Known pathogenic gene variants and new candidates detected in sudden unexpected infant death using whole genome sequencing.

The purpose of this study is to gain insights into potential genetic factors contributing to the infant's vulnerability to Sudden Unexpected Infant Death (SUID). Whole Genome Sequencing (WGS) was performed on 144 infants that succumbed to SUID, and 573 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences. Variants of interest were identified in 88 genes, in 64.6% of our cohort. Seventy-three of these have been previously associated with SIDS/SUID/SUDP. Forty-three can be characterized as cardiac genes and are related to cardiomyopathies, arrhythmias, and other conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes reported to be pathogenic for various systemic disorders and in two genes associated with immunological function. Variants in eight genes are implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) and have not been previously described in SIDS/SUID/SUDP. Seventy-two infants met the triple risk hypothesis criteria. Our study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism have important mechanistic implications for the pathophysiology of SUID.

Immediate effect of caffeine on sympathetic nerve activity: why coffee is safe? A single-centre crossover study.

PURPOSES: Habitual coffee drinking is ubiquitous and generally considered to be safe despite its transient hypertensive effect. Our purpose was to determine the role of the sympathetic nervous system in the hypertensive response. METHODS: In a single-centre crossover study, medical caregivers were studied after consumption of standard coffee (espresso), water and decaffeinated coffee (decaff) given in random order at least 1 month apart. Plasma caffeine levels, mean arterial pressure, heart rate, total peripheral resistance and muscle sympathetic activity were recorded. Baroreflex activity was assessed using burst incidence and RR interval changes to spontaneous blood pressure fluctuations. RESULTS: A total of 16 subjects (mean [± standard error] age 34.4 ± 2 years; 44% female) were recruited to the study. Three agents were studied in ten subjects, and two agents were studied in six subjects. Over a 120-min period following the consumption of standard coffee, mean (± SE) plasma caffeine levels increased from 2.4 ± 0.8 to 21.0 ± 4 µmol/L and arterial pressure increased to 103 ± 1 mmHg compared to water (101 ± 1 mmHg; p = 0.066) and decaff (100 ± 1 mmHg; p = 0.016). Peripheral resistance in the same period following coffee increased to 120 ± 4% of the baseline level compared to water (107 ± 4; p = 0.01) and decaff (109 ± 4; p = 0.02). Heart rate was lower after both coffee and decaff consumption: 62 ± 1 bpm compared to water (64 bpm; p = 0.01 and p = 0.02, respectively). Cardio-vagal baroreflex activity remained stable after coffee, but sympathetic activity decreased, with burst frequency of 96 ± 3% versus water (106 ± 3%; p = 0.04) and decaff (112 ± 3%; p = 0.001) despite a fall in baroreflex activity from - 2.2 ± 0.1 to - 1.8 ± 0.1 bursts/100 beats/mmHg, compared to water (p = 0.009) and decaff (p = 0.004). CONCLUSION: The hypertensive response to coffee is secondary to peripheral vasoconstriction but this is not mediated by increased sympathetic nerve activity. These results may explain why habitual coffee drinking is safe.

Sleep syncope: a prospective cohort study.

PURPOSE: Sleep syncope is defined as a form of vasovagal syncope which interrupts sleep. Long term follow-up has not been reported. METHODS: Between 1999 and 2013 we diagnosed vasovagal syncope in 1105 patients of whom 69 also had sleep syncope. We compared these 69 patients in the sleep syncope group to 118 patients with classical vasovagal syncope consecutively investigated between 1999 and 2003. We compared baseline demography, syncope history, tilt test results and follow-up findings. RESULTS: At baseline, age and gender distribution (mean ± standard deviation) of the classical VVS and sleep synocope groups were similar: 46 ± 21 vs. 47 ± 15 years (p = 0.53), and 55% versus 66% female (p = 0.28), respectively. Abdominal discomfort and vagotonia were more frequent in sleep syncope patients: 80% versus 8% and 33% versus 2% (p < 0.001). Childhood syncope and blood-needle phobia were also more frequent in sleep syncope patients: 58% versus 15% and 69% versus 19% (p < 0.001). Positive tilt test results were similar for the two groups (93% [classical VVS] vs. 91%; p = 0.56). Blood pressure, heart rate and stroke volume changed in a similar manner from baseline to syncope (p = 0.32, 0.34 and 0.18, respectively). Mean duration of follow-up for the classical VVS and sleep syncope groups, as recorded in the electronic records, were 17 (3-21) and 15 (7-27) years, respectively. Rates of mortality and of permanent pacemaker insertion were similar in the two groups: 16.2% (classical VVS) versus 7.6% (p = 0.09) and 3% (classical VVS) versus 3% (p = 0.9). Incidence of sleep episodes decreased from 1.9 ± 3 to 0.1 ± 0.3 episodes per year (p < 0.001). CONCLUSION: Sleep syncope is a subtype of vasovagal syncope with characteristic symptoms. Despite the severity of the sleep episodes, the prognosis is very good. Very few patients require permanent pacing, and nearly all respond to education and reassurance.

Different Types of Syncope Presenting to Clinic: Do We Miss Cardiac Syncope?

BACKGROUND: In the outpatient setting, differentiation of cardiac syncope (CS) from other more common forms of syncope is difficult, particularly in the elderly. We examined the frequency of the different types of syncope in a clinic population and estimated missed CS cases. METHODS: We retrospectively examined the relevant data for patients assessed in our Christchurch Hospital syncope clinic over a 5-year study period (1 January 2011-31 December 2015). Patients who were later found to have cardiac syncope (and were not initially diagnosed in our clinic) were counted as "missed" cases. RESULTS: Eight hundred thirty-nine (839) patients (median age 57, interquartile range: 35-73 years, 56% female) were assessed during the study period. Vasovagal syncope (VVS) was the most frequent diagnosis (42.8%) followed by drug-related postural hypotension (DRPH) (26.6%). Cardiac syncope was initially diagnosed in only 3.1%. Of 30 CS patients initially assessed in syncope clinic who later required pacing, 18 (2.1%) were missed CS. In this group, 12-lead electrocardiograph (ECG) was normal in 50% and the majority (n=10) were tilt-positive. The 2.5-year mortality was 5.7% (n=48) including three sudden unexpected cardiac deaths. CONCLUSION: Vasovagal syncope and DRPH were by far the most frequent diagnoses. Cardiac syncope was less frequent because patients were selected mainly from an outpatient population, not the emergency department. In a small number of patients, CS was missed for the following reasons: (1) coexistence of cardiac conduction system disease with VVS and DRPH in the elderly, and (2) insensitivity of 12-lead ECG, in-hospital telemetry and out-of-hospital Holter monitoring for detecting conduction system disease early in its development.

Sympathetic overactivity in dialysis patients-Underappreciated and clinically consequential.

Cardiovascular morbidity and mortality remain frustratingly common in dialysis patients. A dearth of established evidence-based treatment calls for alternative therapeutic avenues to be embraced. Sympathetic hyperactivity, predominantly due to afferent nerve signaling from the diseased native kidneys, has been established to be prognostic in the dialysis population for over 15 years. Despite this, tangible therapeutic interventions have, to date, been unsuccessful and the outlook for patients remains poor. This narrative review summarizes established experimental and clinical data, highlighting recent developments, and proposes why interventions to ameliorate sympathetic hyperactivity may well be beneficial for this high-risk population.

Introduction of portable bedside echocardiography to acute general medicine.

We reviewed the medical records of all patients who underwent portable bedside echocardiography under general medicine over a 15-month period. The mean age of patients was 67 years (range 16-95) (n = 201). Indications for scanning included syncope (27%), murmur (17%) and dyspnoea (14%); findings included valve abnormalities (46%), left ventricular hypertrophy (26%) and dilated left ventricle (15%). Bedside echocardiography is a useful extension of the physical examination but is operator-dependent, and its routine use in general medicine will depend on the availability of training, group reporting sessions and quality assurance.

Troponin release after exertional vasovagal syncope.

Troponin release following exertional vasovagal syncope has not previously been reported. A young man was investigated after being admitted twice with exertional syncope, each time followed by a 10-fold spike in troponin I over 24 h. Treadmill exercise tests reproduced his symptoms and demonstrated a vasovagal mechanism. During recovery, despite lying supine, he remained hypotensive for 5 min, with profound bradycardia and ST segment depression. We suspected that intense cardiovagal neural activity may have caused the troponin leak.

Effectiveness of EDACS Versus ADAPT Accelerated Diagnostic Pathways for Chest Pain: A Pragmatic Randomized Controlled Trial Embedded Within Practice.

STUDY OBJECTIVE: A 2-hour accelerated diagnostic pathway based on the Thrombolysis in Myocardial Infarction score, ECG, and troponin measures (ADAPT-ADP) increased early discharge of patients with suspected acute myocardial infarction presenting to the emergency department compared with standard care (from 11% to 19.3%). Observational studies suggest that an accelerated diagnostic pathway using the Emergency Department Assessment of Chest Pain Score (EDACS-ADP) may further increase this proportion. This trial tests for the existence and size of any beneficial effect of using the EDACS-ADP in routine clinical care. METHODS: This was a pragmatic randomized controlled trial of adults with suspected acute myocardial infarction, comparing the ADAPT-ADP and the EDACS-ADP. The primary outcome was the proportion of patients discharged to outpatient care within 6 hours of attendance, without subsequent major adverse cardiac event within 30 days. RESULTS: Five hundred fifty-eight patients were recruited, 279 in each arm. Sixty-six patients (11.8%) had a major adverse cardiac event within 30 days (ADAPT-ADP 29; EDACS-ADP 37); 11.1% more patients (95% confidence interval 2.8% to 19.4%) were identified as low risk in EDACS-ADP (41.6%) than in ADAPT-ADP (30.5%). No low-risk patients had a major adverse cardiac event within 30 days (0.0% [0.0% to 1.9%]). There was no difference in the primary outcome of proportion discharged within 6 hours (EDACS-ADP 32.3%; ADAPT-ADP 34.4%; difference -2.1% [-10.3% to 6.0%], P=.65). CONCLUSION: There was no difference in the proportion of patients discharged early despite more patients being classified as low risk by the EDACS-ADP than the ADAPT-ADP. Both accelerated diagnostic pathways are effective strategies for chest pain assessment and resulted in an increased rate of early discharges compared with previously reported rates.

Human muscle sympathetic nerve responses to urocortin-2 in health and stable heart failure.

Sympatholytic and vasodilator drugs have been of major therapeutic benefit in patients with heart failure (HF). Urocortin-2 (Ucn2) is a small corticotrophin-related peptide distributed throughout the cardiovascular system which inhibits cardiac sympathetic nerve activity (CSNA) and is also a powerful vasodilator. This study analysed the effects of a 60-min infusion of Ucn2 (25 µg) on muscle sympathetic nerve activity (MSNA) recorded from the lower limb in eight healthy men and four men with stable HF. During Ucn2 infusion, mean arterial pressure fell to a nadir of 84 ± 2 compared to 95 ± 2 mmHg during placebo (P = 0.001) and heart rate increased to a maximum of 74 ± 1 compared to 64 ± 1 b.p.m. (P < 0.001). Total peripheral resistance fell by 23 ± 4% compared with an increase of 23 ± 4% (P < 0.001) and cardiac output increased by 22 ± 4 compared to 4 ± 4% (P = 0.001). The MSNA burst frequency increased by 9 ± 2 compared to 1 ± 2 burst/min (P = 0.005) and burst area/min by 133 ± 7 vs 107 ± 7% (P = 0.01). Burst incidence and baroreflex sensitivity were not significantly altered. Qualitatively similar changes were observed in stable HF patients. Ucn2-induced vasodilatation increased MSNA in humans, as opposed to the decrease in CSNA we observed in sheep. Therefore, if Ucn2 has a central inhibitory effect on MSNA, it was over-run by off-loading the cardiovagal baroreflex. Alternatively, CSNA may be less responsive to baroreflex off-loading than MSNA.

Low-dose B-type natriuretic peptide raises cardiac sympathetic nerve activity in sheep.

The reported effects of atrial natriuretic peptide (ANP) on sympathetic nerve activity (SNA) are variable, dependent on concomitant hemodynamic actions, and likely to be regionally differentiated. There are few reports of the effect of B-type natriuretic peptide (BNP) on SNA and none have measured cardiac SNA (CSNA) by direct microneurography. We measured the effects of low-dose ANP and BNP (2.4 pmol·kg(-1)·min(-1) infused for 120 min) on CSNA and hemodynamics in conscious sheep (n = 8). While there was a trend for mean arterial pressure and cardiac output to fall with both ANP and BNP, changes were not significant compared with vehicle control. However, BNP did significantly reduce systolic arterial (97 ± 4.2 vs. 107 ± 6.8 mmHg during control; P = 0.043) and pulse pressures (0.047) and increase heart rate (110 ± 6.7 vs. 96 ± 7.3 beats/min; P = 0.044). Trends for these hemodynamic parameters to change with ANP did not achieve statistical significance. ANP also had no significant effect on any CSNA parameters measured. In contrast, BNP induced a rise in both CSNA burst frequency (∼20 bursts/min higher than control, P = 0.011) and burst area (∼40% higher than control, P = 0.013). BNP-induced rises in burst incidence (bursts/100 beats), and burst area per 100 beats, however, were not significant. In conclusion, BNP infused at low doses that only had subtle effects on hemodynamics increased CSNA burst frequency and burst are per minute. This increase in CSNA may in large part be secondary to an increase in heart rate as CSNA burst incidence and burst area per 100 beats were not significantly increased. This study provides no evidence for inhibition of CSNA by natriuretic peptides.

A single nucleotide polymorphism in the corticotropin receptor gene is associated with a blunted cortisol response during pediatric critical illness.

OBJECTIVES: The cortisol response during critical illness varies widely among patients. Our objective was to examine single nucleotide polymorphisms in candidate genes regulating cortisol synthesis, metabolism, and activity to determine if genetic differences were associated with variability in the cortisol response among critically ill children. DESIGN: This was a prospective observational study employing tag single nucleotide polymorphism methodology to examine genetic contributions to the variability of the cortisol response in critical illness. Thirty-one candidate genes and 31 ancestry markers were examined. SETTING: Patients were enrolled from seven pediatric critical care units that constitute the Eunice Kennedy Shriver Collaborative Pediatric Critical Care Research Network. SUBJECTS: Critically ill children (n = 92), age 40 weeks gestation to 18 years old, were enrolled. INTERVENTIONS: Blood samples were obtained from all patients for serum cortisol measurements and DNA isolation. Demographic and illness severity data were collected. MEASUREMENTS AND MAIN RESULTS: Single nucleotide polymorphisms were tested for association with serum free cortisol concentrations in context of higher illness severity as quantified by Pediatric Risk of Mortality III score greater than 7. A single nucleotide polymorphism (rs1941088) in the MC2R gene was strongly associated (p = 0.0005) with a low free cortisol response to critical illness. Patients with the AA genotype were over seven times more likely to have a low free cortisol response to critical illness than those with a GG genotype. Patients with the GA genotype exhibited an intermediate free cortisol response to critical illness. CONCLUSIONS: The A allele at rs1941088 in the MC2R gene, which encodes the adrenocorticotropic hormone (corticotropin, ACTH) receptor, is associated with a low cortisol response in critically ill children. These data provide evidence for a genetic basis for a portion of the variability in cortisol production during critical illness. Independent replication of these findings will be important and could facilitate development of personalized treatment for patients with a low cortisol response to severe illness.

Oxymetazoline and hypertensive crisis in a child: can we prevent it?

BACKGROUND: Oxymetazoline nasal spray is not FDA approved for use in children less than 6 years; however, its safety and efficacy are widely accepted, and it is in widespread use in children prior to procedures that may lead to epistaxis. We report a case of intraoperative oxymetazoline toxicity in a 4-year-old boy that led to a hypertensive crisis. While examining the possible causes for this problem, we became aware that the method of drug delivery led to an unanticipated overdose. The position in which the bottle is held causes pronounced variation in the quantity of oxymetazoline dispensed. METHODS: To examine the impact that bottle position has on the volume delivered, we measured the volume of oxymetazoline dispensed with the bottle in the upright and inverted position. We also measured the volume of a drop of oxymetazoline dispensed from the bottle. Because an additional source of oxymetazoline exposure is from packing the nares with surgical pledgets, we analyzed the volume of oxymetazoline absorbed by each pledget. RESULTS: Squeezing the bottle in the upright position results in a fine spray of fluid that averaged 28.9 ± 6.8 µl and was largely independent of effort. This volume is nearly identical to the measured volume of a drop of oxymetazoline, which was 30 µl. However, squeezing the bottle in the inverted position resulted in a steady stream of fluid, and the volume administered was completely effort dependent. Multiple tests in the inverted position demonstrated an average volume of 1037 ± 527 µl, with a range of 473-2196 µl. Lastly, the volume of oxymetazoline absorbed by each surgical pledget was 1511 ± 184 µl. DISCUSSION: Our testing indicates that bottle position during oxymetazoline administration can cause up to a 75-fold increase in intended drug administration.

Known pathogenic gene variants and new candidates detected in Sudden Unexpected Infant Death using Whole Genome Sequencing.

Purpose: To gain insights into potential genetic factors contributing to the infant's vulnerability to Sudden Unexpected Infant Death (SUID). Methods: Whole Genome Sequencing (WGS) was performed on 145 infants that succumbed to SUID, and 576 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences. Results: Variants of interest were identified in 86 genes, 63.4% of our cohort. Seventy-one of these have been previously associated with SIDS/SUID/SUDP. Forty-three can be characterized as cardiac genes and are related to cardiomyopathies, arrhythmias, and other conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes reported to be pathogenic for various systemic disorders. Variants in eight genes are implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) and have not been previously described in SIDS/SUID/SUDP. Seventy-two infants met the triple risk hypothesis criteria (Figure 1). Conclusion: Our study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism have important mechanistic implications for the pathophysiology of SUID.

Influence of ABCB1 (P-glycoprotein) haplotypes on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: A single nucleotide polymorphism in ABCB1, which encodes P-glycoprotein, has retrospectively been associated with symptoms of nortriptyline-induced postural hypotension in depressed patients. This finding needs to be replicated in independent studies before recommendations regarding pharmacogenetic testing can be made. WHAT THIS STUDY ADDS: In a prospective study of healthy volunteers homozygous for ABCB1 (1236-2677-3435, TTT/TTT or CGC/CGC), a single dose of nortriptyline was administered, plasma exposure was determined and blood pressure and heart rate were monitored during posture change. No differences between ABCB1 haplotype groups were found in plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline. The heart rate response to posture change was increased with nortriptyline, whereas there was no difference in blood pressure response. However, no differences between haplotype groups were observed except that the pre dose heart rate response to standing was greater in the TTT than CGC homozygotes. The association between ABCB1 polymorphisms and nortriptyline-induced postural hypotension found in a previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline. AIMS To investigate the influence of ABCB1 (1236-2677-3435) polymorphisms on nortriptyline pharmacokinetics and nortriptyline-induced postural hypotension in healthy volunteers. METHODS: Genetic screening of 67 healthy volunteers identified eight CGC homozygotes and nine TTT homozygotes of ABCB1 (1236-2677-3435), who were administered a single dose of nortriptyline 25 mg. Plasma exposure of nortriptyline and its active metabolites, E- and Z-10-hydroxynortriptyline, was determined over 72 h. Heart rate and blood pressure responses to posture change (active standing and passive head-up tilt) were measured continuously using finger plethysmography. RESULTS: There were no differences in plasma exposure between ABCB1 haplotype groups, as the geometric mean (95% CI) AUC(0,72 h) ratios were 0.98 (0.94, 1.03), 1.02 (0.96, 1.09) and 0.95 (0.80, 1.10) for nortriptyline, E- and Z-10-hydroxynortriptyline, respectively. The pre dose heart rate response to standing was greater in the TTT than CGC homozygotes (mean (95% CI) difference 7.4 (1.5, 13.4) beats min(-1) , P = 0.02). At t(max) at 8 h post dose, nortriptyline increased the heart rate response to posture change in all subjects with mean (95% CI) Δ heart rate values of 7.4 (3.6, 11.3) beats min(-1) on active standing (P = 0.0009) and 4.8 (2.0, 7.6) beats min(-1) on head-up tilt (P = 0.002), but no difference was observed between haplotype groups. There was no difference in blood pressure response to posture change in either group. CONCLUSION: The association between ABCB1 polymorphisms and nortriptyline-induced postural hypotension found in the previous study could not be confirmed. The results raise the possibility of a predisposition in heart rate response in the TTT homozygotes rather than an effect of nortriptyline.

Vasovagal syncope triggered by recent moderate weight loss?

AIM: In adults, the onset of vasovagal syncope is often unexplained. We wished to explore if moderate weight loss triggers the onset of vasovagal syncope (VVS). METHODS: A retrospective case-control study comparing demographic characteristic, syncope symptoms, and tilt-table results of patients who had recently lost weight (n=57), with randomly selected weight-stable patients (n=73), and controls, patients without syncope (n=24). RESULTS: VVS was diagnosed in 480 out of 1,209 clinic patients of whom 57 (11.9%) reported moderate weight loss. The mean (SD) reported weight loss was 11.5 (7) kg over 18.7 (13) months. Age and gender did not differ between groups: in the weight loss, weight stable, and control groups the mean age was 44.8, 45.2, and 44 years respectively; and proportion female 60%, 64%, and 54%. Body weight, mass index and calculated blood volume at presentation were also similar in the different groups. Weight loss preceded or coincided the onset of syncope in 80% of patients; the length of time over which weight loss occurred was associated with the length of time of syncope symptoms, product moment correlation coefficient 0.45, p=0.001. Syncope in childhood and teenage years was less frequent in the weight loss group compared to the weight stable group: 37% vs 53%. After 10 minutes of head-up tilt, stroke volume was preserved in both syncope groups compared to controls; percentage of baseline mean (SD) in the weight loss, weight stable, and control groups: 71(18), 69(10), and 61 (11) respectively; despite lower blood pressure in the weight loss groups with mean (SD) 90 (14) mmHg, 93 (13) and 103 (14) respectively. CONCLUSIONS: Some patients have onset of VVS within a few months of weight loss resulting in earlier presentation to clinic. The physiological mechanism for this is uncertain.