Prediction of Pacemaker Requirement in Patients With Unexplained Syncope: The DROP Score.

BACKGROUND: Implantable loop recorders (ILR) are increasingly utilised in the evaluation of unexplained syncope. However, they are expensive and do not protect against future syncope. OBJECTIVES: To compare patients requiring permanent pacemaker (PPM) implantation during ILR follow-up with those without abnormalities detected on ILR in order to identify potential predictors of benefit from upfront pacing. METHODS: We analysed 100 consecutive patients receiving ILR: Group 1 (n=50) underwent PPM insertion due to bradyarrhythmias detected on ILR; Group 2 (n=50) had no arrhythmias detected on ILR over >3 years follow-up. Baseline clinical characteristics, syncope history, electrocardiographic and echocardiographic parameters were assessed to identify predictors of ultimate requirement for pacing. RESULTS: Group 1 (64% male, median age 70.8 years; IQR 65.5-78.8) were older than Group 2 (58% male, median 60.2 years; IQR 44.0-73.0 p=0.001) and were less likely to have related historical factors such as overheating, posture and exercise (98% vs 70% p<0.001). PR interval was also longer in Group 1 (192±51 vs 169±23 p=0.006) with greater prevalence of distal conduction system disease (30% vs 4.3% p=0.002). Significant univariate predictors for PPM insertion were distal conduction disease (p=0.007), first degree atrioventricular (AV) block (p=0.003), absence of precipitating factors (p=0.004), and age >65 years (p=0.001). Injury sustained, recurrent syncope, history of atrial fibrillation (AF) or heart failure, left atrial (LA) size and left ventricular ejection fraction (LVEF) were not predictive. These significant predictors were incorporated into the DROP score1 (0-4). Using time-to-event analysis, no patients with a score of 0 progressed to pacing, while higher scores (3-4) strongly predicted pacing requirement (log-rank p<0.001). CONCLUSION: The DROP score may be helpful in identifying patients likely to benefit from upfront permanent pacemaker (PPM) insertion following unexplained syncope. Larger prospective studies are required to validate this tool.

Tolerability and efficacy of sacubitril/valsartan in clinical practice.

BACKGROUND: Heart failure (HF) is a major cause of morbidity and mortality. Sacubitril/valsartan has demonstrated reductions in HF hospitalisation, and all-cause mortality in patients with heart failure with reduced ejection fraction. AIMS: To assess the tolerability and efficacy of sacubitril/valsartan in an intention to treat patient cohort. METHODS: Sixty-five patients who were commenced on sacubitril/valsartan in 2017 at a major metropolitan centre in Victoria were retrospectively audited. Clinical outcomes and quality of life scores were obtained pre and post sacubitril/valsartan commencement through phone and regular clinic follow up, 6-12 months after commencement of sacubitril/valsartan. RESULTS: Fourteen percent of patients were able to achieve maximal dose (97/103 mg twice daily) whilst 37% remained on 49/51 mg and 23% on 24/26 mg. The mean systolic blood pressure reduced from 118 ± 18 mmHg to 109 ± 15 mmHg with symptomatic hypotension (30%) being the most common side-effect leading to dose reduction or drug cessation. Left ventricular ejection fraction improved from 29.1 ± 9.7% to 33.8 ± 9.9% (P < 0.05) on drug. There was also a significant improvement in quality of life scores; EQ5D-VAS 40 pre versus 67 post sacubitril/valsartan (P < 0.05), and New York Heart Association class (P < 0.05). Importantly, 10 patients lost an existing indication for device based therapy after treatment with sacubitril/valsartan. CONCLUSIONS: Sacubitril/valsartan is a much needed therapeutic advancement in the treatment of HF. Our study indicates it is well tolerated with improvements in cardiac function and symptoms. Sacubitril/valsartan could redefine the definition of 'optimal medical therapy' when assessing patients for device based therapies.

The Effect of Transitional Care on 30-Day Outcomes in Patients Hospitalised With Acute Heart Failure.

BACKGROUND: Patients admitted to hospital with acute heart failure (AHF) are at increased risk of readmission and mortality post-discharge. The aim of the study was to examine health service utilisation within 30 days post-discharge from an AHF hospitalisation. METHODS: This was a prospective, observational, non-randomised study of consecutive patients hospitalised with acute HF to one of 16 Victorian hospitals over a 30-day period each year and followed up for 30 days post-discharge. The project was conducted annually over three consecutive years from 2015 to 2017. RESULTS: Of the 1,197 patients, 56.3% were male with an average age of 77±13.23 years. Over half of the patients (711, 62.5%) were referred to an outpatient clinic and a third (391, 34.4%) to a HF disease management program. In-hospital mortality was 5.1% with 30 day-mortality of 9% and readmission rate of 24.4%. Patients who experienced a subsequent readmission less than 10 days post-discharge and between 11 and 20 days post-discharge had a five- to six-fold increase in risk of mortality (adjusted OR 5.02, 95% CI 2.11-11.97; OR 6.45, 95% CI 2.69-15.42; respectively) compared to patients who were not readmitted to hospital. An outpatient appointment within 30 days post-discharge significantly reduced the risk of 30-day mortality by 81% (95% CI 0.09-0.43). CONCLUSION: Patients admitted to hospital with AHF who experience a subsequent readmission within 20 days post-discharge are at increased risk of dying. However, early follow-up post-discharge may reduce this risk. Early post-discharge follow-up is vital to address this vulnerable period after a HF admission.

The evolving face of heart failure management.

BACKGROUND: Heart failure (HF) is a major cause of morbidity and mortality in Australia. While the therapeutic options available for HF remain limited, recent studies have expanded treatment options to include angiotensin-neprilysin inhibitors (ARNIs) and sodium-glucose co-transporter-2 (SGLT2) inhibitors. OBJECTIVE: The aim of this article is to provide an update on the management of HF for general practitioners (GPs), who play a pivotal part in the management of patients with complex presentations. By reviewing the stepwise diagnosis, treatment and monitoring of patients with HF, it is hoped that this article encourages GPs to take an active role in the management of patients with HF. Specifically, the aim is to increase familiarity with ARNIs and SGLT2 inhibitors, maximising their uptake and benefit for patients with HF. DISCUSSION: ARNIs and SGLT2 inhibitors reduce morbidity and confer a survival benefit in the treatment of HF with reduced ejection fraction, yet they remain underused. Further familiarisation with these new classes of medication will enable increased uptake, which will benefit patients with HF.

Persistence of muscle sympathetic nerve activity during vasovagal syncope.

AIMS: To determine whether sympathetic nerve firing to skeletal muscle vasculature is withdrawn during vasovagal syncope (VVS) precipitated by passive graded head-up tilt (HUT) table testing. METHODS AND RESULTS: We performed passive graded HUT table testing in 18 patients with a history of recurrent postural VVS whom we evaluated during the syncopal event. All patients developed typical VVS during testing. Blood pressure was measured continuously via intra-brachial arterial line. Muscle sympathetic nerve activity (MSNA) was measured using an electrode in the peroneal nerve. Passive graded HUT was then applied. No pharmacological agents were used to provoke syncope. The recording site was maintained through the syncopal event in 10 of 18 patients and we were able to demonstrate persistence of MSNA during syncope in 9. The predominant haemodynamic pattern of syncope in this cohort was mixed--hypotension and bradycardia, with heart rate not falling <40 b.p.m. (n = 10). CONCLUSION: Our data challenge the established view that the final trigger for human orthostatic vasovagal reactions is sympathetic nervous system inhibition. Efferent sympathetic nerve traffic to the skeletal muscle vasculature was nearly always maintained through the faint. This finding supports an alternative viewpoint, that vasodilator mechanisms underlie the blood pressure fall in VVS.

Cognitive function, health-related quality of life, and symptoms of depression and anxiety sensitivity are impaired in patients with the postural orthostatic tachycardia syndrome (POTS).

The Postural Orthostatic Tachycardia Syndrome (POTS) is a condition in which heart rate increases abnormally when the individual assumes an upright position. In addition to the marked tachycardia, presyncope, and syncope, patients with POTS often complain of light-headedness, fatigue, and difficulty in concentrating. The present study assessed individuals with POTS for psychiatric comorbidity, anxiety sensitivity and health related quality of life and examined general cognitive ability. Data was obtained from patients with POTS (n = 15, 12 female, aged 30 ± 3 years) and age matched healthy subjects (n = 30, 21 female, aged 32 ± 2 years). Patients with POTS commonly presented with symptoms of depression, elevated anxiety and increased anxiety sensitivity, particularly with regards to cardiac symptoms, and had a poorer health related quality of life in both the physical and mental health domains. While patients with POTS performed worse in tests of current intellectual functioning (verbal and non-verbal IQ) and in measures of focused attention (digits forward) and short term memory (digits back), test results were influenced largely by years of education and the underlying level of depression and anxiety. Acute changes in cognitive performance in response to head up tilt were evident in the POTS patients. From results obtained, it was concluded that participants with POTS have an increased prevalence of depression and higher levels of anxiety. These underlying symptoms impact on cognition in patients with POTS, particularly in the cognitive domains of attention and short-term memory. Our results indicate that psychological interventions may aid in recovery and facilitate uptake and adherence of other treatment modalities in patients with POTS.

Recurrent postural vasovagal syncope: sympathetic nervous system phenotypes.

BACKGROUND: The pathophysiology of vasovagal syncope is poorly understood, and the treatment usually ineffective. Our clinical experience is that patients with vasovagal syncope fall into 2 groups, based on their supine systolic blood pressure, which is either normal (>100 mm Hg) or low (70-100 mm Hg). We investigated neural circulatory control in these 2 phenotypes. METHODS AND RESULTS: Sympathetic nervous testing was at 3 levels: electric, measuring sympathetic nerve firing (microneurography); neurochemical, quantifying norepinephrine spillover to plasma; and cellular, with Western blot analysis of sympathetic nerve proteins. Testing was done during head-up tilt (HUT), simulating the gravitational stress of standing, in 18 healthy control subjects and 36 patients with vasovagal syncope, 15 with the low blood pressure phenotype and 21 with normal blood pressure. Microneurography and norepinephrine spillover increased significantly during HUT in healthy subjects. The microneurography response during HUT was normal in normal blood pressure and accentuated in low blood pressure phenotype (P=0.05). Norepinephrine spillover response was paradoxically subnormal during HUT in both patient groups (P=0.001), who thus exhibited disjunction between nerve firing and neurotransmitter release; this lowered norepinephrine availability, impairing the neural circulatory response. Subnormal norepinephrine spillover in low blood pressure phenotype was linked to low tyrosine hydroxylase (43.7% normal, P=0.001), rate-limiting in norepinephrine synthesis, and in normal blood pressure to increased levels of the norepinephrine transporter (135% normal, P=0.019), augmenting transmitter reuptake. CONCLUSIONS: Patients with recurrent vasovagal syncope, when phenotyped into 2 clinical groups based on their supine blood pressure, show unique sympathetic nervous system abnormalities. It is predicted that future therapy targeting the specific mechanisms identified in the present report should translate into more effective treatment.

Cardiac repolarization variability in patients with postural tachycardia syndrome during graded head-up tilt.

OBJECTIVE: The aim of this study was to assess cardiac ventricular repolarization in patients with postural tachycardia syndrome (POTS) and further the possible link between ventricular repolarization and sympathetic nervous system activity. METHODS: We recorded body surface ECGs together with plasma noradrenaline (NE) spillover, and muscle sympathetic nerve activity (MSNA) in twelve healthy control subjects (CON; 5 males; age: 23±2 yrs) and 13 subjects with postural tachycardia syndrome (POTS; 4 males; 32±13 yrs) during graded head-up tilt (0°-20°-30°-40°). Ventricular repolarization was assessed by computing various measures of beat-to-beat QT interval variability and T wave amplitude. RESULTS: In patients with POTS, baseline heart rates were higher and MSNA increases during tilt were more pronounced than in CON. None of the QT variability measures was significantly affected by tilt or different between CON and POTS when corrected for heart rate. Contrary, the T wave amplitude flattened due to tilt (p<0.001) and this effect was significantly more pronounced in POTS (32% at 40°) than in CON (21% at 40°; p=0.03). CONCLUSIONS: Beat-to-beat variability of the QT interval is normal in patients with POTS. However, significantly more attenuated T waves during head-up tilt together with elevated MSNA levels suggest increased sympathetic outflow to the ventricular myocardium in patients with POTS. SIGNIFICANCE: Monitoring of the T wave during tilt test may provide a non-invasive tool for assessing excessive sympathetic outflow to the ventricular myocardium.

Diagnostic performance of multisequential cardiac magnetic resonance imaging in acute cardiac allograft rejection.

AIMS: We evaluated cardiac magnetic resonance imaging (CMR) as a non-invasive test for cardiac allograft rejection. METHODS AND RESULTS: We performed CMR on 50 heart-transplant recipients. Acute rejection was confirmed in 11 cases by endomyocardial biopsy (EMB) and presumed in 8 cases with a recent fall in left-ventricular ejection fraction (LVEF) not attributable to coronary allograft vasculopathy. Control patients had both normal LVEF and no significant rejection on EMB. Cardiac magnetic resonance imaging evaluated myocardial function, oedema, and early and late post-Gadolinium-DTPA contrast enhancement. Patients with confirmed rejection demonstrated elevated early relative myocardial contrast enhancement (4.1 +/- 0.3 vs. 2.8 +/- 0.2, P < 0.001) and a trend to higher oedema suggested by higher relative myocardial intensity on T(2)-weighted imaging compared to controls (2.1 +/- 0.1 vs. 1.7 +/- 0.1, P = 0.1). With rejection defined as increased early contrast enhancement or myocardial oedema, the sensitivity and specificity of CMR compared with EMB were 100 and 73%, respectively. Eight patients with presumed rejection also had elevated early myocardial contrast enhancement compared with controls, (8.7 +/- 1.9 vs. 2.8 +/- 0.2, P < 0.05), which reduced following increased immunosuppression (8.7 +/- 1.9 vs. 4.6 +/- 1.2, P < 0.05). In these patients LVEF improved following increased immunosuppression (32 +/- 5 vs. 46 +/- 5%, P < 0.05). CONCLUSION: Cardiac magnetic resonance imaging is a promising modality for non-invasive detection of cardiac allograft rejection.

Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome.

BACKGROUND: Clinical observations in patients with postural tachycardia syndrome (POTS) suggest abnormal sympathetic nervous system activity and a dysfunction of the norepinephrine (NE) transporter (NET). METHODS AND RESULTS: We examined sympathetic nervous system responses to head-up tilt by combining NE plasma kinetics measurements and muscle sympathetic nerve activity recordings and by quantifying NET protein content in peripheral sympathetic nerves in patients with POTS compared with that in controls. POTS patients had an elevated heart rate during supine rest (81+/-2 bpm versus 66+/-2 bpm in healthy subjects [HS], P<0.01). Head-up tilt to 40 degrees induced a greater rise in heart rate in patients with POTS (+24+/-4 bpm versus +13+/-2 bpm in HS, P<0.001). During rest in the supine position, muscle sympathetic nerve activity, arterial NE concentration, and whole-body NE spillover to plasma were similar in both groups. Muscle sympathetic nerve activity response to head-up tilt was greater in the POTS group (+29+/-3 bursts/min in patients with POTS and +13+/-2 bursts/min in HS, P<0.001), but the NE spillover rise was similar in both groups (51% in the POTS subjects and 50% in the HS). Western blot analysis of NET protein extracted from forearm vein biopsies in patients with POTS and HS demonstrated a decrease in the expression of NET protein in patients with POTS. CONCLUSIONS: Patients with POTS exhibit a decrease in NET protein in their peripheral sympathetic nerves. Paradoxically, whole-body NE spillover to plasma during rest in the supine position and in response to head-up tilt is not altered despite excessive nerve firing rate in response to the head-up tilt.

Postural syncope: mechanisms and management.

Postural syncope is a transient loss of consciousness secondary to a reduction in cerebral blood flow and is typically precipitated by standing. It is the commonest cause of recurrent transient loss of consciousness. Recurrent unexplained postural syncope is most often due to one of the five disorders of circulatory control: vasovagal syncope, postural tachycardia syndrome, chronic autonomic failure, initial orthostatic hypotension, or persistently low supine systolic blood pressure. Failure to identify the underlying cause of postural syncope can result in ongoing morbidity, impaired quality of life and high health care costs. With a detailed history, examination, blood pressure assessment and electrocardiography, most disorders of circulatory control can be diagnosed. In difficult cases, analysis of sympathetic nervous system and circulatory responses during head-up tilting can aid diagnosis. Treatment is challenging and compounded by a lack of evidence. Most patients can be managed in an outpatient setting, and hospital admission or emergency department assessment is rarely warranted.

Chronic falciparum malaria causing massive splenomegaly 9 years after leaving an endemic area.

A 28-year-old woman from Sudan who had lived for 9 years in Victoria, Australia, was diagnosed with falciparum malaria 2 months after splenectomy for massive splenomegaly of unknown cause. Chronic falciparum malaria can occasionally present years after leaving endemic areas in partially immune patients. It should be considered in such patients with presentations possibly related to malaria, including splenomegaly, anaemia, or a long history of intermittent fevers and chills.