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Pubblicazioni - Perna Dott. Enrico
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Exercise oscillatory ventilation and prognosis in heart failure patients with reduced and mid-range ejection fraction.
Eur J Heart Fail2019 Dec;21(12):1586-1595. doi: 10.1002/ejhf.1595.
Rovai Sara, Corrà Ugo, Piepoli Massimo, Vignati Carlo, Salvioni Elisabetta, Bonomi Alice, Mattavelli Irene, Arcari Luca, Scardovi Angela B, Perrone Filardi Pasquale, Lagioia Rocco, Paolillo Stefania, Magrì Damiano, Limongelli Giuseppe, Metra Marco, Senni Michele, Scrutinio Domenico, Raimondo Rosa, Emdin Michele, Lombardi Carlo, Cattadori Gaia, Parati Gianfranco, Re Federica, Cicoira Mariantonietta, Villani Giovanni Q, Minà Chiara, Correale Michele, Frigerio Maria, Perna Enrico, Mapelli Massimo, Magini Alessandra, Clemenza Francesco, Bussotti Maurizio, Battaia Elisa, Guazzi Marco, Bandera Francesco, Badagliacca Roberto, Di Lenarda Andrea, Pacileo Giuseppe, Maggioni Aldo, Passino Claudio, Sciomer Susanna, Sinagra Gianfranco, Agostoni Piergiuseppe,
Abstract
AIMS:
Exercise oscillatory ventilation (EOV) is a pivotal cardiopulmonary exercise test parameter for the prognostic evaluation of patients with chronic heart failure (HF). It has been described in patients with HF with reduced ejection fraction (<40%, HFrEF) and with HF with preserved ejection fraction (>50%, HFpEF), but no data are available for patients with HF with mid-range ejection fraction (40-49%, HFmrEF). The aim of the study was to evaluate the prognostic role of EOV in HFmrEF patients.
METHODS AND RESULTS:
We analysed 1239 patients with HFmrEF and 4482 patients with HFrEF, enrolled in the MECKI score database, with a 2-year follow-up. The study endpoint was the composite of cardiovascular death, urgent heart transplant, and ventricular assist device implantation. We identified EOV in 968 cases (16% and 17% of cases in HFmrEF and HFrEF, respectively). HFrEF EOV+ patients were significantly older, and their parameters suggested a more severe HF than HFrEF EOV- patients. A similar behaviour was found in HFmrEF EOV+ vs. EOV- patients. Kaplan-Meier analysis, irrespective of ejection fraction, showed that EOV is associated with a worse survival, and that patients with HFrEF and HFmrEF EOV+ had a significantly worse outcome than the EOV- of the same ejection fraction groups. EOV-associated survival differences in HFmrEF patients started after 18?months of follow-up.
CONCLUSION:
Exercise oscillatory ventilation has a similar prevalence and ominous prognostic value in both HFmrEF and HFrEF patients, indicating a group of patients in need of a more intensive follow-up and a more aggressive therapy. In HFmrEF, the survival curves between EOV+ and EOV- patients diverged only after 18?months.
© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.
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Psychological outcomes of left ventricular assist device long-term treatment: A 2-year follow-up study.
Artif Organs2020 Jan;44(1):67-71. doi: 10.1111/aor.13531.
Voltolini Alessandra, Salvato Gerardo, Frigerio Maria, Cipriani Manlio, Perna Enrico, Pisu Mirella, Mazza Umberto
Abstract
Left ventricular assist device (LVAD) is an effective therapy for patients with advanced or refractory heart failure. It may represent a temporary treatment in heart transplant (HTX) candidates (Bridge-To-Transplant-BTT), or a permanent therapy for patients unsuitable for HTX (Destination Therapy-DT). Living with the device may be stressful for both the patients and their caregivers. Currently, evidence on the psychological assessment of LVAD recipients, and factors influencing the patients' psychological adaptation to the device in the long-term period is limited. Here, we explored the quality of life in 20 patients who were treated with LVAD with BTT (n = 13) or DT indication (n = 7) before (T0), 1 year (T1) and 2 years (T2) after implantation, using the EuroQoL-5D-5L test. We also analyzed the influence of sociodemographic (eg, age, gender) and clinical variables (eg, the INTERMACS level and number of hospital admissions) on the quality of life at T2. We found a significant improvement in the self-perceived quality of life 2 years after LVAD implantation. Patients significantly improved in the domains of physical activity and anxiety and depression symptoms. Interestingly, we also demonstrated that the treatment indication was related to changes in self-assessed quality of life, which improved over time in patients implanted with DT indication, whereas it decreased from T1 to T2 in patients with BTT indication. Taken together, these findings suggest that LVAD-related emotional distress and coping strategies need to be carefully evaluated before and in the long-term after LVAD implantation.
© 2019 International Center for Artificial Organ and Transplantation and Wiley Periodicals, Inc.
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Safety of centrifugal left ventricular assist device in patients previously treated with MitraClip system.
Int J Cardiol2019 05;283():131-133. doi: S0167-5273(18)36049-2.
Ammirati Enrico, Van De Heyning Caroline M, Musca Francesco, Brambatti Michela, Perna Enrico, Cipriani Manlio, Cannata Aldo, Mondino Michele, Moreo Antonella, De Bock Dina, Pretorius Victor, Claeys Marc J, Adler Eric D, Russo Claudio F, Frigerio Maria
Abstract
INTRODUCTION:
No data regarding the safety of continuous-flow left ventricular assist device (CF-LVAD) implantation in patients with previous MitraClip have been reported. Thus, it remains unknown whether an initial treatment strategy with MitraClip therapy might complicate future heart failure management in patients who are also considered for CF-LVAD.
METHODS:
We retrospectively identified 6 patients (median age of 62?years; 2 women) who had been treated with MitraClip, that were eventually implanted with a CF-LVAD (all Heartware HVAD) in 3 hospitals between 2013 and 2018.
RESULTS:
Patients were treated in 4 cases with 2 clips, and in 2 cases with 1 clip. Median time from MitraClip implantation to CF-LVAD implant was 282?days (interquartile range 67 to 493), and median time on CF-LVAD support was 401?days (interquartile range 105 to 492?days). Two patients underwent a heart transplant, 3 patients died on support, and 1 is alive on support. In all cases, there was a reduction of functional mitral regurgitation without MitraClip-related complications.
CONCLUSIONS:
Based on this small case series, implantation of a CF-LVAD appears safe in patients with a previously positioned MitraClip system, at least, with 1 or 2 clips in place, with no need for additional mitral valve surgery.
Copyright © 2019 Elsevier B.V. All rights reserved.
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Antithrombotic therapy in ventricular assist device (VAD) management: From ancient beliefs to updated evidence. A narrative review.
Int J Cardiol Heart Vasc2018 Sep;20():20-26. doi: 10.1016/j.ijcha.2018.06.005.
Morici Nuccia, Varrenti Marisa, Brunelli Dario, Perna Enrico, Cipriani Manlio, Ammirati Enrico, Frigerio Maria, Cattaneo Marco, Oliva Fabrizio
Abstract
Platelets play a key role in the pathogenesis of ventricular assist device (VAD) thrombosis; therefore, antiplatelet drugs are essential, both in the acute phase and in the long-term follow-up in VAD management. Aspirin is the most used agent and still remains the first-choice drug for lifelong administration after VAD implantation. Anticoagulant drugs are usually recommended, but with a wide range of efficacy targets. Dual antiplatelet therapy, targeting more than one pathway of platelet activation, has been used for patients developing a thrombotic event, despite an increased risk of bleeding complications. Although different strategies have been attempted, bleeding and thrombotic events remain frequent and there are no uniform strategies adopted for pharmacological management in the short and mid- or long-term follow up. The aim of this article is to provide an overview of the evidence from randomized clinical trials and observational studies with a focus on the pathophysiologic mechanisms underlying bleeding and thrombosis in VAD patients and the best antithrombotic regimens available.
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Scheduled intermittent inotropes for Ambulatory Advanced Heart Failure. The RELEVANT-HF multicentre collaboration.
Int J Cardiol2018 Dec;272():255-259. doi: S0167-5273(18)34420-6.
Oliva Fabrizio, Perna Enrico, Marini Marco, Nassiacos Daniele, Cirò Antonio, Malfatto Gabriella, Morandi Fabrizio, Caico Ivan, Perna Gianpiero, Meloni Sabina, Vincenzi Antonella, Villani Alessandra, Vecchi Andrea Lorenzo, Minoia Chiara, Verde Alessandro, De Maria Renata,
Abstract
BACKGROUND:
Ambulatory Advanced Heart Failure (AAHF) is characterized by recurrent HF hospitalizations, escalating diuretic requirements, intolerance to neurohormonal antagonists, end-organ dysfunction, short-term reduced life expectancy despite optimal medical management (OMM). The role of intermittent inotropes in AAHF is unclear. The RELEVANT-HF registry was designed to obtain insight on the effectiveness and safety of compassionate scheduled repetitive 24-hour levosimendan infusions (LEVO) in AAHF patients.
METHODS:
185 AAHF NYHA class III-IV patients, with ?2 HF hospitalizations/emergency visits in the previous 6?months and systolic dysfunction, were treated with LEVO at tailored doses (0.05-0.2??g/kg/min) without prior bolus every 3-4?weeks. We compared data on HF hospitalizations (percent days spent in hospital, DIH) in the 6?months before and after treatment start.
RESULTS:
Infusion-related adverse events occurred in 23 (12.4%) patients the commonest being ventricular arrhythmias (16, 8.6%). During follow-up, 37 patients (20%) required for clinical instability treatment adjustments (decreases in infusion dose, rate of infusion or interval). From the 6?months before to the 6?months after treatment start we found lower DIH (9.4 (8.2) % vs 2.8 (6.6) %, p?
CONCLUSIONS:
In AAHF patients, who remain symptomatic despite OMM, LEVO is well tolerated and associated with lower overall length of hospital stay during six months. This multicentre clinical experience underscores the need for a randomized controlled trial of LEVO impact on outcomes in AAHF patients.
Copyright © 2018 Elsevier B.V. All rights reserved.
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Dose-dependent efficacy of ?-blocker in patients with chronic heart failure and atrial fibrillation.
Int J Cardiol2018 Dec;273():141-146. doi: S0167-5273(18)34278-5.
Campodonico Jeness, Piepoli Massimo, Clemenza Francesco, Bonomi Alice, Paolillo Stefania, Salvioni Elisabetta, Corrà Ugo, Binno Simone, Veglia Fabrizio, Lagioia Rocco, Sinagra Gianfranco, Cattadori Gaia, Scardovi Angela B, Metra Marco, Senni Michele, Scrutinio Domenico, Raimondo Rosa, Emdin Michele, Magrì Damiano, Parati Gianfranco, Re Federica, Cicoira Mariantonietta, Minà Chiara, Limongelli Giuseppe, Correale Michele, Frigerio Maria, Bussotti Maurizio, Perna Enrico, Battaia Elisa, Guazzi Marco, Badagliacca Roberto, Di Lenarda Andrea, Maggioni Aldo, Passino Claudio, Sciomer Susanna, Pacileo Giuseppe, Mapelli Massimo, Vignati Carlo, Lombardi Carlo, Filardi Pasquale Perrone, Agostoni Piergiuseppe,
Abstract
BACKGROUND:
The usefulness of ?-blockers in heart failure (HF) patients with permanent atrial fibrillation (AF) has been questioned.
METHODS AND RESULTS:
We analyzed data from HF patients (958 patients (801 males, 84%, age 67?±?11?years)) with AF enrolled in the MECKI score database. We evaluated prognosis (composite of cardiovascular death, urgent heart transplant, or left ventricular assist device) of patients receiving ?-blockers (n?=?777, 81%) vs. those not treated with ?-blockers (n?=?181, 19%). We also analyzed the role ?1-selectivity and the role of daily ?-blocker dose. To account for different HF severity, Kaplan-Meier survival curves were normalized for relevant confounding factors and for treatment strategies. Dose was available in 629 patients. Median follow-up was 1312 (577-2304) days in the entire population, 1203 (614-2420) and 1325 (569-2300) days in patients not receiving and receiving ?-blockers. 224 (23%, 54/1000?events/year), 163 (21%, 79/1000?events/year), and 61 (34%, 49/1000?events/year) events were recorded, respectively. At 10-year patients treated with ?-blockers had a better outcome (HR 0.447, p?
CONCLUSION:
HF patients with AF taking a ?-blocker have a better outcome (with a survival improvement in parallel with daily dose but no differences as regards ?1 selectivity) but this does not mean that ?-blockers improve outcomes in these patients as we cannot control for all the potential confounders associated with ?-blocker use.
Copyright © 2018. Published by Elsevier B.V.
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Single-center outbreak of Pneumocystis jirovecii pneumonia in heart transplant recipients.
Transpl Infect Dis2018 Jun;20(3):e12880. doi: 10.1111/tid.12880.
Veronese Giacomo, Ammirati Enrico, Moioli Maria Cristina, Baldan Rossella, Orcese Carlo Andrea, De Rezende Gisele, Veronese Silvio, Masciocco Gabriella, Perna Enrico, Travi Giovanna, Puoti Massimo, Cipriani Manlio, Tiberi Simon, Cirillo Daniela, Frigerio Maria
Abstract
BACKGROUND:
Pneumocystis jirovecii pneumonia (PJP) outbreaks are described in solid organ transplant recipients. Few reports suggest interhuman transmission with important infection control implications. We described a large PJP outbreak in heart transplant (HTx) recipients.
METHODS:
Six cases of PJP occurred in HTx recipients within 10 months in our hospital. Demographics, clinical characteristics, treatment and outcomes were described. To identify contacts among individuals a review of all dates of out-patient visits and patient hospitalizations was performed. Cross exposure was also investigated using genotyping on PJ isolates.
RESULTS:
At the time of PJP-related hospitalization, patients' mean age was 49 ± standard deviation 4 years, median time from HTx was 8 (25%-75% interquartile range [Q1-Q3] 5-12) months and none of the cases were on prophylaxis. At PJP-related admission, 5 patients had CMV reactivation, of whom 4 were on antiviral preemptive treatment. Median in-hospital stay was 30 (Q1-Q3, 28-48) days; and 2 cases required intensive care unit admission. All patients survived beyond 2 years. Transmission map analysis suggested interhuman transmission in all cases (presumed incubation period, median 90 [Q1-Q3, 64-91] days). Genotyping was performed in 4 cases, demonstrating the same PJ strain in 3 cases.
CONCLUSIONS:
We described a large PJP cluster among HTx recipients, supporting the nosocomial acquisition of PJP through interhuman transmission. Based on this experience, extended prophylaxis for more than 6 months after HTx could be considered in specific settings. Further work is required to understand its optimal duration and timing based on individual risk factor profiles and to define standardized countermeasures to prevent and limit PJP outbreaks.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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End-stage heart failure: Two surgical approaches with different rehabilitative outcomes.
PLoS One2017 ;12(10):e0185717. doi: 10.1371/journal.pone.0185717.
Racca Vittorio, Castiglioni Paolo, Panzarino Claudia, Oliva Fabrizio, Perna Enrico, Ferratini Maurizio
Abstract
BACKGROUND:
A rising number of patients are surgically treated for heart failure at the more advanced stage, thanks to the increasing use of left ventricular assist device (LVAD) as a reliable alternative to heart transplantation (HTx). However, it is still unknown whether differences exist between the two surgical approaches in the efficacy of rehabilitation programmes. Therefore, aim of this study was to evaluate whether functional capacity and rehabilitative outcomes differ between HTx and implantation of LVAD.
METHODS AND RESULTS:
We enrolled 51 patients with HTx and 46 with LVAD upon admission to our rehabilitation-unit. We evaluated six-minute walking test (6MWT), resting oxygen saturation (SaO2) and nutritional assessment before and after a standardised cardiovascular rehabilitation programme. HTx and LVAD groups differed in age, anthropometric variables, gender distribution. Upon enrolment, 6MWT distance was similar in the two groups, whereas malnutrition was less frequent and the waist circumference/height ratio (WHtR) was greater in LVAD patients. SaO2 was greater in HTx patients. Rehabilitation improved SaO2, 6MWT distance and nutritional status. The difference in malnutrition disappeared, but WHtR remained higher in the LVAD and SaO2 higher in the HTx patients; the 6MWT distance improved more in the HTx patients. Multivariate linear regression analysis confirmed that the type of intervention was independent predictor of 6MWT distance after rehabilitation.
CONCLUSIONS:
HTx patients improve more rapidly and perform better after rehabilitation, suggesting the need for more tailored rehabilitation training for LVAD patients.
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[Psychological evaluation and support in patients with left ventricular assist devices: preliminary data at 6-month follow-up].
G Ital Cardiol (Rome)2016 Nov;17(11):940-946. doi: 10.1714/2498.26204.
Voltolini Alessandra, Minotti Anna, Verde Alessandro, Cipriani Manlio, Garascia Andrea, Turazza Fabio, Macera Francesca, Perna Enrico, Russo Claudio F, Fumagalli Emilia, Frigerio Maria
Abstract
BACKGROUND:
Heart disease has an impact on patient's identity and self-perception. Taking into account the wide literature about psychological aspects before and after heart transplant, it clearly emerges that there is a lack of data and results for patients up to implantation of ventricular assist devices (VAD). The aim of the present study was to explore quality of life and factors correlated with psychological adjustment in patients supported with VAD.
METHODS:
From February 2013 to August 2014, 18 patients (17 male, mean age 57 years) under clinical evaluation before and after VAD implantation were enrolled. During interviews, patients were assessed with EuroQoL-5D questionnaire to monitor improvement of quality of life before implantation and at 3 and 6 months; critical issues, needs and point of views of patients have been described.
RESULTS:
A significant improvement in the quality of life score was observed at 3 (score 38 [interquartile range 30-40] vs 75 [60-80], p<0.05) and 6 months (38 [30-40] vs 70 [60-80], p<0.05). Overall, patients' psychological state investigated by the test showed a clear and positive trend. All patients need to empower through complete information about the device, related risks and life expectancy. Interdisciplinary approach improved compliance with therapy.
CONCLUSIONS:
Successful treatment and efficient psychological care are closely related to assessment and continuous clinical support. This approach ensures a better selection of patients and improves their compliance. Further data are needed to support our preliminary observations and to explore long-term quality of life.
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Ticagrelor for left ventricular assist device thrombosis: A new therapeutic option to be evaluated with caution.
Int J Cardiol2016 Oct;221():58-9. doi: 10.1016/j.ijcard.2016.06.304.
Morici Nuccia, Perna Enrico, Cipriani Manlio, Femia Eti Alessandra, Oliva Fabrizio, Frigerio Maria, Cattaneo Marco
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Mid-term survival after continuous-flow left ventricular assist device versus heart transplantation.
Heart Vessels2016 May;31(5):722-33. doi: 10.1007/s00380-015-0654-4.
Ammirati Enrico, Oliva Fabrizio G, Colombo Tiziano, Russo Claudio F, Cipriani Manlio G, Garascia Andrea, Guida Valentina, Colombo Giulia, Verde Alessandro, Perna Enrico, Cannata Aldo, Paino Roberto, Martinelli Luigi, Frigerio Maria
Abstract
There is a paucity of data about mid-term outcome of patients with advanced heart failure (HF) treated with left ventricular assist device (LVAD) in Europe, where donor shortage and their aging limit the availability and the probability of success of heart transplantation (HTx). The aim of this study is to compare Italian single-centre mid-term outcome in prospective patients treated with LVAD vs. HTx. We evaluated 213 consecutive patients with advanced HF who underwent continuous-flow LVAD implant or HTx from 1/2006 to 2/2012, with complete follow-up at 1 year (3/2013). We compared outcome in patients who received a LVAD (n = 49) with those who underwent HTx (n = 164) and in matched groups of 39 LVAD and 39 HTx patients. Patients that were treated with LVAD had a worse risk profile in comparison with HTx patients. Kaplan-Meier survival curves estimated a one-year survival of 75.5 % in LVAD vs. 82.3 % in HTx patients, a difference that was non-statistically significant [hazard ratio (HR) 1.46; 95 % confidence interval (CI) 0.74-2.86; p = 0.27 for LVAD vs. HTx]. After group matching 1-year survival was similar between LVAD (76.9 %) and HTx (79.5 %; HR 1.15; 95 % CI 0.44-2.98; p = 0.78). Concordant data was observed at 2-year follow-up. Patients treated with LVAD as bridge-to-transplant indication (n = 22) showed a non significant better outcome compared with HTx with a 95.5 and 90.9 % survival, at 1- and 2-year follow-up, respectively. Despite worse preoperative conditions, survival is not significantly lower after LVAD than after HTx at 2-year follow-up. Given the scarce number of donors for HTx, LVAD therapy represents a valid option, potentially affecting the current allocation strategy of heart donors also in Europe.
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Deletion of the activated protein-1 transcription factor JunD induces oxidative stress and accelerates age-related endothelial dysfunction.
Circulation2013 Mar;127(11):1229-40, e1-21. doi: 10.1161/CIRCULATIONAHA.112.000826.
Paneni Francesco, Osto Elena, Costantino Sarah, Mateescu Bogdan, Briand Sylvie, Coppolino Giuseppe, Perna Enrico, Mocharla Pavani, Akhmedov Alexander, Kubant Ruslan, Rohrer Lucia, Malinski Tadeusz, Camici Giovanni G, Matter Christian M, Mechta-Grigoriou Fatima, Volpe Massimo, Lüscher Thomas F, Cosentino Francesco
Abstract
BACKGROUND:
Reactive oxygen species are major determinants of vascular aging. JunD, a member of the activated protein-1 family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to reactive oxygen species homeostasis in the vasculature remains unknown.
METHODS AND RESULTS:
Endothelium-dependent vasorelaxation was impaired in young and old JunD(-/-) mice (6 and 22 months old) compared with age-matched wild-type mice. JunD(-/-) mice displayed an age-independent decline in endothelial nitric oxide release and endothelial nitric oxide synthase activity and increased mitochondrial superoxide formation and peroxynitrite levels. Furthermore, vascular expression and activity of the free radical scavengers manganese and extracellular superoxide dismutase and aldehyde dehydrogenase 2 were reduced, whereas the NADPH oxidase subunits p47phox, Nox2, and Nox4 were upregulated. These redox changes were associated with premature vascular aging, as shown by reduced telomerase activity, increased ?-galactosidase-positive cells, upregulation of the senescence markers p16(INK4a) and p53, and mitochondrial disruption. Interestingly, old wild-type mice showed a reduction in JunD expression and transcriptional activity resulting from promoter hypermethylation and binding with tumor suppressor menin, respectively. In contrast, JunD overexpression blunted age-induced endothelial dysfunction. In human endothelial cells, JunD knockdown exerted a similar impairment of the O2(-)/nitric oxide balance that was prevented by concomitant NADPH inhibition. In parallel, JunD expression was reduced in monocytes from old versus young healthy subjects and correlated with mRNA levels of scavenging and oxidant enzymes.
CONCLUSIONS:
JunD provides protection in aging-induced endothelial dysfunction and may represent a novel target to prevent reactive oxygen species-driven vascular aging.
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p66(Shc) protein, oxidative stress, and cardiovascular complications of diabetes: the missing link.
J Mol Med (Berl)2009 Sep;87(9):885-91. doi: 10.1007/s00109-009-0499-3.
Francia Pietro, Cosentino Francesco, Schiavoni Marzia, Huang Yale, Perna Enrico, Camici Giovani G, Lüscher Thomas F, Volpe Massimo
Abstract
Diabetes affects more than 150 million people worldwide, and it is estimated that this would increase to 299 million by the year 2025. The incidence of and mortality from cardiovascular disease are two- to eightfold higher in subjects with diabetes than in those without, coronary artery disease accounting for the large majority of deaths. Among the full spectrum of biochemical effects of high glucose, generation of oxygen-derived free radicals is one of the main pathophysiological mechanisms linking hyperglycemia to atherosclerosis, nephropathy, and cardiomyopathy. The adaptor protein p66(Shc) is implicated in mitochondrial reactive oxygen species (ROS) generation and translation of oxidative signals into apoptosis. Indeed, p66(Shc-/-) mice display prolonged lifespan, reduced production of intracellular oxidants, and increased resistance to oxidative stress-induced apoptosis. Accordingly, a series of studies defined the pathophysiological role of p66(Shc) in cardiovascular disease where ROS represent a substantial triggering component. As p66(Shc) modulates the production of cellular ROS, it represents a proximal node through which high glucose exerts its deleterious effects on different cell types; indeed, several studies tested the hypothesis that deletion of the p66(Shc) gene may confer protection against diabetes-related cardiovascular complications. The present review focuses on the reported evidence linking p66(Shc) signaling pathway to high glucose-associated endothelial dysfunction, atherogenesis, nephropathy, and cardiomyopathy.
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