Background: Postural tachycardia syndrome (POTS) is a common form of chronic orthostatic intolerance. The remarkable increase in heart rate (HR) upon standing is the hallmark of this syndrome. Treatment of POTS patients is challenging and includes drugs that slow the HR. Ivabradine is a selective If channel blocker designed to slow the HR, as an anti-anginal agent. In view of its ability to slow the HR, we posited that ivabradine may be an ideal medication for treating POTS patients. This report provides the results of an investigation in which we studied ivabradine’s effect on the hemodynamics and sympathovagal balance in POTS patients.
Methods: An open-label trial, without a placebo control, was performed in eight patients with POTS of two years’ standing. Characterization of symptoms, hemodynamics, autonomic function tests, and HR and blood pressure (BP) variability were determined while patients were in a supine position and during a 20-minute head-up tilt before and after a single oral dose of 7.5 mg ivabradine.
Results: Ivabradine slowed the HR of POTS patients at rest by 4±1 bpm (P<0.05). During a 5-minute head-up tilt, the HR decreased from 118±4 bpm to 101±5 bpm (P<0.01). Ivabradine did not affect the BP when patients were at rest in a supine position or in head-up tilt position. Cardiovascular vagal and sympathetic tone, extrapolated from the time and frequency domains of the HR and BP variability, were also not affected by ivabradine.
Conclusions: Ivabradine is an effective drug for slowing the HR of POTS patients at rest and during tilting, without producing significant adverse effects. Moreover, ivabradine exerts its effects without influencing the sympathovagal balance.
This brief introduction is followed by a published version of my Nobel Laureate lecture, re-published herein with the kind permission of the Nobel Foundation. Much has happened since my original research, for which that prize was awarded. Hence, I am pleased to offer a few thoughts about the future of my research and its possible impact on humankind.
Although the original work on nuclear transfer and reprogramming was done over half a century ago, advances continue to be made. In particular the Takahashi and Yamanaka induced pluripotent stem cells (iPS) procedure has opened up the field of cell replacement to a great extent. Now, more recently, further advances make this whole field come closer to actual usefulness for humans. Recently, in the UK, the government approved the use of mitochondrial replacement therapy to avoid the problems associated with genetically defective mitochondria in certain women. Although the House of Commons (members of Parliament) and the House of Lords had to debate and discuss whether to allow this kind of human therapy, I was very pleased to find that both bodies approved this procedure. This means that a patient can choose to make use of the procedure; it does not in any way force an individual to have a procedure that they are not comfortable with. In my view, this is a great advance in respect to giving patients a choice about the treatment they receive. I am told that the UK is the first country in the world to approve mitochondrial replacement therapy.
Now that the Clustered Regularly Interspaced Short Palindromic Repeat (CRISPr) technology is being widely used and works well, one can foresee that there will be those who wish to use this technology to make genetic changes to humans. For example, if a human has a gene that makes it susceptible to infection or any other disorder, the removal of that gene might give such a person immunity from that disease. If this gene deletion is done within the germ line, the genetic change will be inherited. However, one can imagine that various people will strongly object and say that this technology should not be allowed. I would very much hope that various regulatory bodies, governments, etc. will allow the choice to remain with the individual. I can see no argument for such bodies to make a law that removes any choice whatsoever by an individual.
The number needed to treat (NNT) is a simple measure of a treatment’s impact, increasingly reported in randomized trials and observational studies. It has been found to be incorrectly calculated in several studies involving varying follow-up times. We discuss the NNT in these contexts and illustrate the concept using several published studies. The computation of the NNT is founded on the cumulative incidence of the outcome. Instead, several published studies use simple proportions that do not account for varying follow-up times, or use incidence rates per person-time. We show how these approaches can lead to erroneous values of the NNT and misleading interpretations. For example, a trial of 3,845 very elderly hypertensives randomized to a diuretic or placebo reported a NNT of 94 treated for 2 years to prevent one stroke, though the correct approach results in a NNT of 63. We also note that meta-analyses involve trials of differing lengths, but often report a single NNT. For example a meta-analysis of 22 trials of the anticholinergic tiotropium in chronic obstructive pulmonary disease reported a NNT of 16 patients “over one year,” even if the trials varied in duration from 3 to 48 months, with the more specifically computed NNTs varying widely from 72, 15, and 250 for the 3-month, 12-month, and 48-month trials, respectively. Finally, we describe the value of the NNT in assessing benefit–risk, such as low-dose aspirin use in secondary prevention, where prevention of mortality was assessed against the risk of gastrointestinal bleeding. As the “number needed to treat” becomes increasingly used in the comparative effectiveness and safety of therapies, its accurate estimation and interpretation become crucial to avoid distorting clinical, economic, and public health decisions.
An anniversary is not only a point of memory—it provides the opportunity for self-examination and paves the way to the future. Every anniversary marks a starting-point that was preceded by a vision. The beginning of any vision is a personal dream—someone wants to improve or repair the world as far as he is able. The vision motivates action; in its aftermath comes the reality. This is the 21st issue of Rambam Maimonides Medical Journal. This issue is particularly important as it marks the completion of five years of creative work pursuing our vision for a high-caliber scientific medical journal. Our vision has become reality.
Whilst painting the vault of the Sistine Chapel, Michelangelo Buonarroti left an autographical sketch that revealed a prominence at the front of his hyper-extended neck. This image was recently diagnosed as goiter. The poet Michelangelo in a sonnet dated 1509 described himself as being afflicted by goiter similarly to the cats in the northern Italian Lombardy, a region with endemic goiter. Several narratives extended this sonnet into a pathological theory. The analyses of Michelangelo’s works, however, his portraits and self-portraits, of poems and major biographies, have not indicated the likelihood of goiter. This investigation makes an attempt to assess the diagnosis on clinical as well as iconographical grounds.
As I shared in my January 2015 editorial, the furor surrounding publication in The Lancet of the open letter by P. Manduca et al. carried potential for bad and for good. Here at Rambam Health Care Campus, we have chosen and will continue to look for the good.
George London was one of the most compelling vocal artists of the early twentieth century. At the age of 47, the great bass-baritone retired from singing. It has been suggested that the premature ending of his operatic career was due to unilateral vocal cord palsy (UVCP). When London retired, the common belief was that this UVCP was caused by viral hepatitis, although there is no evidence to support such an etiology. London’s medical records eliminate the possible etiology of a neck neoplasm, and the long period of time between a heart attack he experienced and his diagnosis of UVCP makes a cardiovascular etiology an unlikely causative factor. London’s relatively young age, the diagnosis of laryngitis prior to his UVCP, and the course of his disease indicate that the underlying cause of the termination of his singing career was post-viral neuropathy. This paper describes the clinical evidence related to London’s vocal cord function and explores the possible causes for his UVCP, which apparently led to his early retirement.
Background: Guidelines and Class 1 evidence are strong factors that help guide surgeons’ decision-making, but dilemmas exist in selecting the best surgical option, usually without the benefit of guidelines or Class 1 evidence. A few studies have discussed the variability of surgical treatment options that are currently available, but no study has examined surgeons’ views on the influential factors that encourage them to choose one surgical treatment over another. This study examines the influential factors and the thought process that encourage surgeons to make these decisions in such circumstances.
Methods: Semi-structured face-to-face interviews were conducted with 32 senior consultant surgeons, surgical fellows, and senior surgical residents at the University of Toronto teaching hospitals. An e-mail was sent out for volunteers, and interviews were audio-recorded, transcribed verbatim, and subjected to thematic analysis using open and axial coding.
Results: Broadly speaking there are five groups of factors affecting surgeons’ decision-making: medical condition, information, institutional, patient, and surgeon factors. When information factors such as guidelines and Class 1 evidence are lacking, the other four groups of factors—medical condition, institutional, patient, and surgeon factors (the last-mentioned likely being the most powerful)—play a significant role in guiding surgical decision-making.
Conclusions: This study is the first qualitative study on surgeons’ perspectives on the influential factors that help them choose one surgical treatment option over another for their patients.
Urological malignancies are a major source of morbidity and mortality in men over 40. Screening for those malignancies has a potential benefit of reducing both. However, even after more than two decades of screening for prostate cancer, the implications of most resulting information are still a matter of debate. Controversy extends over several aspects of prostate cancer screening programs, including age of onset, defining populations at risk, most appropriate intervals, as well as the optimal methods to be used for screening. The medical community is still divided regarding the effectiveness of prostate cancer-related death prevention and its benefits-to-harms ratio, reflecting an inconsistency regarding screening recommendations. Similarly, benefits of screening for urothelial and kidney tumors are yet lacking high- level evidence, although recent evidence supports screening of populations at risk. Clearly, the current era of evolving molecular and genetic biomarkers harbors the potential to change screening practice. In this paper, we review current guidelines as well as giving an update on new developments which might influence screening strategies in common urological malignancies.
Objectives: Peripartum cardiomyopathy (PPCM) is a serious complication of pregnancy. Studies investigating the risk factors that worsen outcomes have yielded conflicting results. The goals of this study were to describe the clinical and echocardiographic characteristics of PPCM in a single tertiary center and to determine the prognostic factors associated with persistence of left ventricular (LV) dysfunction in these women.
Study Design: This retrospective cross-sectional population-based cohort study included all patients with PPCM confirmed by echocardiography who delivered at our center from 2004 to 2014. Two groups were compared to determine long-term maternal outcome: (1) those who recovered normal LV function; and (2) those with residual systolic LV dysfunction.
Results: There were 148,994 deliveries during the study period. Of these, 89,196 patients were Bedouin and 59,798 were non-Bedouin. Forty-six patients met the PPCM study inclusion criteria. The PPCM prevalence for the total deliveries was 1:3,239. The PPCM prevalence among Bedouin patients was 1:2,787 versus non-Bedouin patients of 1:4,983 (P=0.037). None of the women had pre-existing chronic hypertension, and there was no maternal death. Patients who had severe or moderate LV dysfunction at the clinical presentation of PPCM were less likely to regain normal LV function than those with mild dysfunction (81.2% versus 56.7%, P=0.009). Based on initial echocardiogram, a trend toward residual LV dysfunction was noted in patients with a dilated left ventricle as compared to those with a non-dilated left ventricle (18.8% versus 6.7%, P=0.32). A hypokinetic right ventricle was found in 15.2% of the women who suffered from PPCM.
Conclusion: In our cohort, Bedouin women may be at increased risk for PPCM, and patients with severe LV dysfunction have a lower chance of recovery from PPCM.
