First Medical Contact-to-Device Time and Heart Failure Outcomes Among Patients Undergoing Primary Percutaneous Coronary Intervention.

Background Expediting reperfusion during primary percutaneous coronary intervention is aimed at salvaging myocardium in ST-segment-elevation myocardial infarction. Few studies have examined the relation between reperfusion time and heart failure (HF) events. Methods and Results: We studied 7597 patients undergoing primary percutaneous coronary intervention from 2007 to 2013 in the Singapore Myocardial Infarct Registry, which captures HF at admission, postadmission in-hospital HF, and HF rehospitalization. We studied the relation of first medical contact to deployment of first device to achieve reperfusion (FTD) time with in-hospital HF events and HF rehospitalization, with mortality modeled as a competing risk. At the population level, median FTD time decreased from 91 minutes (interquartile range, 69-114) in 2007 to 58 minutes (45-75) in 2013 ( P=0.001), whereas mortality remained unchanged (in-hospital: range 5.3%-7.3%; P=0.190 and 1-year: range 7.8%-10.9%; P=0.505). HF at admission increased from 12.2% in 2007 to 18.4% in 2013, P=0.020, whereas postadmission in-hospital HF decreased from 12.8% in 2007 to 7.1% in 2013, P=0.030. HF rehospitalization increased from 1.2% in 2007 to 2.6% in 2013 ( P=0.003), for 30-day HF rehospitalization, and 3.8% in 2007 to 5.6% in 2013 ( P=0.037), for 1-year HF rehospitalization. At the individual level, among patients with HF at admission (N=1191), longer FTD time was associated with more 30-day HF rehospitalization (compared with ≤60 minutes, adjusted hazard ratio, 1.68 [0.73-3.86] for 60-90 minutes, 2.88 [1.19-6.92], for 90-120 minutes, and 2.84 [1.08-7.44] for >120 minutes). Longer FTD time was associated with a greater risk of postadmission in-hospital HF (compared with ≤60 minutes, adjusted hazard ratio, 1.18 [0.96-1.44] for 60-90 minutes, 1.59 [1.25-2.03] for 90-120 minutes, and 1.67 [1.26-2.21] for >120 minutes). Conclusions: Temporal reductions in FTD time were associated with decrease in postadmission in-hospital HF. Among patients presenting with HF at admission, delays in FTD beyond 90 minutes were associated with more 30-day HF rehospitalization.

Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by the presence of high plasma low density lipoproteins cholesterol (LDL-c). Patients with FH, with mutation detected, are at increased risk of premature cardiovascular disease compared to those without mutations. The aim of the study was to assess the type of mutations in patients, clinically diagnosed with FH in Singapore. METHODS: Patients (probands) with untreated/highest on-treatment LDL-c>4.9 mmol/l were recruited (June 2015 to April 2017). Anthropometric, biochemical indices, blood and family history were collected. DNA was extracted and Next Generation Sequencing (NGS) was performed in 26 lipid-related genes, including LDLR, APOB and PCSK9, and validated using Sanger. Multiplex-ligation probe analyses for LDLR were performed to identify large mutation derangements. Based on HGVS nomenclature, LDLR mutations were classified as "Null"(nonsense, frameshift, large rearrangements) and "Defective"(point mutations which are pathogenic). RESULTS: Ninety-six probands were recruited: mean age: (33.5 ±â€¯13.6) years. 52.1% (n = 50) of patients had LDLR mutations, with 15 novel mutations, and 4.2% (n = 4) had APOB mutations. Total cholesterol (TC) and LDL-c were significantly higher in those with LDLR mutations compared to APOB and no mutations [(8.53 ±â€¯1.52) vs. (6.93 ±â€¯0.47) vs. (7.80 ±â€¯1.32)] mmol/l, p = 0.012 and [(6.74 ±â€¯0.35) vs. (5.29 ±â€¯0.76) vs. (5.98 ±â€¯1.23)] mmol/l, p=0.005, respectively. Patients with "null LDLR" mutations (n = 13) had higher TC and LDL-c than "defective LDLR" mutations (n = 35): [(9.21 ±â€¯1.60) vs. (8.33 ±â€¯1.41)]mmol/l, p = 0.034 and [(7.43 ±â€¯1.47) vs. (6.53 ±â€¯1.21)]mmol/l, p=0.017, respectively. CONCLUSIONS: To our knowledge, this is the first report of mutation detection in patients with clinically suspected FH by NGS in Singapore. While percentage of mutations is similar to other countries, the spectrum locally differs.

Therapeutic temperature management (TTM): post-resuscitation care for adult cardiac arrest, with recommendations from the National TTM Workgroup.

Therapeutic temperature management (TTM) was strongly recommended by the 2015 International Liaison Committee on Resuscitation as a component of post-resuscitation care. It has been known to be effective in improving the survival rate and neurologic functional outcome of patients after cardiac arrest. In an effort to increase local adoption of TTM as a standard of post-resuscitation care, this paper discusses and makes recommendations on the treatment for local providers.

Non-fluoroscopic navigation systems for radiofrequency catheter ablation for supraventricular tachycardia reduce ionising radiation exposure.

INTRODUCTION: The use of non-fluoroscopic systems (NFS) to guide radiofrequency catheter ablation (RFCA) for the treatment of supraventricular tachycardia (SVT) is associated with lower radiation exposure. This study aimed to determine if NFS reduces fluoroscopy time, radiation dose and procedure time. METHODS: We prospectively enrolled patients undergoing RFCA for SVT. NFS included EnSiteTM NavXTM or CARTO® mapping. We compared procedure and fluoroscopy times, and radiation exposure between NFS and conventional fluoroscopy (CF) cohorts. Procedural success, complications and one-year success rates were reported. RESULTS: A total of 200 patients over 27 months were included and RFCA was guided by NFS for 79 patients; those with atrioventricular nodal reentrant tachycardia (AVNRT), left-sided atrioventricular reentrant tachycardia (AVRT) and right-sided AVRT were included (n = 101, 63 and 36, respectively). Fluoroscopy times were significantly lower with NFS than with CF (10.8 ± 11.1 minutes vs. 32.0 ± 27.5 minutes; p < 0.001). The mean fluoroscopic dose area product was also significantly reduced with NFS (NSF: 5,382 ± 5,768 mGy*cm2 vs. CF: 21,070 ± 23,311 mGy*cm2; p < 0.001); for all SVT subtypes. There was no significant reduction in procedure time, except for left-sided AVRT ablation (NFS: 79.2 minutes vs. CF: 116.4 minutes; p = 0.001). Procedural success rates were comparable (NFS: 97.5% vs. CF: 98.3%) and at one-year follow-up, there was no significant difference in the recurrence rates (NFS: 5.2% vs. CF: 4.2%). No clinically significant complications were observed in both groups. CONCLUSION: The use of NFS for RFCA for SVT is safe, with significantly reduced radiation dose and fluoroscopy time.

Successful placement of a deflectable decapolar catheter via the right femoral vein approach in a patient with coronary sinus ostial atresia and persistent left superior vena cava.

The authors illustrate the successful ablation of a left-sided posterior accessory pathway via a retrograde aortic approach in a patient with coronary ostial atresia associated with persistent left-sided superior vena cava. This is an extremely rare anomaly which should be considered by cardiac electrophysiologists when there is difficulty cannulating the coronary sinus via the right atrial route. Awareness of this route obviates the need for additional venous access.

Targeted neuronal nitric oxide synthase transgene delivery into stellate neurons reverses impaired intracellular calcium transients in prehypertensive rats.

Hypertension is associated with the early onset of cardiac sympathetic hyperresponsiveness and enhanced intracellular Ca(2+) concentration [Ca(2+)](i) in sympathetic neurons from both prehypertensive and hypertensive, spontaneously hypertensive rats (SHRs). Oxidative stress is a hallmark of hypertension, therefore, we tested the hypothesis that the inhibitory action of the nitric oxide-cGMP pathway on [Ca(2+)](i) transients is impaired in cardiac sympathetic neurons from the SHR. Stellate ganglia were isolated from young prehypertensive SHRs and age-matched normotensive Wistar-Kyoto rats. [Ca(2+)](i) was measured by ratiometric fluorescence imaging. Neurons from the prehypertensive SHR ganglia had a significantly higher depolarization evoked [Ca(2+)](i) transient that was also associated with decreased expression of neuronal nitric oxide synthase (nNOS), ß1 subunit of soluble guanylate cyclase and cGMP when compared with the Wistar-Kyoto rat ganglia. Soluble guanylate cyclase inhibition or nNOS inhibition increased [Ca(2+)](i) in the Wistar-Kyoto rats but had no effect in SHR neurons. A nitric oxide donor decreased [Ca(2+)](i) in both sets of neurons, although this was markedly less in the SHR. A novel noradrenergic cell specific vector (Ad.PRSx8-nNOS/Cherry) or its control vector (Ad.PRSx8-Cherry) was expressed in sympathetic neurons. In the SHR, Ad.PRSx8-nNOS/Cherry-treated neurons had a significantly reduced peak [Ca(2+)](i) transient that was associated with increased tissue levels of nNOS protein and cGMP concentration compared with gene transfer of Ad.PRSx8-Cherry alone. nNOS inhibition significantly increased [Ca(2+)](i) after Ad.PRSx8-nNOS/Cherry expression. We conclude that artificial upregulation of stellate sympathetic nNOS via targeted gene transfer can directly attenuate intracellular Ca(2+) and may provide a novel method for decreasing enhanced cardiac sympathetic neurotransmission.

Abnormal intracellular calcium homeostasis in sympathetic neurons from young prehypertensive rats.

Hypertension is associated with cardiac noradrenergic hyperactivity, although it is not clear whether this precedes or follows the development of hypertension itself. We hypothesized that Ca(2+) homeostasis in postganglionic sympathetic neurons is impaired in spontaneously hypertensive rats (SHRs) and may occur before the development of hypertension. The depolarization-induced rise in intracellular free calcium concentration ([Ca(2+)](i); measured using fura-2-acetoxymethyl ester) was significantly larger in cultured sympathetic neurons from prehypertensive SHRs than in age matched normotensive Wistar-Kyoto rats. The decay of the [Ca(2+)](i) transient was also faster in SHRs. The endoplasmic reticulum Ca(2+) content and caffeine-induced [Ca(2+)](i) amplitude were significantly greater in the young SHRs. Lower protein levels of phospholamban and more copies of ryanodine receptor mRNA were also observed in the young SHRs. Depleting the endoplasmic reticulum Ca(2+) store did not alter the difference of the evoked [Ca(2+)](i) transient and decay time between young SHRs and Wistar-Kyoto rats. However, removing mitochondrial Ca(2+) buffering abolished these differences. A lower mitochondrial membrane potential was also observed in young SHR sympathetic neurons. This resulted in impaired mitochondrial Ca(2+) uptake and release, which might partly be responsible for the increased [Ca(2+)](i) transient and faster decay in SHR sympathetic neurons. This Ca(2+) phenotype seen in early development in cardiac stellate and superior cervical ganglion neurons may contribute to the sympathetic hyperresponsiveness that precedes the onset of hypertension.

Oral amiodarone provoking inferior ST elevation and unmasking Brugada-like electrocardiogram feature.

A woman presented with broad complex tachycardia. She was converted to sinus rhythm with intravenous amiodarone and continued on oral amiodarone. The amiodarone was stopped 3 weeks later as she was pregnant. Electrocardiogram (ECG) then revealed coved-type ST elevation in C1, suggestive of Brugada syndrome, and widespread inferior ST elevation. Electrocardiogram several months later showed resolution of inferior ST elevation.

Pravastatin normalises peripheral cardiac sympathetic hyperactivity in the spontaneously hypertensive rat.

Hypertension is associated with heightened cardiac sympathetic drive whilst statins reduce angiotensin II (ATII) signalling, superoxide anion production and increase nitric oxide bioavailability, events that can potentially reduce peripheral cardiac sympathetic neurotransmission. We therefore investigated whether pravastatin alters peripheral cardiac sympathetic control in the spontaneously hypertensive rat (SHR). SHRs (16-18 weeks) had significantly (p<0.05) enhanced atrial (3)H-norepinephrine ((3)H-NE) release to field stimulation compared to normotensive WKYs. 2-week pravastatin supplementation significantly reduced (3)H-NE release to levels observed in the WKY. In-vivo, pravastatin lowered resting heart rate (HR) in the SHR despite not affecting arterial blood pressure or serum cholesterol. In SHR atria/right stellate ganglion preparations, the HR response to stellate stimulation (1, 3, and 5 Hz) was also significantly reduced by pravastatin whilst the HR response to exogenous NE (0.025-5 µmol) remained similar. The nitric oxide synthase (NOS) inhibitor l-NAME (1 mmol/l) increased (3)H-NE release by similar amounts in atria from supplemented and non-supplemented SHRs, whilst Western blotting showed no difference in protein levels of nNOS, eNOS, guanylyl cyclase, or the NADPH oxidase subunits Gp91 and P40 phox. Pravastatin significantly reduced cardiac ATII levels and angiotensin converting enzyme 1 and 2 expressions whilst protein levels of the ATII receptor (ATR(1)) remained unchanged in the SHR. Immunohistochemistry co-localised ATR(1) with tyrosine hydroxylase positive neurons in the stellate ganglion. The ATR(1) antagonist Losartan (5 µmol) equalised release of (3)H-NE to comparable levels in supplemented and non-supplemented SHRs. These results suggest 2-week pravastatin treatment reduces cardiac ATII, and prevents its facilitatory effect on NE release thus normalising cardiac sympathetic hyper-responsiveness in SHRs.

L-arginine supplementation reduces cardiac noradrenergic neurotransmission in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) are known to have cardiac noradrenergic hyperactivity due to an impaired nitric oxide (NO)-cGMP pathway. We hypothesized that dietary l-arginine supplementation may correct this autonomic phenotype. Male SHR and Wistar Kyoto rats (WKY) aged 16-18 weeks were given l-arginine (10 g/L in drinking water) for 1 week. Separate control groups received no supplementation. The SHR control had a significantly lower plasma l-arginine than WKY control, but this was increased to a comparable level following l-arginine. Atrial cGMP was lower in the SHR control compared with the WKY control (2.4+/-0.4 pmol/mg vs 3.9+/-0.5 pmol/mg, p<0.05), but increased to 4.1+/-0.5 pmol/mg protein (n=8, p<0.05) with l-arginine. Evoked [(3)H]norepinephrine release in isolated spontaneously beating right atria from the SHR control (328+/-19%, n=19) was 28% higher than the WKY control (256+/-20%, n=14, p<0.05), but was reduced to 258+/-11% with l-arginine feeding (n=24, p<0.01). Soluble guanylyl cyclase (sGC) inhibition caused a greater increase of evoked norepinephrine release in the l-arginine fed SHR compared with the non-fed SHR. l-arginine feeding did not reduce evoked norepinephrine release in the WKY. In-vitro heart rate response to exogenous norepinephrine (0.1-5 mumol/L) was similar between l-arginine fed (n=13) and non-fed SHR (n=10), suggesting that l-arginine supplementation worked pre-synaptically. Myocardial tyrosine hydroxylase protein was decreased in SHR following l-arginine supplementation, providing a link to reduced synthesis of norepinephrine. In conclusion, l-arginine supplementation corrects local cardiac noradrenergic hyperactivity in the SHR, probably via increased pre-synaptic substrate availability of NOS-sGC-cGMP pathway and reduced tyrosine hydroxylase levels.

Noradrenergic cell specific gene transfer with neuronal nitric oxide synthase reduces cardiac sympathetic neurotransmission in hypertensive rats.

Nitric oxide-cGMP pathway can inhibit cardiac norepinephrine (NE) release. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress impairing this pathway. We tested the hypothesis that the gene transfer of neuronal NO synthase (nNOS) could restore sympathetic balance in the spontaneously hypertensive rat (SHR). An adenovirus (5x10(10) particles) constructed with a noradrenergic neuron-specific promoter (PRS x8) encoding nNOS (Ad.PRS-nNOS) or enhanced green fluorescence protein (Ad.PRS-eGFP) was targeted to the right atrial wall by percutaneous injection in age-matched male SHRs and Wistar-Kyoto (WKY) rats. Five days after transduction, right atria were removed, and evoked [(3)H] norephinephrine (NE) release, NOS activity, and cGMP were measured. In the Ad.PRS-eGFP treated group, tissue levels of cGMP were significantly lower in the SHR compared with the WKY atria. NE release was also greater in the SHR, and soluble guanylate cyclase inhibition did not alter evoked [(3)H] NE release in the Ad.PRS-eGFP-treated SHR. All atria treated with Ad.PRS-nNOS had enhanced nNOS activity when compared with Ad.PRS-eGFP atria. Ad.PRS-nNOS in WKY rats reduced NE release compared with the Ad.PRS-eGFP group. Guanylate cyclase inhibition enhanced NE release in both Ad.PRS-nNOS- and Ad.PRS-eGFP-treated WKY atria. Ad.PRS-nNOS restored cGMP levels in the SHR to those seen in the WKY atria. In the SHR, Ad.PRS-nNOS also attenuated NE release compared with Ad.PRS-eGFP group. This was reversed by guanylate cyclase inhibition. We conclude that artificial upregulation of sympathetic nNOS via gene transfer with a noradrenergic promoter may provide a novel approach for correcting peripheral sympathetic hyperactivity in hypertension.