A 25-year-long journey into interventional cardiology: looking back, and rushing forward.

Cardiovascular disease remains decade after decade a leading cause of mortality, morbidity and resource use globally as well as locally. We have had the opportunity of being involved in several iterative breakthroughs in invasive cardiovascular procedures, ranging from the advent of coronary stents to transcatheter mitral valve repair. Building up such extensive clinical and research experience, we hereby present 25 years of cardiovascular interventions at Pineta Grande Hospital and Casa di Salute S. Lucia, respectively in Castel Volturno, and S. Giuseppe Vesuviano, both in the Italian Campania region, where the same team of interventional cardiologists has managed to adopt and master several cardiovascular innovations for the benefit of thousands of patients. Our experience showcases the evolution of invasive cardiology, especially in diagnostic and therapeutic practices. Key highlights include advancements in coronary procedures, with the introduction of bare-metal stents, drug-eluting stents and drug-coated balloons, despite the setback of bioresorbable vascular scaffolds, as well as transcatheter aortic valve implantation and innovative approaches to mitral regurgitation. Furthermore, this overview scrutinizes procedural challenges, patient outcomes, and quality of life improvements, providing a rich tapestry of clinical experiences and research insights. It serves as a testament to the dynamic nature of interventional cardiology, offering a forward-looking perspective on future trends and technologies. We hope that this overview will prove an informative and insightful read for those seeking to understand the intricate journey of invasive cardiovascular care over the past decades and its trajectory into the future.

Peripheral diagnostic and interventional procedures using an automated injection system for carbon dioxide (CO2): case series and learning curve.

INTRODUCTION: The administration of iodinated contrast media in doses sufficient for diagnosis and procedural guidance, when coincident with renal insufficiency, presents a considerable risk of exacerbating and hastening renal failure. Carbon dioxide has been proposed in the past as an alternative, but only recently dedicated injection systems have become available. We aimed to review our ongoing experience with an automated carbon dioxide injector for peripheral diagnostic and interventional procedures. METHODS: Details on 21 patients undergoing peripheral procedures with carbon dioxide angiography were systematically collected. An automated injector enabling customized and repeated carbon dioxide injections was used in all cases, with iodinated contrast media used only as bailout. RESULTS: No major or minor complications occurred in these patients, either during the procedure or up to discharge. Comparison according to phase of the learning curve showed that with accruing experience operators relied progressively more on carbon dioxide only, as there was a significantly reduced need for additional iodinated contrast media injections per procedure (from 2.5±2.1 to 0.6±2.1 injections per patient, p=0.005). Accordingly, in the second phase of our learning curve, iodinated contrast media were avoided in 91% of cases in comparison to 20% of procedures performed in the beginning of our experience (p=0.002). Concomitantly, no significant change in the duration of the procedure occurred. CONCLUSIONS: Carbon dioxide-based angiography using an automated injection system is feasible and safe in patients undergoing diagnostic or interventional procedures for infra-diaphragmatic conditions, especially for transcatheter renal sympathetic denervation.

A registry on distal popliteal and infrapopliteal revascularization with coronary drug-eluting stents.

AIMS: Endovascular therapy for popliteal and infrapopliteal artery disease in patients with critical limb ischemia (CLI) remains challenging, given the high risk of adverse events. Favorable results for coronary balloon-expandable drug-eluting stents (DESs) in this arterial district have been reported in selected studies, but uncertainty persists on their risk-benefit balance in real-world patients. We, thus, sought to appraise our outcomes with DES implantation for distal popliteal or infrapopliteal lesions. METHODS: Our institutional databases were retrospectively queried to identify patients undergoing DES implantation for distal popliteal or infrapopliteal artery disease. Baseline, lesion, procedural, and outcome data were systematically collected. RESULTS: A total of 25 patients were treated with coronary DES, 12 (48.0%) for distal popliteal and 13 (52.0%) for infrapopliteal lesions. Four (16.0%) patients received two stents, whereas the others only one. Breakdown of DES was as follows: biolimus-eluting, everolimus-eluting, paclitaxel-eluting, and sirolimus-eluting stents in, respectively, two (8.0%), one (4.0%), one (4.0%), and 21 (84.0%), with an average stent length of 33.6 ±â€Š13.1 mm. Improvement in Fontaine stage was achieved in 23 (92.0%) patients at 1 month and in 22 (88.0%) patients at long-term (28.8 ±â€Š20.6 months). In this highly selected case series, no repeat revascularizations or unplanned amputations were recorded, whereas two (8.0%) patients died, the first 15.5 months and the second 19.5 months after the procedure. CONCLUSION: Implantation of coronary balloon-expandable DES appears feasible, safe, and effective in selected patients with focal lesions in the distal popliteal and infrapopliteal arteries.

Tirofiban induces VEGF production and stimulates migration and proliferation of endothelial cells.

Tirofiban is a fibrinogen receptor antagonist, generated using the tripeptide Arg-Gly-Asp (RGD) as a template. RGD activates integrin receptors and integrin-mediated signals are necessary for normal cells to promote survival and stimulate cell cycle progression. We investigated whether tirofiban activated growth-stimulatory signals in endothelium. For this study human umbilical vein endothelial cells (HUVEC) and human aortic endothelial cells (HAEC) were used. Analysis of cell proliferation, by cell counts, showed that the number of endothelial cells doubled after 72 h of culture in the absence of tirofiban, while they were tripled and even quadrupled, in the presence of increasing doses of the drug. Moreover, tirofiban-stimulated cells had a greater ability to migrate through the transwell filters of Boyden chamber, compared to unstimulated cells. The scratch assay, which mimics cell migration during wound healing, showed that tirofiban stimulated HUVECs to migrate into the leading hedge of the scratch. Western blot showed that tirofiban increased the expression levels of VEGF and the downstream effectors Erk and cyclin D. An inhibitor of VEGFR2 counteracted tirofiban-induced-proliferation, suggesting a role for VEGF in such effect. Our study shows that tirofiban stimulates the migration and proliferation of endothelial cells suggesting that it can promote endothelial repair. Ex vivo cultures of arterial rings confirmed the growth stimulatory effect of tirofiban on endothelium. Thus, the benefits of tirofiban in those with acute coronary syndromes undergoing PTCA may be due to rapid endothelization of damaged vessel, besides antiplatelet effects.

Atorvastatin sensitises vascular smooth muscle cells, but not endothelial cells, to TNF-α-induced cell death.

OBJECTIVE: Stimuli activating vascular smooth muscle cell death can constrain the neointimal response to arterial damage and prevent vascular thickening. Conversely, endothelial cell death increases endothelial dysfunction and thrombosis risk. We investigated the combined effect of atorvastatin and TNF-α on vascular cell death. METHODS AND RESULTS: Cell death was investigated in cultures of human aortic smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs). Atorvastatin downregulated NF-κB and enhanced JNK activity and cell death in VSMC cultured with TNF- α. In the absence of TNF-α, percentages (mean and StDev) of annexin V positive cells were 17.4 ± 6.6%, 19.3 ± 5.9%, 22.9 ± 9.4% and 35.0 ± 20.0 % with 0, 1, 3 and 10 µM atorvastatin, respectively. The cytotoxic effect of statin was significant at the highest dose of 10 µM (p=0.001). In the presence of TNF-α, percentages of annexin V positive cells were 27.1 ± 10.6%, 34.2 ± 8.5%, 37.4 ± 14.6, and 54.1 ± 20.0% with 0, 1, 3 and 10 µM atorvastatin, respectively. The cytotoxic effect of statin was significant at each dose used (p≤0.02), in the presence of TNF-α. The cell death sensitising effect of atorvastatin was apparently mediated by down modulation of PKCß activity, because it was reproduced by the specific PKCß inhibitor LY317615 and prevented by the PKC activator phorbol-12-myristate-13-acetate (PMA). This effect was cell context dependent because it was not observed in HUVECs. PKCß was found to be constitutively active in VSMCs but not in HUVECs, thereby explaining the differential effect among the two cell types. Measurement of phosphoPKCß protein levels in arterial specimens confirmed increased activation of this kinase in the smooth muscle layer, in comparison with endothelium. We show that PKCß provides survival signals to vascular smooth muscle cells and not the endothelium. CONCLUSION: Our study suggests that atorvastatin enhances TNF-α-induced cell death in vascular smooth muscle- but not endothelial - cells; by a cell-context-dependent mechanism, involving PKCß inhibition.

Synergy between direct coronary stenting technique and use of the novel thin strut cobalt chromium Skylor™ stent: the MACE in follow up patients treated with Skylor stent [MILES Study].

BACKGROUND: Despite significant improvements in stent platform, currently available bare-metal stents (BMS) are still associated with restenosis. Thin-strut design cobalt-chromium alloys hold the promise of improving results of BMS, especially when implanted with direct technique. We performed an observational study to appraise outcomes of the novel Skylor™ stent, stratifying outcomes according to stenting technique. METHODS AND RESULTS: We included all consecutive patients undergoing coronary stenting with Skylor™ at 2 centers between 2006 and 2009. The primary end-point was the long-term rate of major adverse cardiac events (MACE, i.e. death, myocardial infarction (MI), coronary artery bypass grafting (CABG) or target vessel revascularization (TVR)). As pre-specified analysis, we compared patients undergoing direct stenting versus those stent implantation following predilation. A total of 1020 patients were included (1292 Skylor™ stents), with procedural success obtained in 99%. Comparing patients undergoing direct stenting (66%) versus pre-dilation (34%) at 16±7 months of follow-up, MACE had occurred in, respectively, 8% versus 14% (p=0.001), with death in 1% versus 2= (p=0.380), MI in 1% versus 2% (p=0.032), CABG in 0.2% versus 2% (p=0.012), and TVR in 6% versus 9% [p=0.071]. Even at multivariable analysis with propensity adjustment, direct stenting was associated with significantly fewer MACE [hazard ratio 0.60 [0.38-0.93], p=0.024]. CONCLUSIONS: This observational study suggests the presence of a beneficial synergy between direct coronary stenting technique and use of the novel thin-strut cobalt-chromium Skylor™ stent in real-world patients undergoing PCI.

Differential effect of atorvastatin and tacrolimus on proliferation of vascular smooth muscle and endothelial cells.

Although considered promising for use in drug-eluting stents (DES), tacrolimus failed clinically. Tacrolimus inhibits growth factor production but can also act as a growth factor on vascular smooth muscle cells (VSMC). This unexpected proliferative stimulus could reverse the beneficial effects of the drug on restenosis. We hypothesized that tacrolimus' association with statins, which lower cholesterol and impair cell proliferation, could restore tacrolimus' beneficial effect by abrogating the aberrant proliferative stimulus. Additionally, since maintenance of endothelial function represents a challenge for new-generation DES, we investigated the combined effect of tacrolimus and atorvastatin on endothelial cells. Human VSMC and umbilical vein endothelial cells (HUVEC) were incubated with 100 nM tacrolimus and increasing doses of atorvastatin (0-3.0 µM). Atorvastatin plus tacrolimus dose-dependently inhibited VSMC proliferation. The percentage of cells incorporating 5-bromo-2'-deoxyuridine (BrdU) in their DNA was 49 ± 14% under basal conditions, 62 ± 15% (P = 0.01) with tacrolimus, 40 ± 22% with 3 µM atorvastatin, and 30 ± 7% (P < 0.05) with 3 µM atorvastatin plus tacrolimus. Atorvastatin downregulated ß-catenin, Erk1 and Erk2, and cyclin B in tacrolimus-stimulated VSMC. In contrast, atorvastatin plus tacrolimus did not affect proliferation of endothelial cells. The percentage of HUVEC incorporating BrdU in their DNA was 47 ± 8% under basal conditions, 58 ± 6% (P = 0.01) with tacrolimus, 45 ± 4% with 3 µM atorvastatin, and 49 ± 1% with 3 µM atorvastatin plus tacrolimus. Both agents stimulated endoglin production by HUVEC. Taken together, these results suggest that, when combined with tacrolimus, atorvastatin exerts a dose-dependent antiproliferative effect on VSMC. In contrast, atorvastatin acts in concert with tacrolimus in HUVEC to stimulate production of endoglin, a factor that has an important role in endothelial repair. Our study supports the conclusion that prevention of postcoronary in-stent restenosis and late thrombosis may benefit of concomitant association of tacrolimus and high doses of atorvastatin.

[A case of percutaneous coronary intervention after transfemoral implantation of a medtronic CoreValve System]. / Un caso di angioplastica percutanea dopo impianto transfemorale di protesi Medtronic CoreValve System.

The association between aortic valve disease and coronary atherosclerosis is common. In the recent era of transcatheter aortic valve implantation there is little experience with coronary artery intervention after valve implantation. We report a case of a 80-year-old male who underwent successful coronary artery intervention few months after a Medtronic CoreValve System percutaneous implantation for severe aortic valve stenosis. Verification of the position of the used wires (crossing from inside the self expanding frame) is of utmost importance before proceeding to coronary intervention. In this case, crossing the aortic valve, coronary angiography and percutaneous coronary intervention were successfully performed. In conclusion, percutaneous coronary intervention in patients with previous Medtronic CoreValve System implantation is feasible and safe.

Relation of brachial artery flow-mediated vasodilation to significant coronary artery disease in patients with peripheral arterial disease.

In patients at risk for coronary atherosclerosis, brachial artery flow-mediated dilation (FMD) rules out significant coronary artery disease (CAD). However, the value of this approach is unknown in patients with peripheral arterial disease who are at increased risk for CAD. This study assessed whether the noninvasive evaluation of endothelial function by brachial artery FMD rules out significant CAD by dipyridamole myocardial perfusion imaging (MPI) in patients with peripheral arterial disease who are asymptomatic for CAD. Forty-four patients with peripheral arterial disease who were asymptomatic for CAD underwent, in the same day, FMD evaluation and dipyridamole MPI using technetium-99m sestamibi single photon-emission computed tomography. MPI results were abnormal in 17 of 44 patients (39%). FMD was significantly less (6.0 +/- 2.3%) in patients with abnormal MPI results compared with those with normal MPI results (7.3 +/- 1.8%, p = 0.04). By multivariate analysis, FMD was the only significant predictor of abnormal MPI results (odds ratio 0.63, p = 0.02). Receiver-operating characteristic curve analysis assessing the ability of FMD to identify patients with summed stress scores > or =3 yielded an area under the curve of 0.74 (p = 0.009). A FMD value >6% provided 92% negative predictive power to rule out abnormal MPI results, with sensitivity of 79% and specificity of 73%. In conclusion, the noninvasive evaluation of endothelial function by FMD has high negative predictive accuracy and good sensitivity and specificity to detect abnormal MPI results in patients with peripheral arterial disease. Thus, it may represent a valuable screening test to rule out significant CAD in these patients.

The identification of reversible dysfunctional myocardium is influenced by the severity of contractile dysfunction and by the length of follow-up.

OBJECTIVES: To evaluate the influence of the severity of regional myocardial dysfunction and of the length of follow-up on the identification of myocardial viability with rest-redistribution Tl single photon emission computed tomography (SPECT) and low-dose dobutamine echocardiography (LDDE). METHODS: Twenty-six patients with chronic coronary artery disease and wall motion abnormalities, candidates for revascularization, were included in this study. All patients underwent, in the same week, Tl SPECT and LDDE for pre-revascularization evaluation of myocardial viability. Reversibility of regional dysfunction was assessed by two-dimensional echocardiography, 40+/-20 days (early follow-up) and 12+/-5 months (late follow-up) after revascularization. RESULTS: In a/dyskinetic segments, Tl SPECT showed similar values of sensitivity (78% vs. 71%, P=NS) and slightly higher values of specificity (43% vs. 18%, P<0.01) compared to hypokinetic segments, in predicting functional recovery at early follow-up. No significant changes were observed in the diagnostic accuracy of Tl SPECT at late follow-up. On the contrary, LDDE provided significantly lower values of sensitivity (56% vs. 94%, P<0.05) and higher values of specificity (73% vs. 9%, P<0.01) in a/dyskinetic compared to hypokinetic segments. Specificity of LDDE in a/dyskinetic segments significantly increased from early (73%) to late follow-up (95%; P<0.05). Similarly, positive predictive value in a/dyskinetic segments significantly increased from early (69%) to late follow-up (96%; P<0.05). CONCLUSIONS: The severity of regional dysfunction and the length of follow-up significantly influence the diagnostic accuracy of LDDE but not of rest-redistribution Tl SPECT in the identification of myocardial viability.

Non-imaging nuclear monitoring of left ventricular function: twenty-five years of technical development and clinical experience.

Although the first non-imaging nuclear probe for clinical application was already available 25 years ago, this technique is still underused for the assessment of ventricular function. Over the years substantial technological progress rendered nuclear probes more accurate and easier to use, and so far the applicability of these devices has been evaluated in several experimental and clinical contexts. Bedside devices can be used in the evaluation of hemodynamically unstable patients and of drug therapy. In patients with several heart diseases, particularly with ischemic cardiomyopathy, accurate information on the changes in ventricular function occurring during routine activities, as well as during structured activities, can be provided using the ambulatory probes. This review will focus on the development and clinical application of these diagnostic tools.