The safety of sodium glucose transporter 2 inhibitors and trends in clinical and hemodynamic parameters in patients with left ventricular assist devices.

BACKGROUND: The safety and impact of sodium glucose transporter 2 inhibitors (SGLT2-I) in patients with left ventricular assist devices (LVAD) are unknown. METHODS: A retrospective analysis of all consecutive patients who underwent LVAD Heart Mate 3 (HM3) implantation at a single medical center and received SGLT2-I therapy following surgery was conducted. LVAD parameters, medical therapy, laboratory tests, echocardiography, and right heart catheterization (RHC) study results were recorded and compared before and after initiation of SGLT2-I. RESULTS: SGLT2-I medications were initiated in 29 (21%) of 138 patients following HM3 implantation (23 (79%) received Empagliflozin and 6 (21%) Dapagliflozin). The mean age at the time of LVAD implantation was 62 ± 6.7 years, 25 (86%) were male, and 23 (79%) had diabetes mellitus. The median time from HM3 implantation to SGLT2-I initiation was 108 days, IQR (26-477). Following SGLT2-I therapy, the daily dose of furosemide decreased from 47 to 23.5 mg/day (mean difference = 23.5 mg/d, 95% CI 8.2-38.7, p = 0.004) and significant weight reduction was observed (mean difference 2.5 kg, 95% CI 0.7-4.3, p = 0.008). Moreover, a significant 5.6 mm Hg reduction in systolic pulmonary artery pressure (sPAP) was measured during RHC (95% CI 0.23-11, p = 0.042) in a subgroup of 11 (38%) patients. LVAD parameters were similar before and after SGLT2-I initiation (p > 0.2 for all). No adverse events were recorded during median follow-up of 354 days, IQR (206-786). CONCLUSION: SGLT2-I treatment is safe in LVAD patients and might contribute to reduction in patients sPAP.

IMITATION SWITCH is required for normal chromatin structure and gene repression in PRC2 target domains.

Polycomb Group (PcG) proteins are part of an epigenetic cell memory system that plays essential roles in multicellular development, stem cell biology, X chromosome inactivation, and cancer. In animals, plants, and many fungi, Polycomb Repressive Complex 2 (PRC2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to assemble transcriptionally repressed facultative heterochromatin. PRC2 is structurally and functionally conserved in the model fungus Neurospora crassa, and recent work in this organism has generated insights into PRC2 control and function. To identify components of the facultative heterochromatin pathway, we performed a targeted screen of Neurospora deletion strains lacking individual ATP-dependent chromatin remodeling enzymes. We found the Neurospora homolog of IMITATION SWITCH (ISW) is critical for normal transcriptional repression, nucleosome organization, and establishment of typical histone methylation patterns in facultative heterochromatin domains. We also found that stable interaction between PRC2 and chromatin depends on ISW. A functional ISW ATPase domain is required for gene repression and normal H3K27 methylation. ISW homologs interact with accessory proteins to form multiple complexes with distinct functions. Using proteomics and molecular approaches, we identified three distinct Neurospora ISW-containing complexes. A triple mutant lacking three ISW accessory factors and disrupting multiple ISW complexes led to widespread up-regulation of PRC2 target genes and altered H3K27 methylation patterns, similar to an ISW-deficient strain. Taken together, our data show that ISW is a key component of the facultative heterochromatin pathway in Neurospora, and that distinct ISW complexes perform an apparently overlapping role to regulate chromatin structure and gene repression at PRC2 target domains.

BNT162b2-vaccine-induced neutralization responses are immune correlates of clinical protection against SARS-CoV-2 in heart transplant recipients.

BACKGROUND: Defining immune correlates of protection against COVID-19 is pivotal for optimizing the use of COVID-19 vaccines, predicting the impact of novel variants on clinical outcomes, and advancing the development of immunotherapies and next-generation vaccines. We aimed to identify vaccine-induced immune correlates of protection against COVID-19-related hospitalizations in a highly vaccinated heart transplant (HT) cohort. METHODS: In a case-control study of HT recipients vaccinated with the BNT162b2 vaccine, patients were prospectively assessed for vaccine-induced neutralization of the wild-type virus, and the Delta and Omicron BA.1, BA.2, BA.4, and BA.5 variants. Comparative analyses with controls were conducted to identify correlates of protection against COVID-19 hospitalization. ROC analyses were performed. Primary outcomes were COVID-19 hospitalizations and severity of SARS-CoV-2 breakthrough infection. RESULTS: The study cohort comprised 59 HT recipients aged 58 (49,65) years with breakthrough infections after three or four monovalent BNT162b2 doses; 41 (69.5%) were men. Thirty-six (61%) patients with COVID-19 were hospitalized; most cases were non-severe (58, 98%). For hospitalized (vs. non-hospitalized) COVID-19 patients, vaccine-induced neutralization titers were significantly lower against all SARS-CoV-2 variants (p < .005). Vaccine-induced neutralization of the wild-type virus and delta and omicron BA.1, BA.2, BA.4, and BA.5 variants was associated with a reduced risk for COVID-19-related hospitalization. The optimal neutralization titer thresholds that were predictive of COVID-19 hospitalizations were 96 (wild-type), 48 (delta), 12 (BA.1), 96 (BA.2), 96 (BA.4), and 48 (BA.5). CONCLUSIONS: BNT162b2-vaccine-induced neutralization responses are immune correlates of protection and confer clinical protection against COVID-19 hospitalizations.

Revascularization outcomes in diabetic patients presenting with acute coronary syndrome with non-ST elevation.

BACKGROUND: To compare the outcomes of diabetic patients hospitalized with non-ST elevation myocardial infarction (NSTEMI) or unstable angina (UA) referred for revascularization by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in a real-life setting. METHODS: The study included 1987 patients with diabetes mellitus enrolled from the biennial Acute Coronary Syndrome Israeli Survey between 2000 and 2016, who were hospitalized for NSTEMI or UA, and underwent either PCI (N = 1652, 83%) or CABG (N = 335, 17%). Propensity score-matching analysis compared all-cause mortality in 200 pairs (1:1) who underwent revascularization by either PCI or CABG. RESULTS: Independent predictors for CABG referral included 3-vessel coronary artery disease (OR 4.9, 95% CI 3.6-6.8, p < 0.001), absence of on-site cardiac surgery (OR 1.4, 95% CI 1.1-1.9, p = 0.013), no previous PCI (OR 1.5, 95% CI 1.1-2.2, p = 0.024) or MI (OR 1.7, 95% CI 1.2-2.6, p = 0.002). While at 2 years of follow-up, survival analysis revealed no differences in mortality risk between the surgical and percutaneous revascularization groups (log-rank p = 0.996), after 2 years CABG was associated with a significant survival benefit (HR 1.53, 95% CI 1.07-2.21; p = 0.021). Comparison of the propensity score matching pairs also revealed a consistent long-term advantage toward CABG (log-rank p = 0.031). CONCLUSIONS: In a real-life setting, revascularization by CABG of diabetic patients hospitalized with NSTEMI/UA is associated with better long-term outcomes. Prospective randomized studies are warranted in order to provide more effective recommendations in future guidelines.

Frailty and clinical outcomes following aortic valve replacement.

BACKGROUND AND AIMS: The Norton score is a well-known scale to assess frailty. Frailty and a low Norton score are associated with complications and mortality in hospitalized patients. We aimed to evaluate whether a low Norton score is associated with surgical complications and death after aortic valve replacement (AVR). METHODS: From 2004 through 2020, we performed an observational study in a large tertiary medical center, which included all patients who had undergone isolated AVR surgery. Of the 1469 study patients, 618 patients (42%) had a low (<18) and 851 patients (58%) a high Norton score (≥18). RESULTS: Frailer patients with a low Norton score had higher in-hospital mortality compared to those with a high Norton score (5.5% vs. 0.8%, p < .001). The Norton score was significantly higher among patients who survived compared to those who died (17.5 ± 2.4 vs. 11.5 ± 5.2, p < .001). A low Norton score was associated with a threefold increased risk of in-hospital mortality (odds ratio 3.03; 95% confidence interval [CI] 1.14-0.09, p = .034). Ten-year mortality rate was higher among frailer patients with a low compared with a high Norton score (25.9%, 13.3%; hazard ratio 0.69, CI 0.48-0.82, p < .001). By adding a Norton score to standard prognostic factors (age, gender, comorbidities, left ventricular ejection fraction, functional class) we showed a significant improvement of 59.4% (p < .001) for predicting 1-year mortality, and 40.6% (p < .001) for predicting 10-year mortality. CONCLUSIONS: Our findings show that the admission Norton score is a powerful marker of short- and long-term mortality, and, therefore, should be considered as a risk stratification tool in patients who are candidates for AVR.

The predictive value of five glomerular filtration rate formulas for long-term mortality in patients undergoing coronary artery bypass grafting.

BACKGROUND AND AIMS: Renal function plays an important role in the management of patients referred for coronary artery bypass grafting (CABG). Current data is insufficient for precise risk stratification using the estimated glomerular filtration rate (eGFR). METHODS: This retrospective study includes 3744 consecutive patients who underwent CABG between 2004 and 2020. We assessed five different eGFR formulas: Cockcroft-Gault (CG), modification of diet in renal disease (MDRD), chronic kidney disease Epidemiology Collaboration (CKD-EPI), Mayo, and inulin clearance-based (IB). RESULTS: The Mayo formula yielded the highest mean eGFR (90 ± 24 ml/min per 1.73 m2 ) and CKD-EPI the lowest (74 ± 21 ml/min per 1.73 m2 ). As a result, more patients were classified as having a normal renal function (57%) with the Mayo formula as compared with the others. Using MDRD as the reference formula, there was a significant and stronger correlation between the values obtained from the CKD-EPI (r = .95, p < .001) and Mayo (Mayo: r = .87, p < .001) compared to the IB (r = .8, p < .001) and CG (r = .79, p < .001) formulas. Multivariable analysis demonstrated that decreased renal function is an independent predictor of 10-year mortality in all five formulas, with risk increasing by 13-17% for each 10-unit decrease in eGFR. Despite the similarities between the formulas, the ability to predict mortality was highest in the Mayo formula and lowest in the CG and IB. CONCLUSIONS: Our data suggest that the Mayo formula may be superior to the other formulas in prognosticating mortality after CABG. We have shown that the Mayo equation classified fewer individuals as having renal dysfunction and more accurately categorized the risk for mortality than did all other formulas.

Weight gain post-heart transplantation is associated with an increased risk for allograft vasculopathy and rejection.

OBJECTIVE: Obesity and overweight are associated with an increased risk for cardiovascular disease. Since fat mass (FM) and fat-free mass (FFM) both contribute to total body weight (TBW), we characterized the post-heart transplantation (HT) change in TBW and its implications for outcomes. METHODS: Post-HT changes in TBW, FM, and FFM were reviewed for 211 HT patients assessed during 1997-2017. Endpoints included cardiac allograft vasculopathy (CAV) and rejection. RESULTS: Median TBW increased by 7.3% at 1 year, with a significant rise in the obese category (28% vs. 13%, p < 0.001) and with FM versus FFM making the main contribution (23% vs. 3%, p < 0.001). When patients were divided according to median TBW change ("high" vs. "low"), Kaplan-Meier analysis showed that 10-year freedom from CAV (log-rank p < 0.005) and rejection (log-rank p < 0.01) was significantly higher for the "low" TBW change group. Consistently, multivariable analyses showed that the "high" group was independently associated with significant 3.5-fold and 4.2-fold increased risks for CAV (95% CI 1.4-8.7, p = 0.01) and rejection (95% CI 1.2-15.4, p = 0.03), respectively. CONCLUSIONS: Weight gain, contributed mostly by FM, is independently associated with an increased risk for CAV and rejection. Follow-up emphasis should be placed on weight gain and preventative measures.

Genetic modification of the diarrhoeal pathogen Cryptosporidium parvum.

Recent studies into the global causes of severe diarrhoea in young children have identified the protozoan parasite Cryptosporidium as the second most important diarrhoeal pathogen after rotavirus. Diarrhoeal disease is estimated to be responsible for 10.5% of overall child mortality. Cryptosporidium is also an opportunistic pathogen in the contexts of human immunodeficiency virus (HIV)-caused AIDS and organ transplantation. There is no vaccine and only a single approved drug that provides no benefit for those in gravest danger: malnourished children and immunocompromised patients. Cryptosporidiosis drug and vaccine development is limited by the poor tractability of the parasite, which includes a lack of systems for continuous culture, facile animal models, and molecular genetic tools. Here we describe an experimental framework to genetically modify this important human pathogen. We established and optimized transfection of C. parvum sporozoites in tissue culture. To isolate stable transgenics we developed a mouse model that delivers sporozoites directly into the intestine, a Cryptosporidium clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system, and in vivo selection for aminoglycoside resistance. We derived reporter parasites suitable for in vitro and in vivo drug screening, and we evaluated the basis of drug susceptibility by gene knockout. We anticipate that the ability to genetically engineer this parasite will be transformative for Cryptosporidium research. Genetic reporters will provide quantitative correlates for disease, cure and protection, and the role of parasite genes in these processes is now open to rigorous investigation.

The Impact of Initiation of an Intensivist-Led Patient Management Protocol on Outcomes After Cardiac Surgery.

OBJECTIVES: Prolonged intensive care unit stay after cardiac surgery is associated with high mortality. The aim of this study was to evaluate the impact of the introduction of a quality improvement program under the supervision of an intensivist on the long-term mortality of high-risk patients with prolonged intensive care unit (ICU) stay after cardiac surgery. DESIGN: Retrospective study of prospectively collected data. SETTING: Cardiac surgery ICU. PARTICIPANTS: A total of 7,549 patients after cardiac surgery. INTERVENTIONS: Patients were divided into two periods: 2004 to 2007, before introducing the quality improvement program (3,315 patients), and 2009 to 2014, after introduction of the program (4,234 patients). In the period from 2004 to 2007, patients were divided into group I (ICU stay ≥ seven days), which included 242 patients, and group III (ICU stay < seven days), which included 3,073 patients. Also, in the period from 2009 to 2014 patients, were divided into group II (ICU stay ≥seven days), which included 326 patients, and group IV (ICU stay < seven days), which included 3,908 patients. Patient outcomes were compared. Follow-up was five years for each group. MEASUREMENTS AND MAIN RESULTS: The European System for Cardiac Operative Risk Evaluation did not differ significantly among the groups. When comparing between group I and group II, 30-day mortality decreased significantly from 24.8% to 16.6%, six-month mortality from 27.3% to 19.3%, one-year mortality from 42.1% to 32.2%, 3-year mortality from 54.5% to 43.3%, and 5-year mortality from 61.2% to 51.8%. In comparing between group III and group IV, the authors did not observe a statistically significant decrease of mortality. CONCLUSIONS: Intensivist-led patient management protocol is associated with decreased long-term mortality in high-risk patients with a prolonged ICU stay.

A Potent Neutralizing Site III-Specific Human Antibody Neutralizes Human Metapneumovirus In Vivo.

Human metapneumovirus (hMPV) is a leading cause of viral lower respiratory tract infection in children. The sole target of neutralizing antibodies targeting hMPV is the fusion (F) protein, a class I viral fusion protein mediating virus-cell membrane fusion. There have been several monoclonal antibodies (mAbs) isolated that neutralize hMPV; however, determining the antigenic sites on the hMPV F protein mediating such neutralizing antibody generation would assist efforts for effective vaccine design. In this report, the isolation and characterization of four new human mAbs, termed MPV196, MPV201, MPV314, and MPV364, are described. Among the four mAbs, MPV364 was found to be the most potent neutralizing mAb in vitro Binding studies with monomeric and trimeric hMPV F revealed that MPV364 had the weakest binding affinity for monomeric hMPV F compared to the other three mAbs, yet binding experiments with trimeric hMPV F showed limited differences in binding affinity, suggesting that MPV364 targets an antigenic site incorporating two protomers. Epitope binning studies showed that MPV364 targets antigenic site III on the hMPV F protein and competes for binding with previously discovered mAbs MPE8 and 25P13, both of which cross-react with the respiratory syncytial virus (RSV) F protein. However, MPV364 does not cross-react with the RSV F protein, and the competition profile suggests that it binds to the hMPV F protein in a binding pose slightly shifted from mAbs MPE8 and 25P13. MPV364 was further assessed in vivo and was shown to substantially reduce viral replication in the lungs of BALB/c mice. Overall, these data reveal a new binding region near antigenic site III of the hMPV F protein that elicits potent neutralizing hMPV F-specific mAbs and provide a new panel of neutralizing mAbs that are candidates for therapeutic development.IMPORTANCE Recent progress in understanding the human immune response to respiratory syncytial virus has paved the way for new vaccine antigens and therapeutics to prevent and treat disease. Progress toward understanding the immune response to human metapneumovirus (hMPV) has lagged behind, although hMPV is a leading cause of lower respiratory tract infection in children. In this report, we advanced the field by isolating a panel of human mAbs to the hMPV F protein. One potent neutralizing mAb, MPV364, targets antigenic site III on the hMPV F protein and incorporates two protomers into its epitope yet is unique from previously discovered site III mAbs, as it does not cross-react with the RSV F protein. We further examined MPV364 in vivo and found that it limits viral replication in BALB/c mice. Altogether, these data provide new mAb candidates for therapeutic development and provide insights into hMPV vaccine development.

Type 2 diabetes mellitus increases the mortality risk after acute coronary syndrome treated with coronary artery bypass surgery.

BACKGROUND: Type 2 diabetes mellitus (DM) is a risk factor for cardiovascular diseases and is common among patients undergoing coronary artery bypass grafting (CABG) surgery. The main objective of our study was to investigate the impact of DM type 2, and its treatment subgroups, on short- and long-term mortality in patients with acute coronary syndrome (ACS) who undergo CABG. METHODS: The study included 1307 patients enrolled from the biennial Acute Coronary Syndrome Israeli Survey between 2000 and 2016, who were hospitalized for ACS and underwent CABG. Of them, 527 (40%) patients were with and 780 (60%) were without DM. RESULTS: Compared with the non-diabetic group, the diabetic group of patients comprised more women and had more comorbidities such as hypertension, dyslipidemia, renal impairment, peripheral vascular disease and prior ischemic heart disease. Overall 30-day mortality rate was similar between DM and non-DM patients (4.2% vs. 4%, p = 0.976). Ten-year mortality rate was higher in DM compared with non-diabetic patients (26.6% vs. 17.7%, log-rank p < 0.001), and higher in the subgroup of insulin-treated patients compared to non-insulin treated patients (31.5% vs. 25.6%, log-rank p = 0.019). Multivariable analysis showed that DM increased the mortality hazard by 1.61-fold, and insulin treatment among the diabetic patients increased the mortality hazard by 1.57-fold. CONCLUSIONS: While type 2 DM did not influence the in-hospital mortality hazard, we showed that the presence of DM among patients with ACS referred to CABG, is a powerful risk factor for long-term mortality, especially when insulin was included in the diabetic treatment strategy.

Donor thyroid hormone therapy is associated with an increased risk of graft dysfunction after heart transplantation.

OBJECTIVE: Heart transplantation (HT) is uniquely associated with the potential impact of thyroid hormone therapy at three intersecting levels-donor, operation, and recipient. We aimed to study the effect of thyroid hormone therapy of the donor on primary graft dysfunction (PGD). METHODS: A retrospective cohort study was conducted on 209 HT recipients assessed from 1997 to 2018; for 33 of the recipients, the donors had received T4 (DT4 group), and for 176, the donors had not (NoDT4 group). The primary endpoint was PGD defined according to the International Society for Heart and Lung consensus statement. RESULTS: Both the incidence (58% vs 35%, P = .022) and the severity of PGD (42% vs 25% moderate/severe, P = .007) were significantly higher in the DT4 recipients. Multivariable analysis showed donor T4 therapy to be independently associated with a ~3.5-fold increased risk for PGD (OR = 3.44, 95% CI 1.26-9.86). These results remained consistent after propensity score analysis. CONCLUSIONS: Donor thyroid hormone therapy is independently associated with an increased risk of PGD. Hypothesizing a "withdrawal effect" as the cause, we suggest that administration of thyroid hormone to the recipient at time of reperfusion could counter this negative effect. Prospective studies are needed to validate this hypothesis-generating study.

Complications of retained pacemaker hardware in heart transplant recipients: case series and review of the literature.

Heart transplantation (HT) in patients with prior cardiovascular implantable electronic devices (CIEDs) is becoming more common, in parallel with the increased use of CIEDs for patients with advanced heart failure. Complete removal of CIED components during HT is not always feasible, and it is thus surprising that the literature addressing the implications of retained CIED components is limited. Indeed, there are neither guidelines nor consensus regarding the need for removal of these CIED fragments. This issue is nonetheless becoming important in light of the increase in the percentage of HT candidates having CIEDs, on the one hand, and newer therapeutic immunosuppressive protocols with higher bacterial infection potential, on the other. Thus, with the aim to study the implications of retained CIED fragments as a step towards establishing a therapeutic approach for the unique population of HT recipients with CIED remnants, we present here a case series of HT patients with retained CIED fragments who developed complications of infections together with a review of the available literature.

Clinically significant incidental QTc prolongation is subject to within-individual variability.

BACKGROUND: Prolonged QTc interval observed in daily practice is often deemed to be drug induced and might result in drug discontinuation, with possible therapeutic consequences. However, whether clinically significant prolonged QTc may be due to within-individual variability occurs has yet to be described. METHODS: A retrospective cohort study documenting within-individual QTc variability in subjects attending annual routine medical evaluation. At each visit, QT interval was measured and corrected for heart rate using Bazett and three other commonly used formulae. Outcome measures were rates of ΔQTc ≥60 msec, absolute QTc ≥500 msec and QTc ≥25% from baseline. RESULTS: A total of 188 subjects [54 (29%)] females were recruited. Mean age at first ECG was 54 ± 12.8 years with mean time interval of 12.2 ± 1.1 months between measurements. Mean Bazett QTc was higher compared to the other 3 formulae: 412 ± 20 vs. 400 ± 16 msec. Using Bazett formula, 18/188 (9.6%) and 5/188 (2.7%) subjects showed at least one measurement with ΔQTc ≥60 msec and QTc ≥500 msec, respectively. Of the former, 5/18 (27.8%) showed QTc ≥25% prolongation. In multivariate analysis, QTc ≥500 msec was significantly associated with number of measurements (HR: 5.01, 95%CI: 1.21-20.78, p = .026) with no effect of other known confounders. Lower rates were demonstrated with the other three formulae. CONCLUSION: In clinical practice, significant prolonged QTc may be attributed to within-individual variability, particularly when adjusting the QT interval with Bazett correction. This should be taken into consideration when decisions on changing current drug regimens are to be made.

Outcomes of isolated surgical aortic valve replacement in the era of transcatheter aortic valve implantation.

BACKGROUND AND AIMS: Until early into the 21st century, the only therapeutic option for aortic valve (AV) stenosis was surgical aortic valve replacement (AVR), but this changed with the introduction of transcatheter aortic valve implantation (TAVI). Our objective was to present the results of surgical AVR performed in low-risk patients in the era of TAVI, in a large tertiary medical center. METHODS: Data from low surgical risk patients (defined as Euroscore < 5) greater than 60 years of age, who underwent isolated AVR surgery between 2004 and 2018, were obtained from our departmental database. Of the 313 study patients, 110 (35%) underwent isolated AVR before 2010 (early period) and 203 patients (65%) underwent the same procedure from 2010 onward (late period). RESULTS: Mean age was 67 ± 5 years and 182 (58%) were male. Fifty-six patients (18%) had a unicuspid or bicuspid AV. Patient characteristics were similar between the early and late periods. There was no in-hospital or 30-day mortality throughout the entire cohort, with one case (0.3%) of postoperative stroke. Permanent pacemaker implantation was required in 2.2% (N = 7). Patients in the early period required significantly more re-exploration due to bleeding/tamponade (8.2% vs 1.5%; P = .008). Long-term mortality (1, 3, and 5 years) was higher in the early compared with the late period (2.7% vs 1%, 7.3% vs 3%, and 15.5% vs 3.4%, respectively; log-rank P = .005). CONCLUSIONS: Surgical AVR provides excellent short- and long-term results with low morbidity and mortality in low surgical risk patients. While patient characteristics did not change dramatically over the years, the long-term results were encouraging.

The impact of diabetes mellitus on the clinical phenotype of hypertrophic cardiomyopathy.

AIMS: Diabetes mellitus (DM) aggravates the clinical features of ischaemic and hypertensive heart diseases and worsens the prognosis of heart failure patients. Hypertrophic cardiomyopathy (HCM) and diabetes coexist fairly frequently in elderly patients but the impact of DM on the clinical phenotype of HCM is yet unknown. We sought to describe if predominant features of heart failure in DM patients exist independently in HCM. METHODS AND RESULTS: We reviewed clinical characteristics of 937 patients, age ≥40, diagnosed with HCM, from two tertiary medical centres in Spain and Israel. A propensity score matched cohort of 294 patients was also analysed. Our cohort comprised 102 HCM patients with diabetes (8.7%). Patients with DM were older at diagnosis {median 56 [interquartile range (IQR) 47-67] vs. 53 (IQR 43-63), P = 0.02} and had a higher prevalence of comorbidities. Hypertrophic cardiomyopathy patients with DM had a higher prevalence of diastolic dysfunction, pulmonary hypertension, significant mitral regurgitation, and pacemaker implantation. Hypertrophic cardiomyopathy patients with DM had a higher New York Heart Association (NYHA) class (P < 0.001) and lower exercise capacity [7.0 METS (IQR 5.0-10.0) vs. 9.0 METS (IQR 6.6-11.0), P = 0.002]. These findings were independent of age, gender, country of origin, hypertension, and coronary artery disease. Patients with diabetes had a significantly higher 15-year mortality (22% vs. 15%, P = 0.03), with no differences in sudden cardiac death, appropriate implanted cardioverter-defibrillator therapy, or heart transplantation. CONCLUSION: Hypertrophic cardiomyopathy patients with diabetes are older and have a higher cardiovascular risk profile. They have a lower functional capacity and more heart failure symptoms due to diastolic dysfunction.

Hippocratic Oath and Heart Failure Journey: An Update on Therapies.

BACKGROUND: The innovation that has taken place in medicine, combined with state-of-the-art technological developments, provides therapeutic options for patients in conditions that were previously considered incurable. This promotion at the same time presents us with new ethical challenges. In this article, we review the journey through life of an advanced heart failure patient, covering a variety of potential clinical and ethics subjects in the field of heart failure treatment. We review the ethical principles of the Hippocratic Oath against the background of the realities of practicing medicine and of the enormous advances in therapeutics.

Relation of Age to Risk of Major Rejections, Allograft Vasculopathy, and Long-Term Mortality in a Contemporary Cohort of Patients Undergoing Heart Transplantation.

OBJECTIVES: To investigate the impact of recipient age on the occurrence of rejections, vasculopathy, and mortality after HTx. METHODS: Study population comprised all consecutive 291 patients who underwent HTx between 1991-2016 and were followed at our center. Patients were categorized by age tertiles: < 46 years (mean 31.4 ± 11.7, range 16-45, n=90), 46-57 years (mean 51.4 ± 3.2, range 46-56, n=92), and ≥ 57 years (mean 61.6 ± 3.4, range 57-73, n=109). RESULTS: Patients aged ≥ 57 years were more often males and had more pre-HTx co-morbidities including hypertension, diabetes, dyslipidemia, and history of smoking (P < 0.05) compared to the younger age groups. Kaplan-Meier analysis by age tertiles showed the rates of major rejections and vasculopathy at 15 years were similar among the three age groups. Mortality rates at 15 years were directly related to the age groups (39%, 52%, 62% log-rank, P = 0.01). However, the association between age and mortality was no longer statistically significant after multivariate analysis (hazard ratio 1.01, 95% confidence interval 1.00-1.03). CONCLUSIONS: In a contemporary cohort of patients undergoing HTx, recipient age does not significantly impact the risk of major rejections, vasculopathy, and long-term mortality.

Kidney Cancer Following Heart Transplantation, a Common Presentation of an Uncommon Malignancy: A Unique Case Series.

BACKGROUND: Heart transplantation (HT) success rate is limited by a high incidence of cancer post-HT. Data on kidney cancer following solid organ transplantation, especially HT, are limited, and only a few cases have been reported. OBJECTIVES: To report a unique case series of detected kidney cancer following HT. METHODS: Between 1997 and 2018, 265 patients who underwent HT were enrolled and prospectively followed in the HT registry of the Sheba Medical Center. RESULTS: The series included 5 patients, 4 men and a woman (age range 35-50 years at HT). The patients were diagnosed with kidney tumors 6-11 years after HT (age range at diagnosis 40-72 years). Two of the men were identical twin brothers. At HT four patients received induction therapy with anti-thymocyte globulin and all received an initial immunosuppressive regimen based on cyclosporine. All male HT recipients had a history of heavy smoking. Two male patients developed allograft vasculopathy, but all had preserved heart function. The 72-year-old woman developed a kidney tumor of the native kidney 5 years after re-HT and kidney transplantation. Two patients had features of multifocal papillary renal cell carcinoma (RCC) and eventually underwent bilateral nephrectomy, while another patient underwent left partial nephrectomy with preserved renal function. CONCLUSIONS: To the best of our knowledge, this is the first case series study describing kidney tumors following HT. With the improving outcomes and life expectancy of HT patients, a better understanding of the factors that determine cancer risk is of the utmost importance and may have a major impact on the non-cardiac surveillance.

Metformin therapy in patients with diabetes mellitus is associated with a reduced risk of vasculopathy and cardiovascular mortality after heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality following heart transplantation (HT). Reduced cardiovascular mortality and morbidity have been reported in non-HT patients treated with metformin. Given the high prevalence of type 2 diabetes mellitus (T2DM) in HT patients, we investigated the association between metformin therapy and cardiovascular outcomes after HT. METHODS: The study population comprised 103 DM patients who had undergone HT between 1994 and 2018 and were prospectively followed-up. We excluded from the study patients with type 1 diabetes mellitus. Fifty-five HT patients (53%) in the cohort were treated with metformin. Clinical data were recorded on prospectively designed forms. The primary outcomes included CAV, survival, and the combined end-point of CAV or cardiovascular mortality. RESULTS: Kaplan-Meier survival analysis showed that the CAV rate at 20 years of follow-up was lower in DM patients treated with metformin than in those who were not (30 vs. 65%; log-rank p = 0.044). Similarly, the combined risk of CAV or cardiovascular mortality was lower in the metformin-treated patients than in those not receiving metformin (32 vs. 68%; log rank p = 0.01). Consistently, multivariate analysis adjusted for age and comorbidities showed that metformin therapy was independently associated with a significant 90% reduction (95% confidence interval 0.02-0.46, p = 0.003) in the risk for the development of CAV, and a 91% reduction (95% confidence interval 0.02-0.42; p = 0.003) in the risk for CAV or cardiovascular mortality. CONCLUSIONS: In diabetic HT patients, metformin therapy is independently associated with a significant reduction in the long-term risk for CAV and the combined end-point of CAV or cardiovascular mortality after HT.