Health-Status Outcomes in Older Patients With Myocardial Infarction: Physiology-Guided Complete Revascularization Versus Culprit-Only Strategy.

BACKGROUND: The FIRE trial (Functional Assessment in Elderly Myocardial Infarction Patients With Multivessel Disease) enrolled 1445 older (aged ≥75 years) patients with myocardial infarction and multivessel disease in Italy, Spain, and Poland. Patients were randomized to physiology-guided complete revascularization or treatment of the only culprit lesion. Physiology-guided complete revascularization significantly reduced ischemic adverse events at 1 year. This prespecified analysis investigated the changes between the 2 study groups in angina status, quality of life, physical performance, and frailty. METHODS: Patients underwent validated scales at hospital discharge (baseline) and 1 year later. Angina status was evaluated using the Seattle Angina Questionnaire, health-related quality of life by EQ visual analog scale, physical performance by short physical performance battery, and frailty by the clinical frailty scale. Mixed models for repeated measures analysis were used to study the association between the treatment arms, time, and scales. RESULTS: Baseline and 1-year Seattle Angina Questionnaire, EQ visual analog scale, short physical performance battery, and clinical frailty scale were collected in around two-thirds of the entire FIRE study population. The mean age was 80.9±4.6 years (female sex, 35.9%). Overall, 35.3% were admitted for ST-segment-elevation myocardial infarction, whereas the others were admitted for non-ST-segment-elevation myocardial infarction. Physiology-guided complete revascularization, compared with culprit-only revascularization, was associated with greater improvement in terms of angina status (Seattle Angina Questionnaire summary score, 7.3 [95% CI, 6.1-8.6] points), health-related quality of life (EQ visual analog scale, 6.2 [95% CI, 4.4-8.1] points), and physical performance (short physical performance battery, 1.1 [95% CI, 0.9-1.3] points). After 1 year, patients randomized to culprit-only revascularization experienced a deterioration in frailty status (clinical frailty scale, 0.2 [95% CI, 0.1-0.3] points), which was not observed in patients randomized to physiology-guided complete revascularization. CONCLUSIONS: The present analysis suggested that a physiology-guided complete revascularization is associated with consistent benefits in terms of angina status, quality of life, physical performance, and the absence of further deterioration of the frailty status. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03772743.

QFR for the Revascularization of Nonculprit Vessels in MI Patients: Insights From the FIRE Trial.

BACKGROUND: The role of quantitative flow ratio (QFR) in the treatment of nonculprit vessels of patients with myocardial infarction (MI) is a topic of ongoing discussion. OBJECTIVES: This study aimed to investigate the predictive capability of QFR for adverse events and its noninferiority compared to wire-based functional assessment in nonculprit vessels of MI patients. METHODS: The FIRE (Functional Assessment in Elderly MI Patients With Multivessel Disease) trial randomized 1,445 older MI patients to culprit-only (n = 725) or physiology-guided complete revascularization (n = 720). In the culprit-only arm, angiographic projections of nonculprit vessels were prospectively collected, centrally reviewed for QFR computation, and associated with endpoints. In the complete revascularization arm, endpoints were compared between nonculprit vessels investigated with QFR or wire-based functional assessment. The primary endpoint was the vessel-oriented composite endpoint (VOCE) at 1 year. RESULTS: QFR was measured on 903 nonculprit vessels from 685 patients in the culprit-only arm. Overall, 366 (40.5%) nonculprit vessels showed a QFR value ≤0.80, with a significantly higher incidence of VOCEs (22.1% vs 7.1%; P < 0.001). QFR ≤0.80 emerged as an independent predictor of VOCEs (HR: 2.79; 95% CI: 1.64-4.75). In the complete arm, QFR was used in 320 (35.2%) nonculprit vessels to guide revascularization. When compared with propensity-matched nonculprit vessels in which treatment was guided by wire-based functional assessment, no significant difference was observed (HR: 0.57; 95% CI: 0.28-1.15) in VOCEs. CONCLUSIONS: This prespecified subanalysis of the FIRE trial provides evidence supporting the safety and efficacy of QFR-guided interventions for the treatment of nonculprit vessels in MI patients. (Functional Assessment in Elderly MI Patients With Multivessel Disease [FIRE]; NCT03772743).

Impact of pre-admission physical activity on benefits of physiology-guided complete revascularization in older patients with myocardial infarction: insights from the FIRE trial.

AIMS: The present analysis from the Functional Assessment in Elderly Myocardial Infarction Patients with Multivessel Disease (FIRE) trial aims to explore the significance of pre-admission physical activity and assess whether the benefits of physiology-guided complete revascularization apply consistently to sedentary and active older patients. METHODS AND RESULTS: Patients aged 75 years or more with myocardial infarction (MI) and multivessel disease were randomized to receive physiology-guided complete revascularization or culprit-only strategy. The primary outcome was a composite of death, MI, stroke, or any revascularization within a year. Secondary endpoints included the composite of cardiovascular death or MI, as well as single components of the primary endpoint. Pre-admission physical activity was categorized into three groups: (i) absent (sedentary), (ii) light, and (iii) vigorous. Among 1445 patients, 692 (48%) were sedentary, whereas 560 (39%) and 193 (13%) performed light and vigorous physical activity, respectively. Patients engaging in light or vigorous pre-admission physical activity exhibited a reduced risk of the primary outcome compared with sedentary individuals [light hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.55-0.91 and vigorous HR 0.14, 95% CI 0.07-0.91, respectively]. These trends were also observed for death, cardiovascular death, or MI. When comparing physiology-guided complete revascularization vs. culprit-only strategy, no significant interaction was observed for primary and secondary endpoints when stratified by sedentary or active status. CONCLUSION: In older patients with MI, pre-admission physical activity emerges as a robust and independent prognostic determinant. Physiology-guided complete revascularization stands out an effective strategy in reducing ischaemic adverse events, irrespective of pre-admission physical activity status. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03772743.

The Functional Assessment in Elderly Myocardial Infarction Patients with Multivessel Disease (FIRE) trial has shown that physiology-guided complete revascularization reduces ischaemic adverse events in older patients with myocardial infarction (MI) and multivessel disease. Older patients who engage in light or vigorous physical activity before hospitalization for MI have a reduced risk of the primary composite outcome of death, MI, stroke, or ischaemia-driven revascularization. These benefits extend to all secondary cardiovascular outcomes as well. In the present subanalysis of the FIRE trial, we find that the positive prognosis associated with physiology-guided complete revascularization holds true even for patients with a sedentary lifestyle. This means that this type of revascularization can effectively reduce ischaemic adverse events in older patients with MI and multivessel disease, regardless of their physical activity levels.

Safety, efficacy and impact on frailty of mini-invasive radial balloon aortic valvuloplasty.

OBJECTIVE: The study was designed to: (1) confirm safety and feasibility of mini-invasive radial balloon aortic valvuloplasty (BAV); (2) assess its impact in terms of quality of life and frailty; and (3) evaluate whether changes in frailty after BAV are associated with death in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: 330 patients undergoing BAV in 16 Italian centres were prospectively included. The primary endpoint was the occurrence of major and minor Valve Academic Research Consortium (VARC)-2 bleeding. Secondary endpoints were scales of quality of life, frailty, evaluated at baseline and 30 days, and their relationship with the occurrence of all-cause death. RESULTS: BAV was performed by radial access in 314 (95%) patients. No VARC-2 major and six (1.8%) VARC-2 minor bleedings occurred in the study population. Quality of life, as well as frailty status, significantly improved 30 days after BAV. At 1 year, patients undergoing TAVI with baseline essential frailty toolset (EFT) <3 or achieving an EFT <3 after BAV had a comparable occurrence of all-cause death (15% vs 19%, p=0.58). On the contrary, patients with EFT ≥3 at 30 days despite BAV showed the worst prognosis (all-cause death: 40% vs 15% and 19%, p=0.006 and p=0.05, respectively). CONCLUSIONS: Mini-invasive radial BAV is safe, feasible and associated with a low rate of vascular complications. Patients improving EFT 30 days after BAV showed a favourable outcome after TAVI. TRIAL REGISTRATION NUMBER: NCT03087552.

Transcatheter Aortic Valve-in-Valve Implantation Using Lotus Valve for Failed Surgical Bioprostheses.

BACKGROUND: Patients with failed bioprostheses are an increasing population at high risk for redo surgery. Valve-in-valve transcatheter aortic valve implantation is a promising alternative but a limited number of first-generation devices have proven efficacy in all cases. METHODS: Patients with degenerated bioprostheses at high risk for redo surgery were included in the registry after being assigned to valve-in-valve intervention by a local heart team. Main basal and follow-up data (at 1 month and 6 months) of patients undergoing valve-in-valve transcatheter aortic valve implantation with the Lotus valve system (Boston Scientific, Natick, MA) in three high-volume Italian centers were entered in the registry. RESULTS: Twelve patients (aged 71.1 ± 14.1 years, 66% male, logistic European System for Cardiac Operative Risk Evaluation score 28.8 ± 22.9) were included in the registry. Implantation success rate was 92%; in 1 patient, the valve was completely retrieved because of unsatisfactory gradients after valve positioning. All procedures were done through femoral access, and all but one required only local anesthesia. In patients with stenosis as pure or mixed mechanism for degeneration (n = 7), mean ventriculoaortic gradient decreased from 46.7 ± 7.0 mm Hg to 16.6 ± 5.7 mm Hg (p < 0.001). No patients had more than mild aortic regurgitation at hospital discharge. Results where confirmed at 1-month and 6-month follow-up, with improvement of New York Heart Association functional status in all patients (functional class I to II in 100% of patients). CONCLUSIONS: The valve-in-valve procedure using the Lotus valve is a feasible alternative to repeat surgery in high-risk patients with degenerated bioprostheses. Using the Lotus valve in this challenging and increasingly frequent scenario could offer a safe and effective strategy that should be explored in larger clinical trials.

Current decision making and short-term outcome in patients with degenerative aortic stenosis: the Pooled-RotterdAm-Milano-Toulouse In Collaboration Aortic Stenosis survey.

AIMS: The aim of this study was to provide a real-world snapshot of contemporary Heart Team decision making on patients with aortic stenosis (AS) and the consequent short-term clinical outcome. METHODS AND RESULTS: This was an international multicentre prospective registry encompassing 390 patients with symptomatic severe AS who were prospectively enrolled. Clinical endpoints and the decisive arguments to opt for surgical or transcatheter aortic valve replacement, or medical therapy were recorded separately. The mean age was 76.4±11.6 years, 55% were male and the STS score was 2.9% (IQR 1.6-6.9). The local Heart Teams considered 43%, 25% and 23% to be at low, intermediate and high operative risk with a calculated STS score of 2.18±1.72, 5.08±2.76 and 13.15±9.43, respectively. Overall, 7% were deemed inoperable. Ninety-four percent of patients at low operative risk were sent for SAVR whereas 64% and 92% of intermediate and high-risk patients underwent TAVI. Only 6% of patients did not receive any kind of aortic valve replacement. Overall, 30-day all-cause mortality was 2.8%. TAVI was associated with more major vascular complications, need for permanent pacemakers and post-procedural aortic regurgitation. SAVR had more life-threatening bleedings and new-onset atrial fibrillation. CONCLUSIONS: The PRAGMATIC AS survey offers a snapshot of the contemporary management of patients with symptomatic severe AS. Multidisciplinary Heart Teams select an optimal strategy based on age, frailty and comorbidities. Nearly half of all patients are sent for TAVI. Only a small minority of patients will not receive valve replacement therapy.

First Lotus aortic valve-in-valve implantation to treat degenerated Mitroflow bioprostheses.

AIMS: Transcatheter aortic valve-in-valve implantation is an emerging alternative to conventional surgical aortic valve replacement (SAVR) in patients with degenerated aortic bioprostheses. This procedure presents a high risk of coronary occlusion, especially during treatment of patients implanted with a bioprosthesis with a lower distance between the leaflets and the coronary ostia, such as the Mitroflow valve (Sorin S.p.A., Milan, Italy). In this report we aim to describe the safety and feasibility of transfemoral valve-in-valve implantation of a new-generation Lotus™ Aortic Valve Replacement System (Boston Scientific, Marlborough, MA, USA) in a case of degenerated Mitroflow bioprostheses. METHODS AND RESULTS: We describe a case of degenerated Sorin Mitroflow bioprostheses successfully treated with the transfemoral new-generation Lotus valve-in-valve system. During the procedure no coronary protection was required and the patient had no MACE at 30-day follow-up. To our knowledge, this is the first report of a Lotus valve implant in a degenerated Mitroflow prosthesis. CONCLUSIONS: The transcatheter valve-in-valve procedure using the new-generation Lotus Valve System is a safe and feasible alternative to repeat cardiac surgery in high-risk patients with surgical degenerated Mitroflow bioprostheses.

Two-year outcomes after first- or second-generation drug-eluting or bare-metal stent implantation in all-comer patients undergoing percutaneous coronary intervention: a pre-specified analysis from the PRODIGY study (PROlonging Dual Antiplatelet Treatment After Grading stent-induced Intimal hyperplasia studY).

OBJECTIVES: This study sought to assess device-specific outcomes after implantation of bare-metal stents (BMS), zotarolimus-eluting Endeavor Sprint stents (ZES-S), paclitaxel-eluting stents (PES), or everolimus-eluting stents (EES) (Medtronic Cardiovascular, Santa Rosa, California) in all-comer patients undergoing percutaneous coronary intervention. BACKGROUND: Few studies have directly compared second-generation drug-eluting stents with each other or with BMS. METHODS: We randomized 2,013 patients to BMS, ZES-S, PES, or EES implantation. At 30 days, each stent group received up to 6 or 24 months of clopidogrel therapy. The key efficacy endpoint was the 2-year major adverse cardiac event (MACE) including any death, myocardial infarction, or target vessel revascularization, whereas the cumulative rate of definite or probable stent thrombosis (ST) was the key safety endpoint. RESULTS: Clinical follow-up at 2 years was complete for 99.7% of patients. The MACE rate was lowest in EES (19.2%; 95% confidence interval [CI]: 16.0 to 22.8), highest in BMS (32.1%; 95% CI: 28.1 to 36.3), and intermediate in PES (26.2%; 95% CI: 22.5 to 30.2) and ZES-S (27.8%; 95% CI: 24.1 to 31.9) groups (chi-square test = 18.9, p = 0.00029). The 2-year incidence of ST in the EES group (1%; 95% CI: 0.4 to 2.2) was similar to that in the ZES-S group (1.4%; 95% CI: 0.7 to 2.8), whereas it was lower compared with the PES (4.6%, 95% CI: 3.1 to 6.8) and BMS (3.6%; 95% CI: 2.4 to 5.6) groups (chi-square = 16.9; p = 0.0001). CONCLUSIONS: Our study shows that cumulative MACE rate, encompassing both safety and efficacy endpoints, was lowest for EES, highest for BMS, and intermediate for PES and ZES-S groups. EES outperformed BMS also with respect to the safety endpoints with regard to definite or probable and definite, probable, or possible ST. (PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY [PRODIGY]; NCT00611286).

Radial versus femoral approach comparison in percutaneous coronary intervention with intraaortic balloon pump support: the RADIAL PUMP UP registry.

BACKGROUND: The role of intraaortic balloon pump (IABP) during percutaneous coronary intervention (PCI) in high-risk acute patients remains debated. Device-related complications and the more complex patient management could explain such lack of clinical benefit. We aimed to assess the impact of transradial versus transfemoral access for PCI requiring IABP support on vascular complications and clinical outcome. METHODS: We retrospectively analyzed 321 consecutive patients receiving IABP support during transfemoral (n = 209) or transradial (n = 112) PCI. Thirty-day net adverse clinical events (NACEs) (composite of postprocedural bleeding, cardiac death, myocardial infarction, target lesion revascularization, and stroke) were the primary end point, with access-related bleeding and hospital stay as secondary end points. RESULTS: Cardiogenic shock and hemodynamic instability were the most common indications for IABP support. Cumulative 30-day NACE rate was 50.2%, whereas an access site-related bleeding occurred in 14.3%. Patients undergoing transfemoral PCI had a higher unadjusted rate of NACEs when compared with the transradial group (57.4% vs 36.6%, P < .01), mainly due more access-related bleedings (18.7% vs 6.3%, P < .01). Such increased risk of NACEs was confirmed after propensity score adjustment (hazard ratio 0.57 [0.4-0.9], P = .007), whereas hospital stay appeared comparable in the 2 groups. CONCLUSIONS: In this observational registry, high-risk patients undergoing PCI and requiring IABP support appeared to have fewer NACEs if transradial access was used instead of transfemoral, mainly due to fewer access-related bleedings. Given the inherent limitations of this retrospective work, including the inability to adjust for unknown confounders, further controlled studies are warranted to confirm or refute these findings.

Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.

BACKGROUND: The optimal duration of dual-antiplatelet therapy and the risk-benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined. We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration-approved drug-eluting or bare-metal stents. METHODS AND RESULTS: We randomly assigned 2013 patients to receive bare-metal, zotarolimus-eluting, paclitaxel-eluting, or everolimus-eluting stent implantation. At 30 days, patients in each stent group were randomly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin. The primary end point was a composite of death of any cause, myocardial infarction, or cerebrovascular accident. The cumulative risk of the primary outcome at 2 years was 10.1% with 24-month dual-antiplatelet therapy compared with 10.0% with 6-month dual-antiplatelet therapy (hazard ratio, 0.98; 95% confidence interval, 0.74-1.29; P=0.91). The individual risks of death, myocardial infarction, cerebrovascular accident, or stent thrombosis did not differ between the study groups; however, there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions, including the recently proposed Bleeding Academic Research Consortium classification. CONCLUSIONS: A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause, myocardial infarction, or cerebrovascular accident. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00611286.

Different clinical models of CD34 + cells mobilization in patients with cardiovascular disease.

To test the role of necrosis, ischemia or both in bone marrow cells (BMC) mobilization in patients with cardiovascular disease. We studied three groups of patients: group 1, Iatrogenic Necrosis, with pure necrosis (28 patients undergoing transcatheter radiofrequency ablation); group 2, Ischemic Necrosis (30 patients with myocardial infarction); group 3, Pure Ischemia (24 patients with unstable angina). As control groups, we studied 27 patients with stable coronary artery disease (CAD), and 20 patients without CAD undergoing angiography for valvular diseases or cardiomiopathy. CD34 + cells and cytokines were evaluated at: T(0) (baseline), 48 h and 5, 7, 10, 14 days thereafter. We observed a significant increase of CD34 + cells at T(3) and T(4) only in Iatrogenic Necrosis and Ischemic Necrosis group. The peak of mobilization was observed ten days after the necrotic event (2.8 ± 1.4 vs. 5.9 ± 1.9 in the group 1, P = 0.03; and 3 ± 1.5 vs. 5.6 ± 2 in the group 2, P = 0.04; respectively). We found a good correlation between CD34 + and vascular endothelial growth factor (VEGF) and stromal derived factor (SDF-1α) peak values (r = 0.77 and r = 0.63, respectively). At multivariable analysis, myocardial necrosis (OR 3.5, 95%CI 2.2-4.2, P < 0.01), VEGF (OR 2, 95%CI 1.1-3, P = 0.01 as above versus below median value), and SDF-1α (OR 1.6, 95%CI 1.1-2.5, P = 0.02 as above versus below median value) emerged as independent predictors of C34 + cells increase. Myocardial necrosis with simultaneous elevation of VEGF and SDF-1α causes a significant CD34 + cells mobilization in patients with cardiovascular disease.

Randomized comparison of 6- versus 24-month clopidogrel therapy after balancing anti-intimal hyperplasia stent potency in all-comer patients undergoing percutaneous coronary intervention Design and rationale for the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY).

BACKGROUND: The optimal duration of clopidogrel therapy after coronary stenting is debated because of the scarcity of randomized controlled trials and inconsistencies arising from registry data. Although prolonged clopidogrel therapy after bare metal stenting is regarded as an effective secondary prevention measure, the safety profile of drug-eluting stents itself has been questioned in patients not receiving ≥ 12 months of dual-antiplatelet therapy. HYPOTHESIS: Twenty-four months of clopidogrel therapy after coronary stenting reduces the composite of death, myocardial infarction, or stroke compared with 6 months of treatment. STUDY DESIGN: PRODIGY is an unblinded, multicenter, 4-by-2 randomized trial. All-comer patients with indication to coronary stenting are randomly treated-balancing randomization-with bare metal stent (no active late loss inhibition), Endeavor Sprint zotarolimus-eluting stent (Medtronic, Santa Rosa, CA) (mild late loss inhibition), Taxus paclitaxel-eluting stent (Boston Scientific, Natick, MA) (moderate late loss inhibition), or Xience V everolimus-eluting stent (Abbott Vascular, Santa Clara, CA) (high late loss inhibition). At 30 days, patients in each stent group are randomly allocated to receive 24 or up to 6 months of clopidogrel therapy-primary end point randomization. With 1,700 individuals, this study will have >80% power to detect a 40% difference in the primary end point after sample size augmentation of 5% and a background event rate of 8%. SUMMARY: The PRODIGY trial aims to assess whether 24 months of clopidogrel therapy improves cardiovascular outcomes after coronary intervention in a broad all-comer patient population receiving a balanced mixture of stents with various anti-intimal hyperplasia potency.

Poor response to clopidogrel: current and future options for its management.

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions (PCI). Clopidogrel, a thienopyridine antiplatelet agent, has been used to prevent vascular complication in atherothrombotic patients, to prevent stent thrombosis in patients undergoing PCI, and in long term prevention of cardiovascular and cerebrovascular events. More than 40 million patients in the world receive clopidogrel but unfortunately about 20% of these are either non or poor responders. Several methods have been used to assess clopidogrel-induced antiplatelet effects. However, none of these tests have been fully standardized or fully agreed upon to measure clopidogrel responsiveness. Nevertheless, many studies using different techniques, platelet agonists and definitions, showed that patients with a poor response to clopidogrel have an increased risk of death, reinfarction and stent thrombosis. The mechanisms leading to poor responsiveness are not fully clarified and are likely multifactorial: genetic factors, accelerated platelet turnover, up-regulation of the P2Y(12) pathways, high baseline platelet reactivity, poor compliance, under-dosing and drug-drug interactions. The management of these patients is very difficult, but some evidence showed that a strategy of higher maintenance dose or switch to different thienopyridine (e.g. ticlopidine or prasugrel) or use of glycoprotein IIb/IIIa inhibitors during PCI may be helpful to overcome poor responsiveness and improve the long-term clinical outcome. This paper reviews the impact of clopidogrel poor responsiveness on clinical outcomes, the mechanisms leading to poor effect and the different assays to assess it. Finally, current and future options for its management is discussed.

Mechanisms of remodelling: a question of life (stem cell production) and death (myocyte apoptosis).

Remodeling myocytes show a typical switch between the embryonic and classical features of apoptosis and/or hypertrophy representing a signal of death (ie, apoptosis) and a signal of life (ie, hypertrophy). The adult myocyte, however, is a terminal cell; usually it is unable to reproduce and death is not genetically programmed (apoptosis), but occurs by necrosis. The reinstatement of apoptosis and development of hypertrophy during remodeling could be part of the switch forward to the embryonic phenotype with reinstatement of the early embryonic genetic program. Hypertrophy and apoptosis are "sons" of the same "mother": the local, tissue neuroendocrine-neurohumoral response to a mechanical stretch of the myocytes consequent to the geometric changes imposed on the viable myocytes by the necrotic ones. As expected, the life and death cycle is very closely regulated by several autocrine systems, one of which is linked to the interleukin-6 family via a regulatory protein named GP-130. Activation of the GP-130 slows down the death signals, thus favoring hypertrophy and reducing fibrosis.