Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. OBJECTIVES: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment. METHODS: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance. RESULTS: Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70). CONCLUSIONS: Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).

Interaction of sex and diabetes in Asian patients with heart failure with mildly reduced left ventricular ejection fraction.

INTRODUCTION: The impact of sex and diabetes mellitus (DM) on patients with heart failure with mildly reduced ejection fraction (HFmrEF) is not well elucidated. This study aims to evaluate sex differences in the clinical profile and outcomes in Asian HFmrEF patients with and without DM. METHODS: Patients admitted nationally for HFmrEF (ejection fraction 40-49%) between 2008 and 2014 were included and followed up until December 2016. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular (CV) death and/or heart failure (HF) rehospitalisations. RESULTS: A total of 2,272 HFmrEF patients (56% male) were included. More women had DM than men (60% versus 55%, P=0.013). Regardless of DM status, HFmrEF females were older, less likely to smoke, had less coronary artery disease, narrower QRS and lower haemoglobin compared to men. The odds of having DM decreases in smokers who are women as opposed to men (Pinteraction =0.017). In multivariate analysis, DM reached statistical analysis for all-cause mortality and combined CV mortality or HF rehospitalisation in both men and women. However, the results suggest that there may be sex differences in terms of outcomes. DM (vs non-DM) was less strongly associated with increased all-cause mortality (adjusted hazards ratio [adj HR] 1.234 vs adj HR 1.290, Pinteraction <0.001] but more strongly associated with the combined CV death/HF rehospitalisation (adj HR 1.429 vs adj HR 1.317, Pinteraction =0.027) in women (vs men). CONCLUSION: Asian women with HFmrEF had a higher prevalence of DM, with differences in clinical characteristics, compared to men. While diabetes conferred poor outcomes regardless of sex, there were distinct sex differences. These highlight the need for sex-specific management strategies.

Myocarditis Following COVID-19 Vaccination: A Systematic Review (October 2020-October 2021).

INTRODUCTION: Reports of SARS-CoV-2 coronavirus (COVID-19) vaccine-related myocarditis, particularly after mRNA vaccines, have raised concerns amongst the general public. This review examined the literature regarding myocarditis post COVID-19 vaccination, drawing from vaccine safety surveillance databases and case reports. METHODS: Combinations of search terms were used in PubMed and COVID-19-specific repositories - LitCovid and the Cochrane COVID-19 Study Register - between 1 October 2020 and 31 October 2021. Manual searches of GoogleScholar and screening of article bibliographies were also performed. RESULTS: Information was obtained from five vaccine safety surveillance databases. Fifty-two (52) case reports totalling 200 cases of possible COVID-19 vaccine-related myocarditis were summarised. Vaccine surveillance databases differed in reporting formats and vaccination rates; however, gross estimates suggested low overall incidence rates of 2-5 per million mRNA vaccines. The incidence appeared to be higher in younger male populations, with onset of symptoms within a few days, usually after the second dose. Some with prior COVID-19 infections had onset after the first dose. Cases with prior unrelated myocarditis were also noted. Almost all presented with chest pain (98.0%). Troponin elevation was universally described and cardiac magnetic resonance imaging was commonly reported based on the updated Lake Louise criteria. Clinical course was mild in the majority, with response to anti-inflammatory treatment. CONCLUSION: COVID-19 vaccine-related myocarditis is an important but rare adverse event. More research is needed into its pathogenesis and reasons for its predominance in young males, while gaps in data exist in those aged <16 years, as well as those with prior COVID-19 infections and prior myocarditis.

Nitrates in combination with hydralazine in cardiorenal syndrome: a randomized controlled proof-of-concept study.

AIMS: Cardiorenal syndrome (CRS) is a common problem of great morbidity and mortality. Hydralazine-isosorbide dinitrate (H-ISDN) may be used in renal failure and may improve exercise capacity in heart failure (HF). Our proof-of-concept study aimed to evaluate early evidence of efficacy, safety, and feasibility of H-ISDN compared with standard of care in CRS. METHODS AND RESULTS: This multi-centre, single-blind, randomized trial in Singapore enrolled CRS patients, defined as chronic HF with concomitant renal failure [estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 ]. The primary outcome was 6 min walk test (6MWT) distance measured at 6 months. Secondary outcomes included study feasibility; efficacy outcomes which included renal, cardiac, and endothelial functions, health-related quality of life using Short Form-36, clinical outcomes; and adverse events. Forty-four patients [71 ± 10 years; 75% male; median (inter-quartile range) N-terminal prohormone brain natriuretic peptide 1346 (481-2272) pg/mL] with CRS (left ventricular ejection fraction 42 ± 12% and eGFR 46 ± 15 ml/min/1.73 m2 ) were randomized into two equal groups. Of these, 39 (89%) had hypertension, 27 (61%) had diabetes mellitus, and 17 (39%) had atrial fibrillation. Six (27%) discontinued H-ISDN owing to intolerance and poor compliance. There was a trend towards improved 6MWT distance with H-ISDN compared with standard of care at 6 months (mean difference 27 m; 95% CI, -12 to 66), with little differences in secondary efficacy outcomes. Giddiness and hypotension occurred more frequently with H-ISDN, but HF hospitalizations and mortality were less. CONCLUSIONS: Our pilot study does not support the addition of H-ISDN on top of standard medical therapy to improve exercise capacity in patients with CRS.

Novel use of low-dose thalidomide in refractory gastrointestinal bleeding in left ventricular assist device patients.

BACKGROUND: Gastrointestinal bleeding (GIB) is a complication reported in patients post left ventricular assist device (LVAD) implantation that is associated with high mortality rates. Thalidomide is an anti-angiogenic compound that may offer a potential option for management of refractory LVAD-related GIB. METHODS: A single-center, retrospective review was conducted from January 2009 to October 2016 at a tertiary cardiology center. It included LVAD patients initiated on thalidomide for refractory GIB. RESULTS: All patients (n = 11) were started on thalidomide 50 mg nocte and there was resolution of GIB in all patients except one (90.9%) during initial thalidomide treatment.The median duration of thalidomide therapy was 98 days (interquartile range: 34-215). The dose of thalidomide was reduced for 2 patients due to adverse effects. Thalidomide therapy was discontinued in 6 patients due to cessation of GIB (n = 4) and adverse effects (n = 2). Reported adverse effects included LVAD thrombosis (n = 2), somnolence (n = 1), neuropathy (n = 1), constipation (n = 1), and transaminitis (n = 1).Recurrent GIB occurred in 4 patients (45.4%) post-discontinuation of thalidomide therapy, which led to the re-initiation of therapy. CONCLUSIONS: Thalidomide appears to be a safe and effective option for management of refractory LVAD-related GIB. Monitoring for recurrent GIB should be performed closely following cessation of thalidomide therapy.

Mechanical circulatory support and heart transplantation in the Asia Pacific region.

Globalization has resulted in epidemiologic transition in developing countries from infectious disease and nutritional deficiencies to non-communicable diseases. Epidemiologic data on heart failure (HF), particularly advanced HF therapy, in Asia are increasingly becoming available, although they remain sparse. Heart transplantation for advanced stage HF remains very low in Asia-approximately 0.075 heart transplants per 1 million population. North America, which comprises 7.5% of the world population, accounted for 55.8% of transplants recorded in the 2012 International Society for Heart and Lung Transplantation (ISHLT) Registry, whereas Asia, with 62.5% of the world population, accounted for 5.7% of transplants. There is also lack of reporting from heart transplant centers in Asia to the ISHLT Registry. Most transplant programs in Asia are in economically stable South East Asian countries, whereas in other parts of developing countries, the cost and health care infrastructures remain prohibitive for the development of these programs. Multi-cultural and racial factors, religious beliefs, and diverse traditions of many centuries have resulted in reluctance to organ donation. Mechanical circulatory support (MCS) is emerging as a viable alternative to transplantation, but despite technical capabilities, limitations in embracing MCS in Asia exist. Discrepant practices in the reimbursement of costly MCS therapy have led to differences in the availability of these devices to patients in the region. The HeartMate II (St. Jude Medical, Inc, St. Paul, MN) left ventricular assist device is currently the most widely used durable device in Asia, whereas the HeartWare HVAD (HeartWare, Inc, Framingham, MA) is used most often in Australia. By September 9, 2015, 341 HeartMate implants (293 as bridge to transplant and 48 as destination therapy) had been performed, of which 180 implants were in Japan. The overall 4-year survival is 88%. The longest duration of support is 6.5 years. By the end of 2015, 243 HeartWare HVADs had been implanted in Asia Pacific. There is a need for focused efforts at improving the reporting of data and intensifying health policy within the region to advocate organ transplantation. Individual governments need to take national responsibility to fulfill organ donation and transplantation needs of their populations. International collaboratives, coordinated by societies such as the ISHLT, will be essential in moving this field forward in Asia Pacific.

Myocardial contractile dysfunction associated with increased 3-month and 1-year mortality in hospitalized patients with heart failure and preserved ejection fraction.

BACKGROUND: There is a clinical need for a contractility index that reflects myocardial contractile dysfunction even when ejection fraction (EF) is preserved. We used novel relative load-independent global and regional contractility indices to compare left ventricular (LV) contractile function in three groups: heart failure (HF) with preserved ejection fraction (HFPEF), HF with reduced ejection fraction (HFREF) and normal subjects. Also, we determined the associations of these parameters with 3-month and 1-year mortality in HFPEF patients. METHODS: 199 HFPEF patients [median age (IQR): 75 (67-80) years] and 327 HFREF patients [69 (59-76) years] were recruited following hospitalization for HF; 22 normal control subjects [65 (54-71) years] were recruited for comparison. All patients underwent standard two-dimensional Doppler and tissue Doppler echocardiography to characterize LV dimension, structure, global and regional contractile function. RESULTS: The median (IQR) global LV contractility index, dσ*/dtmax was 4.30s(-1) (3.51-4.57s(-1)) in normal subjects but reduced in HFPEF [2.57 (2.08-3.64)] and HFREF patients [1.77 (1.34-2.30)]. Similarly, median (IQR) regional LV contractility index was 99% (88-104%) in normal subjects and reduced in HFPEF [81% (66-96%)] and HFREF [56% (41-71%)] patients. Multi-variable logistic regression analysis on HFPEF identified sc-mFS <76% as the most consistent predictor of both 3-month (OR=7.15, p<0.05) and 1-year (OR=2.57, p<0.05) mortality after adjusting for medical conditions and other echocardiographic measurements. CONCLUSION: Patients with HFPEF exhibited decreased LV global and regional contractility. This population-based study demonstrated that depressed regional contractility index was associated with higher 3-month and 1-year mortality in HFPEF patients.