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.

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 systematic review.

Background: Sleep syncope is a subtype of vasovagal syncope in which patients experience syncope after awakening from their sleep. The aim was to investigate the association of clinical characteristics and gastrointestinal symptoms with syncope, as well as the body position in which symptoms began. Methods: A systematic search of studies was performed in MEDLINE and EMBASE without language restrictions, from inception to 9 January 2022. Studies were included if they reported data on the proportion of patients who experienced symptoms (nausea, vomiting, abdominal pain, and diarrhea) associated with syncope. Results: Data were included for 116 patients in 13 studies. Patients were 46.9 ± 4.3 years and 61.4% were female. In 52.5% of patients, a supine body position at the time of syncope was reported. A history of phobias was reported by 67.6% of patients, and 96.5% of patients also had typical daytime vasovagal syncope. In the 5 studies reporting the results of head-up tilt testing (n = 77), 90.9% of patients had positive tests. Gastrointestinal symptoms were present in the majority of patients with reported rates of 65.6% for upper gastrointestinal symptoms and 86.0% for lower gastrointestinal symptoms. Conclusion: Patients with sleep syncope patients are predominantly female with a history of daytime vasovagal syncope. Gastrointestinal symptoms are present in the majority of patients and is therefore an important feature of sleep syncope.

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.

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.

Pacing in vasovagal syncope: A physiological paradox?

The physiological principles underlying pacemaker treatment in patients with vasovagal syncope have never been reviewed. Current knowledge suggests that pacing the right heart is unlikely to correct blood pressure during a vasovagal reaction. In adults, the reason for this is that stroke volume is dictated by central blood volume contained in the cardiopulmonary vessels within the chest (ie, left ventricular preload). Preceding posture-triggered vasovagal syncope, there is a significant fall in central blood volume and therefore in stroke volume and cardiac output long before the onset of bradycardia. This explains why high rate cardiac pacing does not improve cardiac output or blood pressure during presyncope. Contradictory results between physiological theory and trial evidence underlying pacemaker treatment at present cannot be explained. Placebo effects during pacing for vasovagal syncope should be considered. More work is needed to solve the dilemma.

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.

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.

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.

Adrenomedullin 2 increases cardiac sympathetic nerve activity in parallel to heart rate in normal conscious sheep.

Both adrenomedullin 2 (AM2) and sympathetic nerve activity (SNA) have been shown to be involved in regulating cardiovascular activity, but whether any interaction between these two systems exists remains to be determined. In this study, we examine the effects of intravenous AM2 infusions on SNA directed toward the heart (cardiac SNA (CSNA)) in healthy sheep studied in the conscious state. In response to AM2, arterial pressure was reduced (P = 0.005) with both heart rate (P < 0.001) and cardiac output (P < 0.001) increased compared with vehicle control response. CSNA burst frequency (bursts/min) and burst area/min both increased during infusion of AM2 (both P < 0.001). However, correcting CSNA indices for concurrent heart rate changes resulted in CSNA burst incidence (bursts/100 beats) and burst area incidence (area/100 beats) being not significantly different between AM2 and control treatments. There were no significant differences demonstrated in plasma epinephrine or norepinephrine levels between the two study days. In conclusion, AM2 administered systemically to normal conscious sheep increases both CSNA and heart rate. However, correction for heart rate responses abrogates the rise in CSNA. It remains unclear whether AM2's primary effect is to act via the central nervous system to directly stimulate CSNA with resultant increase in heart rate, or to induce a rise in heart rate by other mechanisms.

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.