectively), while aortic pressure remained unchanged in both groups. Thus, nifedipine given intracoronary in the post-stenotic area just before balloon occlusion prevents left ventricular filling dynamic alteration by preserving early filling.

This study evaluated the effects of digoxin infusion (0.014 mg/kg in 10 min i.v.) on large coronary arteries measured by quantitative digital angiography. Twenty-two patients (aged 47 +/- 12), divided in 3 groups were studied. The effects of digoxin infusion (after 10 and 20 min) and sublingual administration of isosorbide dinitrate were investigated in Group I (patients with angiographically normal coronary arteries, n = 9) and in Group II (patients with atherosclerotic coronary arteries, n = 8). In Group III (n = 5) to determine whether or not the effects of digoxin were mediated by activation of alpha-adrenergic receptors, coronary angiographies were performed after alpha-adrenoceptor blockade (phentolamine 0.11 mg/kg, i.v.). In Group I, 10 min after the end of digoxin infusion, cross-sectional area decreased from 7.7 +/- 4.1 mm2 to 6.0 +/- 2.2 mm2, and after 20 min to 5.6 +/- 2.6 mm2 (p0.05). Isosorbide dinitrate reverted digoxin-induced vasoconstriction as cross-sectional area increased to 8.5 +/- 3.4 mm2 (NS versus baseline). By 20 min after digoxin infusion heart rate was significantly reduced from 79 +/- 16 to 74 +/- 13 b/min (p0.01). Peripheral vascular resistances increased significantly 10 min after digoxin infusion (from 1396 +/- 693 to 1693 +/- 984 dyne*s*cm-5, p0.05), whereas cardiac output did not change. In Group II, minimal stenosis diameter decreased significantly 20 min after digoxin infusion from 1.6 +/- 0.5 mm to 1.4 +/- 0.5 mm (p0.05). Again, isosorbide dinitrate reverted digoxin-induced vasoconstriction as minimal stenosis diameter increased (NS versus control).(ABSTRACT TRUNCATED AT 250 WORDS)

Central sympathetic stimulation results in direct vascular vasoconstriction mediated by activation of alpha-adrenergic receptors. However, it is unknown whether this vasoconstriction is mediated by alpha 1 or alpha 2-adrenoceptor subtypes. In patients with congestive heart failure (CHF), both circulating and neuronally released catecholamines produces vasoconstriction via alpha-adrenergic stimulation. This vasoconstriction produces detrimental hemodynamic effect in CHF patients since it increases right and left ventricular filling pressures and pulmonary and systemic vascular resistances. While the myocardial alpha 1-adrenoceptors seems not to be down-regulated in heart failure, the functional integrity of vascular alpha 1 and alpha 2-adrenoceptors in CHF remains to be elucidated. Accordingly, the present study was designed to assess whether the limb vascular response to alpha 1 or alpha 2-adrenoceptor stimulation is impaired in patients with CHF. We studied 25 control subjects and 19 patients with CHF due to primary dilated cardiomyopathy. Forearm blood flow was measured by venous occlusion plethysmography. Sympathetic stimulation was produced by cold. The intraarterial pump-infusions of BHT 933 (a selective alpha 2-adrenoceptors agonist agent, 0.1, 1, 10 micrograms/kg/min for 5 min) produced the same peripheral vasoconstriction in CHF and in control subjects: 32 +/- 23.9%, 47.3 +/- 20% and 55 +/- 26.1% respectively at I, II, and III dose in CHF and 28.7 +/- 38.6%, 36 +/- 14.5%, and 57 +/- 13.8% respectively at I, II, and III dose in control subjects. The dose response to BHT 933 was not different in the 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The studies reviewed here examine the role of heart rate reduction in the beneficial effect observed following beta-adrenoceptor blockade during exercise-induced ischemia in conscious dogs. To further study the effects of heart rate reduction on regional blood flow in an ischemic bed without collateral circulation, anesthetized swine with controlled coronary perfusion were also studied. Measurements of regional myocardial blood flow (microspheres) and contractile function (sonomicrometers) during steady state exercise in dogs with chronic coronary artery stenosis indicated the existence of severe regional contractile dysfunction and subendocardial ischemia. The administration of beta-adrenoceptor blockade (1.0 mg/kg atenolol) improved regional contractile function when heart rate was reduced from 220 to 165 beats/min. Atrial pacing during exercise to prevent the bradycardia following beta-adrenoceptor blockade eliminated the improved regional function and blood flow. Thus, the beneficial effect of beta-blockade was only apparent when exercise heart rate was reduced. In anesthetized swine with constant inflow coronary perfusion, two levels of coronary hypoperfusion were examined at heart rates of 91 beats/min or 55 beats/min. Bradycardia was produced using the bradycardic agent UL-FS 49 (0.3 mg/kg). Regional contractile function and subendocardial blood flow were markedly improved at the lower heart rate for either level of reduced coronary perfusion, indicating a redistribution of blood flow towards the subendocardium. The improvement in contractile function was larger than predicted on the basis of the improvement in blood flow per min to the subendocardium. Independent relationships between regional contractile function and the subendocardial blood flow per min were observed for each heart rate. Thus, the studies in conscious exercising dogs indicated that heart rate reduction is an essential mechanism for the improvement of ischemic regional myocardial contractile function during exercise by beta-blockade. This is likely the result of the marked improvement in subendocardial blood flow per beat which accompanies the reduced heart rate; regional myocardial blood flow per beat appears to be a predictor of regional contractile function during ischemia both at rest and during exercise.

This describes our preliminary experience with percutaneous brachial approach for cardiac catheterization, by using 5 French (F) preformed catheters. Thirty patients (pts) were studied from the left arm (Group A) with a 5F sheath and 5F Judkins catheters and 30 from the right arm (Group B) with 5F sheath and 5F Amplatz catheters. Pigtail catheters (5F) were used for the left ventricular angiograms in all patients. In 10 patients arterial velocity signals and radial and ulnar artery blood pressures were monitored with the Doppler ultrasonic velocity detector before and immediately after each procedure, and 24 hours later. Arterial puncture was carried out successfully in each patient by using a 18-gauge Potts-Cournand needle. The puncture site was as close as possible to the ante cubital fossa where the artery is less mobile. Both coronary arteries were selectively opacified and the left ventricular angiography was done on every patient. The diagnostic quality of the angiograms was evaluated by the visual analogue scale and the results were not different from those obtained with the femoral approach in our catheterization laboratory. In 3 out of 30 pts in group B it was impossible to obtain a good left coronary opacification with Amplatz catheters for anatomical reasons, thus the right femoral approach was preferred. Brachial artery occlusion occurred in 1 patient from group B and needed surgical thrombectomy carried out to restore normal radial and ulnar pulses.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-six patients with significant coronary artery stenosis and no previous myocardial infarction and 25 subjects with normal coronary arteries underwent 99mTc RNV before and after coronary vasodilatation induced by dipyridamole, 0.75 mg/kg, given IV over 10 min. In subjects with normal coronary arteries, dipyridamole induced an increase in LVEF (from 66 +/- 8 to 76 +/- 8 percent; mean +/- SD; p less than 0.001); in patients with significant coronary artery stenosis (greater than or equal to 75 percent narrowing of at least one major vessel), dipyridamole injection did not affect LVEF (from 63 +/- 12 to 62 +/- 12 percent). In ten patients a complete, successful PTCA was performed and the RNV with the dipyridamole test repeated. The EF did not change with the dipyridamole test before PTCA (63 +/- 7 to 65 +/- 9 percent), but increased significantly after PTCA (62 +/- 11 to 70 +/- 9 percent; p less than 0.01). Sensitivity and specificity of EF changes after dipyridamole infusion were 75 and 76 percent, respectively. The test produced no major side effects or complications. Radionuclide angiography with dipyridamole helps to detect coronary artery stenosis and might be used to assess the effects of angioplasty on coronary flow reserve.