Long-Term Outcome of Infective Endocarditis Involving Cardiac Implantable Electronic Devices: Impact of Comorbidities and Lead Extraction.

(1) Background: Management of cardiac implantable electronic device-related infective endocarditis (CIED-IE) hinges on complete hardware removal. We assessed whether long-term prognosis is affected by device removal, considering baseline patient comorbid conditions; (2) Methods: A total of 125 consecutive patients hospitalized for CIED-IE were included in this retrospective analysis. Outcomes were in-hospital, one-year, and long-term mortality. There were 109 patients who underwent device removal, 91 by transvenous lead extraction (TLE) and 18 by open heart surgery (OHS); (3) Results: TLE translated into lower hospital mortality (4.4% vs. 22.5% with OHS; p = 0.03). Septic pulmonary embolism was the only independent predictor of in-hospital mortality (OR:7.38 [1.49-36.6], p = 0.013). One-year mortality was in contrast independently associated to tricuspid valve involvement (p = 0.01) and Charlson comorbidity index (CCI, p = 0.039), but not the hardware removal modality. After a median follow-up of 41 months, mortality rose to 24%, and was significantly influenced only by CCI. Specifically, patients with a higher CCI who were also treated with TLE showed a survival rate not significantly different from those managed with medical therapy only; (4) Conclusions: In CIED-IE, TLE is the strategy of choice for hardware removal, improving early outcomes. Long-term benefits of TLE are lessened by comorbidities. In cases of CIED-IE with high CCI, a more conservative approach might be an option.

Incidence, Risk Factors and Clinical Implications of Glucose Metabolic Changes after Heart Transplant.

Diabetes mellitus (DM) arising de novo after transplant is a common complication, sharing many features with type 2 DM but also specific causes, such as administration of steroids and immunosuppressive drugs. Although post-transplant DM (PTDM) is generally assumed to worsen recipients' outcomes, its impact on renal function, cardiac allograft vasculopathy and mortality remains understudied in heart transplant (HT). We evaluated incidence and risk factors of PTDM and studied glucose metabolic alterations in relation to major HT outcomes. 119 subjects were included in this retrospective, single centre, observational study. A comprehensive assessment of glucose metabolic state was done pre-transplant and a median of 60 months [IQR 30-72] after transplant. Most patients were males (75.6%), with prior non-ischemic cardiomyopathy (64.7%) and median age of 58 years [IQR 48-63]. 14 patients developed PTDM, an incidence of 3.2 cases/100 patient-years. Patients with worsening glucose metabolic pattern were the only who showed a significant increase of BMI and metabolic syndrome prevalence after transplant. 23 (19.3%) patients died during follow up. Early mortality was lower in those with stably normal glucose metabolism, whereas improvement of glucose metabolic state favorably affected mid-term mortality (log-rank p = 0.028). No differences were observed regarding risk of infections and cancer. PTDM is common, but glucose metabolism may also improve after HT. PTDM is strictly related with BMI increase and metabolic syndrome development and may impact recipient survival.

Predicting major events in ambulatory patients with advanced heart failure awaiting heart transplantation: a pilot study.

AIMS: In heart failure (HF), prognostic risk scores focus on all-cause mortality prediction. However, in advanced HF (AdHF) ambulatory patients awaiting heart transplantation (HTx), hospitalizations for acutely decompensated/worsening HF are relevant to clinical decision-making, but unpredicted by common risk functions. METHODS: Among consecutive ambulatory patients added to the waitlist for HTx, event discriminators within 2 years from recruitment were assessed prospectively by area under the curve from receiver-operating characteristic curves, and by Cox proportional hazards models. Primary composite end points included the first between all-cause mortality and acutely decompensated/worsening HF requiring hospitalization and specific treatments. RESULTS: In 89 patients, 36 primary composite events were recorded in a 2-year follow-up (40% of the study sample), and associated with nonischemic etiology and nonsinus rhythm, with lower systolic blood pressure (BP), lower plasma sodium and hemoglobin concentrations, and with higher N-terminal pro-brain natriuretic peptide (NT-proBNP), larger left ventricular (LV) dimensions and lower LV ejection fraction, greater proportion of significant mitral regurgitation, lower tricuspid annulus peak systolic excursion (TAPSE), lower percentage of predicted distance at 6-minute walking test (%p6MWT) and lower global symptoms burden by the Kansas City Cardiomyopathy Questionnaire, lower peak oxygen uptake by cardiopulmonary exercise, and higher wedge pressure by right heart catheterization, as compared with those with no events (P < 0.05). Only Metabolic Exercise Cardiac Kidney Index (MECKI) at recruitment was higher with patients reporting events, which predicted composite end points in addition to and independently of NT-proBNP, and lower systolic BP (all P < 0.05). In an alternative risk model, severe mitral regurgitation and lower TAPSE replaced MECKI and BP but not NT-proBNP (all P < 0.01). CONCLUSION: Higher NT-pro-BNP, lower systolic BP and higher MECKI may contribute to predicting all-cause death and acutely decompensated/worsening HF among ambulatory patients awaiting HTx, with lower TAPSE and severe mitral regurgitation representing further alternative independent prognosticators.

Risk Factors and Outcome of Multidrug-Resistant Infections after Heart Transplant: A Contemporary Single Center Experience.

(1) Background: The aim of this study was to assess risk factors for multidrug-resistant/extensively drug-resistant (MDR/XDR) bacterial infections in heart transplant (HT) patients within three months after surgery and its impact on patient outcome. (2) Methods: Retrospective analysis of clinical, hemato-chemical, imaging, treatment and outcome data from 47 heart transplant recipients from January 2016 to December 2018. MDR/XDR infections were compared to non-MDR/XDR and noninfected patients. (3) Results: Most participants were males, median age 51 years: 35 (74.5%) developed an infection after HT; 14 (29.8%) were MDR/XDR infections. Prolonged hospital stay before HT correlated to MDR/XDR infection (p < 0.001). Sequential organ failure assessment (SOFA) score at sampling day was higher in MDR/XDR (p = 0.027). MDR/XDR were mostly blood-stream (BSI) (p = 0.043) and skin-soft tissue (SSTI) (p = 0.047) infections. Gram-negative infections were the most frequent, specifically carbapenem-resistant Klebsiella pneumoniae. Antibiotic therapy duration for MDR/XDR infections was longer (p = 0.057), eradication rate lower (p = 0.083) and hospital stay longer (p = 0.005) but not associated with a worse outcome. (4) Conclusions: MDR/XDR infections affect compromised HT recipients with a history of prolonged hospitalization, causing a lower rate of eradication and increased hospital stay. These frequently present as BSI and SSTI. We emphasize the need to prevent contamination of central venous catheters and the surgical site.

Effect of Sacubitril-Valsartan in reducing depression in patients with advanced heart failure.

BACKGROUND: Depression is highly prevalent in Heart Failure (HF). Treatment with sacubitril/valsartan improved quality of life and survival in HF patients. Aim of the study was to investigate prospectively the effect of sacubitril/valsartan on depression in advanced HF patients in waiting list for heart transplant (HT). METHODS: 37 consecutive patients with advanced HF in waiting list for HT were treated with sacubitril/valsartan. We analyzed data derived from the assessment performed the year before the beginning of sacubitril/valsartan, at study entry, and at one year of follow-up. Depression was assessed with Beck Depression Inventory II (BDI) scale. Cognitive function were assessed with Mini-Mental State Examination (MMSE). Functioning was evaluated measuring meters at 6 Minute Walking Test (6MWT) and maximum rate of oxygen consumption (VO2 max). RESULTS: At baseline, 64.9% of HF patients were in NYHA III and 35.1% NYHA IIIB, BDI was 15.2 ± 5.2 with 59.5% of patients with a score > 13. MMSE was 27.8 ± 2.6. After one year of follow-up NYHA class improved significantly, with 56.8% in NYHA II, 40.5% in NYHA III and 2.7% NYHA in IIIB (p < 0.001). VO2 max and 6MWT increased. Notably, BDI was 9.5 ± 3.9 with 21.6% of patients with a score > 13. MMSE remain stable (28.2 ± 2.1) (p = 0.104). No statistical differences are observed between data collected in the evaluation 1-year before and soon before treatment with sacubitril/valsartan. Multivariate regression analysis demonstrate a relationship between reduction in BDI-II score and improvement in six-minute walking test independently by the effect of sex, age, selective serotonin reuptake inhibitors, VO2 max, NT-proBNP, PAPs, NYHA class differences evaluated at follow-up versus baseline. CONCLUSIONS: Our study showed a reduction in depressive symptomatology in heart transplant waiting list patients treated with sacubitril/valsartan. The improvement in depressive symptomatology was paralleled by 6MWT increase in the follow-up.

Lipid Accumulation in Hearts Transplanted From Nondiabetic Donors to Diabetic Recipients.

BACKGROUND: Early pathogenesis of diabetic cardiomyopathy (DMCM) may involve lipotoxicity of cardiomyocytes in the context of hyperglycemia. There are many preclinical studies of DMCM pathogenesis, but the human evidence is still poorly understood. OBJECTIVES: By using a nondiabetic mellitus (non-DM) heart transplanted (HTX) in diabetes mellitus (DM) recipients, this study conducted a serial study of human heart transplant recipients evaluating cardiac effects of diabetic milieu (hyperglycemia and insulin resistance) on lipotoxic-mediated injury. We evaluated cardiomyocyte morpho-pathology by seriated biopsies of healthy implanted hearts in DM recipients during 12-month follow-up from HTX. Because metformin reduces ectopic lipid accumulation, we evaluated the effects of the drug in a nonrandomized subgroup. METHODS: The DMCM-AHEAD (Diabetes and Lipid Accumulation and Heart Transplant) prospective ongoing study (NCT03546062) evaluated 158 first HTX recipients (82 non-DM, 76 DM of whom 35 [46%] were receiving metformin). HTX recipients were undergoing clinical standard evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsies). Biopsies evaluated immune response, Oil Red-O staining, ceramide, and triacylglycerol levels. Lipotoxic factors and insulin resistance were evaluated by reverse transcriptase-polymerase chain reaction. RESULTS: There was a significant early and progressive cardiomyocyte lipid accumulation in DM but not in non-DM recipients (p = 0.019). In the subgroup receiving metformin, independently from immunosuppressive therapy that was similar among groups, lipid accumulation was reduced in comparison with DM recipients not receiving the drug (hazard ratio: 6.597; 95% confidence interval: 2.516 to 17.296; p < 0.001). Accordingly, lipotoxic factors were increased in DM versus non-DM recipients, and, relevantly, metformin use was associated with fewer lipotoxic factors. CONCLUSIONS: Early pathogenesis of human DMCM started with cardiomyocyte lipid accumulation following HTX in DM recipients. Metformin use was associated with reduced lipid accumulation independently of immunosuppressive therapy. This may constitute a novel target for therapy of DMCM.

Sacubitril/valsartan in patients listed for heart transplantation: effect on physical frailty.

AIMS: The aim of this study was to investigate prospectively the effect of sacubitril/valsartan in advanced heart failure (HF) patients in waiting list for heart transplantation (HT) and the effect on physical frailty (PF). METHODS AND RESULTS: We treated 37 consecutive patients with advanced HF with sacubitril/valsartan. Patients were followed up until HT, device implant, or last follow-up visit after 2 years of follow-up. At baseline, mean New York Heart Association (NYHA) class was 3.1 ± 0.4, with 64.9% in NYHA III and 35.1% NYHA IIIB. Left ventricular ejection fraction was 23.5 ± 5.8%, VO2 max was 10.3 ± 2.3 mL/kg/min, cardiac index was 2.3 ± 0.5 L/min/m2 , and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) was 4943.0 ± 5326.8 pg/mL. After a mean follow-up of 17.1 ± 4.4 months, no deaths were observed, but NYHA class improved significantly with 56.8% in NYHA II, 40.5% in NYHA III, and 2.7% in NYHA IIIB (P < 0.001). VO2 max and 6 min walk test (6MWT) increased, whereas pulmonary systolic blood pressure, E/E', VE/VCO2 slope, and NT-pro-BNP decreased. At right heart catheterization performed after 1 year of follow-up, cardiac index and pulmonary vascular resistance remained stable, while a decrease in systolic pulmonary artery pressure and pulmonary capillary wedge pressure is observed. Furosemide dosage decrease from 102.7 ± 69.4 to 78.7 ± 66.3 mg (P = 0.040). PF decreased from 3.35 ± 1.0 at baseline to 1.57 ± 1.3 at the end of follow-up (P < 0.001), with a reduction in all PF domains. CONCLUSIONS: Our study showed a rapid improvement in PF in HT waiting list patients treated with sacubitril/valsartan. The improvement in all PF domains was paralleled by VO2 and 6MWT increase and together with an NT-pro-BNP reduction constant over the follow-up.

Direct antiviral treatment of chronic hepatitis C in heart transplant recipients.

Direct-acting antiviral agents (DAAs) are a safe and effective treatment for chronic hepatitis C (CHC). This may be particularly valuable for patients with severe comorbidities or baseline conditions, including non-liver solid organ transplant. We report cases of two heart transplant recipients with CHC treated with DAAs (sofosbuvir and daclatasvir) achieving sustained virological response. Treatment was well tolerated and no relevant side effects were observed. The drug-drug interactions and graft function were carefully monitored.

Infection of Retained Defibrillator Lead Fragment after Heart Transplant.

A 59-year old heart transplant recipient was admitted due to continuous pain in her left axilla. A purulent collection was found at the site of prior defibrillator placement, where a remnant proximal segment of an electric lead was found. Two years before, the patient had had pocket infection treated with revision, but without device extraction. The remnant lead was eventually removed transvenously without complications. This is the first description of infection complicating retention of lead fragments after heart transplant. The role of biofilm and net immune state on the persistence and late recurrence of infection is discussed.

Clinical significance of hyperhomocysteinemia in infective endocarditis: A case-control study.

Blood coagulation plays a key role in the pathogenesis of infective endocarditis (IE). Conditions associated with thrombophilia could enhance IE vegetation formation and promote embolic complications.In this study, we assessed prevalence, correlates, and clinical consequences of hyper-homocysteinemia (h-Hcy) in IE.Homocysteine (Hcy) plasma levels were studied in 246 IE patients and 258 valvular heart disease (VHD) patients, as well as in 106 healthy controls.IE patients showed Hcy levels comparable to VHD patients (14.9 [3-81] vs 16 [5-50] µmol/L, respectively; P = 0.08). H-Hcy was observed in 48.8% of IE patients and 55.8% of VHD (P = 0.13). Vegetation size and major embolic complications were not related to Hcy levels. IE patients with h-Hcy had a higher prevalence of chronic kidney disease and a higher 1-year mortality (19.6% vs 9.9% in those without h-Hcy; OR 2.21 [1.00-4.89], P = 0.05). However, at logistic regression analysis, h-Hcy was not an independent predictor of 1-year mortality (OR 1.87 [95% CI 0.8-4.2]; P = 0.13).Our data suggest h-Hcy in IE is common, is related to a worse renal function, and may be a marker of cardiac dysfunction rather than infection. H-Hcy does not appear to favor IE vegetation formation or its symptomatic embolic complications.

Safety of treatment with high-dose daptomycin in 102 patients with infective endocarditis.

Daptomycin is commonly used at doses >6 mg/kg/day for various indications, including infective endocarditis (IE). A systematic assessment of skeletal muscle, renal, haematological, hepatic and pulmonary toxicity of high-dose daptomycin (HDD) in IE is lacking. A total of 102 IE patients treated with HDD were included in this non-comparative, observational, single-centre cohort study conducted from 2007 to 2014. The incidence, timing, severity and evolution of adverse events (AEs) were assessed. Patients had a median age of 61.5 years and a high prevalence of co-morbidities. Staphylococci were cultured in 87.2% of cases (62.2% meticillin-resistant). The median daptomycin dose was 8.2 mg/kg/day for a median of 20 days (range, 1-60 days). HDD was withdrawn due to AEs in 12 patients (11.8%). On-treatment death occurred in 4 cases (3.9%, none HDD-related). Muscle toxicity occurred in 15 patients in a median of 15 days after HDD starts, which was largely mild and reversible with ongoing HDD use. Mild renal toxicity was observed in 9 patients (8.8%) after a median of 12 days of HDD (RIFLE-Risk in 8, Injury in 1). A rise of peripheral blood eosinophils occurred in 16 patients (15.7%). There were three cases of eosinophilic interstitial pneumonia. Four patients (3.9%) had mild allergic or idiosyncratic reactions. No other hepatic or haematological AEs were observed. Our current experience with 102 patients suggests that HDD is safe in significantly ill IE patients with multiple co-morbidities. Muscle toxicity was clinically negligible. Most importantly, there was no significant renal toxicity. Eosinophils should be carefully monitored.

Recipient-born bloodstream infection due to extensively drug-resistant Acinetobacter baumannii after emergency heart transplant: report of a case and review of the literature.

Infections due to drug-resistant Gram-negative rods are an emerging risk factor for increased mortality after solid organ transplant. Extensively drug-resistant (XDR) Acinetobacter baumannii (Acb) is a major threat in several critical care settings. The limited available data on the outcome of XDR Acb infections in organ transplant recipients mostly comes from cases of donor-derived infections. However, recipients of life-saving organs are often critically ill patients, staying long term in intensive care units, and therefore at high risk for nosocomial infections. In this report, we describe our experience with the exceedingly complex management of a recipient-born XDR Acb bloodstream infection clinically ensued shortly after heart transplant. We also review the current literature on this mounting issue relevant for intensive care, transplant medicine and infectious diseases.

Prevalence and significance of two major inherited thrombophilias in infective endocarditis.

The pathogenesis of infective endocarditis (IE) involves activation of the haemostasis system at the site of endocardial defects. Whether prothrombotic conditions are associated with IE by enhancing early vegetation formation is unknown. In this study, we assess the prevalence and clinical significance of two major conditions associated with thrombophilia in patients with IE. Mutations G20210A of the prothrombin (PTH) gene and G1691A of factor V (FV Leiden) gene were studied by means of allele-specific polymerase chain reaction in 203 IE patients, 175 valvular heart disease (VHD) patients and 200 blood donors (BD). IE patients show higher cumulative frequencies of mutated alleles of PTH and FV Leiden [6.4 vs 3.25 %; OR 2.03 (95 % CI 0.97-3.66); p = 0.047] compared to BD, but not VHD. Device-related IE is enriched with FV Leiden, and prosthetic valve IE with PTH mutations (allele frequency 8.3 vs 2.2 % in native valve IE; p = 0.021). Vegetation size and embolic complications are not influenced by the examined thrombophilias. A trend for a higher mortality was observed in IE patients with any of the two thrombophilias studied. Our data do not support a role for factor V Leiden and G20210A prothrombin gene mutations in the susceptibility to IE. Whether any of these genetic polymorphisms play a role in a specific subtype of IE needs to be re-examined in larger studies.

Infective endocarditis due to multidrug resistant gram-negative bacilli: single centre experience over 5 years.

BACKGROUND: Infective endocarditis (IE) due to gram-negative (GN) bacilli is uncommon. Although multi- and extensively-drug resistant (MDR/XDR) GN infections are emerging, very few data are available on IE due to these microrganisms. METHODS: In this study, we describe the clinical characteristics, course and outcome of five contemporary, definite, MDR/XDR GNIE cases seen at our centre. RESULTS: All patients had been admitted to a hospital during the 6months before IE onset, 2 were on hemodialysis and 3 on intravenous medications. Three of the 5 cases were hospital-acquired. Intracardiac prosthetic devices were present in all cases (3 central venous lines, 2 prosthetic heart valves, 2 pacemakers). Mean Charlson comorbidity index was 5.8. Causative pathogens were XDR Pseudomonas aeruginosa (2 cases), XDR Acinetobacter baumannii, MDR Burkolderia cepacia and MDR Escherichia coli (1 case each). Concomitant pathogens with a MDR/XDR phenotype were isolated in 4 patients. Both valves and intracardiac devices and left and right sides of the heart were involved. The rate of complications was high. Antibiotic treatment hinged on the use of colistin, a carbapenem or both. Cardiovascular surgical procedures were performed in 3 patients. Despite aggressive therapeutic regimens, outcomes were poor. Clearance of bacteremia was obtained in 3 patients, in-hospital death occurred in 3 patients, only 1 patient survived during follow up. CONCLUSIONS: MDR/XDR GN are emerging as a cause of IE in carriers of intracardiac prostheses with extensive healthcare contacts and multiple comorbidities. Resistant GNIE has a complicated course and shows a dismal prognosis.

Predicting the occurrence of embolic events: an analysis of 1456 episodes of infective endocarditis from the Italian Study on Endocarditis (SEI).

BACKGROUND: Embolic events are a major cause of morbidity and mortality in patients with infective endocarditis. We analyzed the database of the prospective cohort study SEI in order to identify factors associated with the occurrence of embolic events and to develop a scoring system for the assessment of the risk of embolism. METHODS: We retrospectively analyzed 1456 episodes of infective endocarditis from the multicenter study SEI. Predictors of embolism were identified. Risk factors identified at multivariate analysis as predictive of embolism in left-sided endocarditis, were used for the development of a risk score: 1 point was assigned to each risk factor (total risk score range: minimum 0 points; maximum 2 points). Three categories were defined by the score: low (0 points), intermediate (1 point), or high risk (2 points); the probability of embolic events per risk category was calculated for each day on treatment (day 0 through day 30). RESULTS: There were 499 episodes of infective endocarditis (34%) that were complicated by ≥ 1 embolic event. Most embolic events occurred early in the clinical course (first week of therapy: 15.5 episodes per 1000 patient days; second week: 3.7 episodes per 1000 patient days). In the total cohort, the factors associated with the occurrence of embolism at multivariate analysis were prosthetic valve localization (odds ratio, 1.84), right-sided endocarditis (odds ratio, 3.93), Staphylococcus aureus etiology (odds ratio, 2.23) and vegetation size ≥ 13 mm (odds ratio, 1.86). In left-sided endocarditis, Staphylococcus aureus etiology (odds ratio, 2.1) and vegetation size ≥ 13 mm (odds ratio, 2.1) were independently associated with embolic events; the 30-day cumulative incidence of embolism varied with risk score category (low risk, 12%; intermediate risk, 25%; high risk, 38%; p < 0.001). CONCLUSIONS: Staphylococcus aureus etiology and vegetation size are associated with an increased risk of embolism. In left-sided endocarditis, a simple scoring system, which combines etiology and vegetation size with time on antimicrobials, might contribute to a better assessment of the risk of embolism, and to a more individualized analysis of indications and contraindications for early surgery.

Current trends in the management of cardiac implantable electronic device (CIED) infections.

Cardiac implantable electronic device (CIED) infections are an emerging clinical problem. A growing number of dedicated and high quality clinical studies are currently being generated. We here review the most recent advances in the diagnosis and treatment of patients with CIED infection including intracardiac lead endocarditis. We discuss the current etiology and risk factors, and appraise the major diagnostic issues, describing our center's therapeutic approach. We also address the management of CIED infection complications.

High-dose daptomycin for cardiac implantable electronic device-related infective endocarditis.

BACKGROUND: Cardiac implantable electronic device (CIED)-related endocarditis is a growing challenge because of increasing incidence and significant mortality. Current treatment is based on complete hardware removal coupled with long-term administration of effective and safe antimicrobials. Daptomycin at the dose of 6 mg/kg/day has been found to be effective in staphylococcal endocarditis, but limited data exist on CIED endocarditis. Moreover, whether higher doses could be more effective but equally safe in this setting is currently unknown. METHODS: We report here our experience with high-dose daptomycin in the treatment of 25 cases of CIED endocarditis due to staphylococci. RESULTS: Patients were mostly elderly and male, with large lead vegetations and severe comorbidities. Pathogens were Staphylococcus epidermidis (56%), Staphylococcus aureus (28%), and other coagulase-negative staphylococci (16%). Only 4 patients (16%) had a normal pretreatment renal function. The median daptomycin daily dose was 8.3 mg/kg (range, 6.4-10.7). Daptomycin was administered for a median of 20 days (range, 8-52). Percutaneous lead extraction was performed in 88% of patients. Two patients (8%) failed to clear bacteremia. The overall clinical success of treatment was 80%, whereas a complete microbiological success was observed in 92% of patients. Creatine phosphokinase values were monitored and increased above normal in 5 cases (20%). No serious adverse event related to high-dose daptomycin was observed and no patient required discontinuation because of muscle toxicity. CONCLUSIONS: Our experience suggests that high-dose daptomycin may be a safe therapeutic option in staphylococcal CIED endocarditis and may be associated with high microbiological responses and clinical success.