• electrophysiology
• quality and outcomes of care
• epidemiology
• cardiac arrhythmias and resuscitation science

In the general population, syncope and orthostatic hypotension (OH) are frequent events that often lead to hospitalisation or a visit to the emergency department. However, as a broad symptom, it is currently unclear whether they are independent risk markers for adverse prognosis or if syncope and OH are actually the initial symptom leading to diagnosis of severe underlying cardiac disease.

Naturally some syncopal events will lead to diagnosis of severe underlying cardiac disease resulting in adverse prognosis, but for the majority, it is considered a benign event without need for any further scrutiny. Within recent years, research has, however, suggested an association between seemingly benign syncopal events in otherwise healthy individuals and increased mortality and early morbidity.1 Syncope is also related to a higher risk of subsequent falls and injury and, when diagnosed, cardiac syncope is particularly associated with increased mortality as compared with non-cardiac syncope.2 The prognosis in the general population is therefore thought to be determined by an underlying cardiac disease,3 which may be unknown at the time of first syncope and therefore syncope might actually be the initial symptom leading to diagnosis.

OH is also a common disorder, with or without signs of underlying neurodegenerative or cardiovascular disease. OH is diagnosed with an orthostatic challenge and requires a decrease in blood pressure of at least 20/10 (systolic/diastolic) mm Hg on standing. It broadly reflects a structural and dysfunctional regulation of the sympathetic system and is highly associated with age-related degeneration and polypharmacy.4 The prevalence and incidence are age dependent and clinicians often face OH as a complication and side effect of the pharmacological treatment of hypertension, ischaemic heart disease and heart failure. This poses significant medication compliance issues, and OH is furthermore associated with reduced quality of life, occasionally syncope, and may result in traumatic injuries. Despite being largely asymptomatic or minimally symptomatic, a diagnosis of OH has been associated with increased mortality and major cardiovascular events.5 6

Epidemiological data on syncope and OH are in particular limited by diagnosis certainty. Large-scale cohort studies using register and administrative data rely on discharging physicians to use adequate and precise diagnostic coding. For syncope and OH, this is problematic since these entities are symptoms and not specific diseases and reflect multiple causes and level of comorbidity burden. When we try to compare such data from large-scale cohort studies (heterogeneous population/usually low risk) in terms of outcome, and treatment, with previous reports from highly selected populations with high event rates of adverse outcomes and mortality, the misperceptions begin. The clinicians need tools to risk stratify and find the right high-risk patients. It is of considerable interest to clinicians, researchers and health administrators to broaden the knowledge regarding the large, often very heterogeneous, bulk of hospitalised patients with syncope and OH, in order to gain information about their outcome and healthcare costs and utilisation.

The Heart publication by Yasa et al 7 from Sweden makes a significant contribution here. The Swedish healthcare system has comprehensive nationwide databases of high quality. This allowed Yasa et al 7 to link data from a detailed population-based cohort of 30 528 individuals from the Malmö Diet and Cancer Study (recruited from 1991 to 1996) with the Swedish National Hospital Discharge Register and the Swedish National Cause of Death. They then identified all individuals who were hospitalised for syncope (1.7%) or OH (1.7%) from baseline through follow-up and then compared these subjects to the rest of the cohort. The mean age at inclusion in the study was 58±8 years and 40% were male with a long time to first hospitalisation for syncope/OH of 12.3±4.5 years. The mean age at time of first OH/syncope was thus 63±7 and 62±7 years. The authors first analysed the factors associated with increased risk of syncope or OH and found that the risk of syncope and OH increased with age, while higher systolic blood pressure at baseline, use of antihypertensive medications (and diuretics) at baseline and prevalent cardiovascular disease predicted syncope. OH was apart from age only associated with baseline diabetes. After exclusion of patients with prevalent cardiovascular disease, they ended up with 29 129 subjects for their further analyses. The main results were that among these patients with no known cardiovascular disease (in multivariable-adjusted analyses), hospitalisation for syncope was associated with future coronary events, development of heart failure, diagnosis of atrial fibrillation, diagnosis of aortic valve stenosis and all-cause mortality. OH was associated with atrial fibrillation, heart failure and all-cause mortality. The average time between hospitalisation for syncope/OH to first cardiovascular event was 3.6 years.

Not surprisingly with such a long follow-up from time of syncope/OH, the overall risk of death and major cardiac events among these on average 62-year-old individuals was quite high (particularly for stroke), but the event rate within the first 5–10 years after hospitalisation for syncope/OH was reassuringly low and presented a cardiovascular mortality rate of less than 5% at 10 years. This is in agreement with data from separate countries and contrast the high annual mortality rate presented in selected studies of much sicker patients with syncope.8

The present paper presents unique insights into development of major cardiac events and prognosis among patients with syncope and OH without known cardiovascular disease in a very large cohort of well-investigated subjects from a population-based study. Only a few similar studies have been published and this type of study can at the present time only be performed in a handful of countries. Some important caveats are however present in the study that limit the applicability. First, the diagnosis of syncope using International Statistical Classification of Diseases and Related Health Problems, 10th Revision, code R559. How sure are we that these syncopal episodes are vasovagal or unexplained? How sure are we that sufficient efforts have been undertaken to make aetiological diagnosis of the syncopal event during the hospitalisation and will this affect later diagnoses through workup (and therefore cardiac events)? Second, an average of 12 years from inclusion in the population study to hospitalisation for OH/syncope is a very long time. Only prevalent cardiovascular disease prior to (baseline) inclusion in the Malmö Diet and Cancer Study was considered and used as an exclusion criterion. How many of these patients developed significant cardiovascular disease during this long period? This question is unfortunately not covered, but should be possible given the reach of the Swedish registers. And third, we lack information on important addition of cardiovascular or perhaps psychotropics/anxiolytics/antidepressant medications through follow-up leading to hospitalisation for OH/syncope. Although plausible that many patients remain on initiated antihypertensive, many more medications and combinations may affect later risk of hospitalisation for syncope and OH.9 Finally, we have no data on ECGs, clinical data at time of syncope/OH and no knowledge on the tests used to diagnose OH or distinguish among the different types of syncope. Therefore, this study does not help the clinicians in individual risk stratification or clinical management of patients. The scope of the paper is, however, much broader and epidemiologically applicable. The study by Yasa et al 7 adds an important input that will set the framework for more studies on how to target and evaluate this group of patients from the background population who seem at low risk but who are at higher risk of developing significant cardiovascular morbidity and increased mortality? It also underlines and is in agreement with recent reports from other countries stating this fact. How effective are we to find and select the high-risk patients and how much effort and costs should be used to find very infrequent cases of true high risk (unknown underlying severe cardiac disease) among a very large number of low-risk healthy patients with benign syncopal events? Today, risk stratification schemes have not yet provided satisfactory results. Whether or not clinical practice and workup should be more investigative and vigilant and include even more cardiac workup than currently such as more echocardiograms and ECG monitoring to identify a given underlying chronic cardiac condition is currently unresolved and not answered by the present study. Answers to these questions and knowledge gaps will hopefully soon be answered and overcome and hopefully more detailed clinical characteristic and merging of registers with more clinical information such as blood tests, ECGs, workup test results and more can be made in the future.