Sinus Tachycardia: a Multidisciplinary Expert Focused Review.

Sinus tachycardia (ST) is ubiquitous, but its presence outside of normal physiological triggers in otherwise healthy individuals remains a commonly encountered phenomenon in medical practice. In many cases, ST can be readily explained by a current medical condition that precipitates an increase in the sinus rate, but ST at rest without physiological triggers may also represent a spectrum of normal. In other cases, ST may not have an easily explainable cause but may represent serious underlying pathology and can be associated with intolerable symptoms. The classification of ST, consideration of possible etiologies, as well as the decisions of when and how to intervene can be difficult. ST can be classified as secondary to a specific, usually treatable, medical condition (eg, pulmonary embolism, anemia, infection, or hyperthyroidism) or be related to several incompletely defined conditions (eg, inappropriate ST, postural tachycardia syndrome, mast cell disorder, or post-COVID syndrome). While cardiologists and cardiac electrophysiologists often evaluate patients with symptoms associated with persistent or paroxysmal ST, an optimal approach remains uncertain. Due to the many possible conditions associated with ST, and an overlap in medical specialists who see these patients, the inclusion of experts in different fields is essential for a more comprehensive understanding. This article is unique in that it was composed by international experts in Neurology, Psychology, Autonomic Medicine, Allergy and Immunology, Exercise Physiology, Pulmonology and Critical Care Medicine, Endocrinology, Cardiology, and Cardiac Electrophysiology in the hope that it will facilitate a more complete understanding and thereby result in the better care of patients with ST.

Orthostatic Hypotension: Management of a Complex, But Common, Medical Problem.

Orthostatic hypotension (OH), a common, often overlooked, disorder with many causes, is associated with debilitating symptoms, falls, syncope, cognitive impairment, and risk of death. Chronic OH, a cardinal sign of autonomic dysfunction, increases with advancing age and is commonly associated with neurodegenerative and autoimmune diseases, diabetes, hypertension, heart failure, and kidney failure. Management typically involves a multidisciplinary, patient-centered, approach to arrive at an appropriate underlying diagnosis that is causing OH, treating accompanying conditions, and providing individually tailored pharmacological and nonpharmacological treatment. We propose a novel streamlined pathophysiological classification of OH; review the relationship between the cardiovascular disease continuum and OH; discuss OH-mediated end-organ damage; provide diagnostic and therapeutic algorithms to guide clinical decision making and patient care; identify current gaps in knowledge and try to define future research directions. Using a case-based learning approach, specific clinical scenarios are presented highlighting various presentations of OH to provide a practical guide to evaluate and manage patients who have OH.

Management of Orthostatic Hypotension in the Hospitalized Patient: A Narrative Review.

Orthostatic hypotension is a frequent cause of falls and syncope, impairing quality of life. It is an independent risk factor of mortality and a common cause of hospitalizations, which exponentially increases in the geriatric population. We present a management plan based on a systematic literature review and understanding of the underlying pathophysiology and relevant clinical pharmacology. Initial treatment measures include removing offending medications and avoiding large meals. Clinical assessment of the patients' residual sympathetic tone can aid in the selection of initial therapy between norepinephrine "enhancers" or "replacers." Role of splanchnic venous pooling is overlooked, and applying abdominal binders to improve venous return may be effective. The treatment goal is not normalizing upright blood pressure but increasing it above the cerebral autoregulation threshold required to improve symptoms. Hypertension is the most common associated comorbidity, and confining patients to bed while using pressor agents only increases supine blood pressure, leading to worsening pressure diuresis and orthostatic hypotension. Avoiding bedrest deconditioning and using pressors as part of an orthostatic rehab program are crucial in reducing hospital stay.

Evaluation of a Clinical Pharmacist Specialist Transition of Care Pathway to Manage Heart Failure Readmissions During a Provider Shortage.

BACKGROUND: Evidence supports scheduling early follow-up after heart failure (HF) hospitalization with a provider capable of managing hypervolemia. Often this service is provided by cardiologists or specialty nurse practitioners. Continuity or "familiar" providers may be better positioned to identify decompensating HF in patients who have advanced HF and/or multiple complicating medical problems. The objective of this study was to evaluate whether a clinical pharmacy specialist (CPS) service, covering the role of a "familiar" provider in an advanced HF specialty clinic (AHFC) during a staffing shortage, may prevent readmission metrics from worsening. METHODS: We evaluated the entire, eligible concurrent cohorts, representing 175 AHFC-CPS and 273 control patient-admissions, respectively. Study- and disease-specific predictors for readmission were assessed. A matched cohort of 202 patient-admissions (101 AHFC-CPS:101 NO-CPS) were evaluated. RESULTS: Subjects were predominantly white, elderly males. While overall "clinic [performance] profiling" outcomes for readmissions (p = 0.43) and mortality (p = 0.66) did not statistically differ between the AHFC-CPS and NO-CPS groups, an imbalance in severity of illness persisted. A survival curve and analysis were constructed, and the hazard ratio for all-cause mortality was 0.69 (p = 0.033). CONCLUSIONS: This retrospective project supports the premise that AHFC-CPS intervention may be a suitable alternative to maintain the volume status for AHFC patients during a staffing short-fall. More work needs to be done to determine intervention effect size, predictors for readmission, specifically in advanced cardiovascular disease, and to evaluate CPS opportunities in the provision of independent HF care, particularly for patients with advanced HF.

Local Passive Heat for the Treatment of Hypertension in Autonomic Failure.

Background Supine hypertension affects a majority of patients with autonomic failure; it is associated with end-organ damage and can worsen daytime orthostatic hypotension by inducing pressure diuresis and volume loss during the night. Because sympathetic activation prevents blood pressure (BP) from falling in healthy subjects exposed to heat, we hypothesized that passive heat had a BP-lowering effect in patients with autonomic failure and could be used to treat their supine hypertension. Methods and Results In Protocol 1 (n=22), the acute effects of local heat (40-42°C applied with a heating pad placed over the abdomen for 2 hours) versus sham control were assessed in a randomized crossover fashion. Heat acutely decreased systolic BP by -19±4 mm Hg (versus 3±4 with sham, P<0.001) owing to decreases in stroke volume (-18±5% versus -4±4%, P=0.013 ) and cardiac output (-15±5% versus -2±4%, P=0.013). In Protocol 2 (proof-of-concept overnight study; n=12), we compared the effects of local heat (38°C applied with a water-perfused heating pad placed under the torso from 10 pm to 6 am) versus placebo pill. Heat decreased nighttime systolic BP (maximal change -28±6 versus -2±6 mm Hg, P<0.001). BP returned to baseline by 8 am. The nocturnal systolic BP decrease correlated with a decrease in urinary volume (r=0.57, P=0.072) and an improvement in the morning upright systolic BP (r=-0.76, P=0.007). Conclusions Local heat therapy effectively lowered overnight BP in patients with autonomic failure and supine hypertension and offers a novel approach to treat this condition. Future studies are needed to assess the long-term safety and efficacy in improving nighttime fluid loss and daytime orthostatic hypotension. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02417415 and NCT03042988.

Management of neurogenic orthostatic hypotension in the heart failure patient.

Neurogenic orthostatic hypotension (nOH) is a common comorbidity in patients with neurodegenerative diseases. It is associated with an increased risk of falls, incident cardiovascular disease, and all-cause mortality. There are over 5 million individuals in the U.S. with heart failure (HF) with an associated 50% mortality rate at 5 years. The prevalence of nOH and HF increase with age and, as the population continues to age, will be increasingly common comorbid conditions. Thus, the effective management of these conditions has important implications for public health. The management of orthostatic hypotension in the context of congestive heart failure is challenging due to the fact that the fundamental principles of management of these disease states are in opposition to each other. In this review, we will discuss the principles of management of nOH and HF and outline strategies for the effective treatment of these comorbid conditions.

Cardiovascular Safety Considerations in the Treatment of Neurogenic Orthostatic Hypotension.

Neurogenic orthostatic hypotension (nOH), a drop in blood pressure upon standing resulting from autonomic malfunction, may cause debilitating symptoms that can affect independence in daily activities and quality-of-life. nOH may also be associated with cardiovascular comorbidities (e.g., supine hypertension, heart failure, diabetes, and arrhythmias), making treatment decisions complicated and requiring management that should be based on a patient's cardiovascular profile. Additionally, drugs used to treat the cardiovascular disorders (e.g., vasodilators, ß-blockers) can exacerbate nOH and concomitant symptoms. When orthostatic symptoms are severe and not effectively managed with nonpharmacologic strategies (e.g., water ingestion, abdominal compression), droxidopa or midodrine may be effective. Droxidopa may be less likely than midodrine to exacerbate supine hypertension, based on conclusions of a limited meta-analysis. In conclusion, treating nOH in patients with cardiovascular conditions requires a balance between symptom relief and minimizing adverse outcomes.

Postural Orthostatic Tachycardia Syndrome (POTS): A critical assessment.

Although diagnostic criteria have been developed characterizing postural orthostatic tachycardia syndrome (POTS), no single set of criteria is universally accepted. Furthermore, there are gaps in the present criteria used to identify individuals who have this condition. The reproducibility of the physiological findings, the relationship of symptoms to physiological findings, the presence of symptoms alone without any physiological findings and the response to various interventions confuse rather than clarify this condition. As many disease entities can be confused with POTS, it becomes critical to identify what this syndrome is. What appears to be POTS may be an underlying condition that requires specific therapy. POTS is not simply orthostatic intolerance and symptoms or intermittent orthostatic tachycardia but the syndrome needs to be characterized over time and with reproducibility. Here we address critical issues regarding the pathophysiology and diagnosis of POTS in an attempt to arrive at a rational approach to categorize the syndrome with the hope that it may help both better identify individuals and better understand approaches to therapy.

Blood Pressure Management in Afferent Baroreflex Failure: JACC Review Topic of the Week.

Afferent baroreflex failure is most often due to damage of the carotid sinus nerve because of neck surgery or radiation. The clinical picture is characterized by extreme blood pressure lability with severe hypertensive crises, hypotensive episodes, and orthostatic hypotension, making it the most difficult form of hypertension to manage. There is little evidence-based data to guide treatment. Recommendations rely on understanding the underlying pathophysiology, relevant clinical pharmacology, and anecdotal experience. The goal of treatment should be improving quality of life rather than normalization of blood pressure, which is rarely achievable. Long-acting central sympatholytic drugs are the mainstay of treatment, used at the lowest doses that prevent the largest hypertensive surges. Short-acting clonidine should be avoided because of rebound hypertension, but can be added to control residual hypertensive episodes, often triggered by mental stress or exertion. Hypotensive episodes can be managed with countermeasures and short-acting pressor agents if necessary.

Aerobic exercise training improves hepatic and muscle insulin sensitivity, but reduces splanchnic glucose uptake in obese humans with type 2 diabetes.

BACKGROUND: Aerobic exercise training is known to have beneficial effects on whole-body glucose metabolism in people with type 2 diabetes (T2D). The responses of the liver to such training are less well understood. The purpose of this study was to determine the effect of aerobic exercise training on splanchnic glucose uptake (SGU) and insulin-mediated suppression of endogenous glucose production (EGP) in obese subjects with T2D. METHODS: Participants included 11 obese humans with T2D, who underwent 15 ± 2 weeks of aerobic exercise training (AEX; n = 6) or remained sedentary for 15 ± 1 weeks (SED; n = 5). After an initial screening visit, each subject underwent an oral glucose load clamp and an isoglycemic/two-step (20 and 40 mU/m2/min) hyperinsulinemic clamp (ISO-clamp) to assess SGU and insulin-mediated suppression of EGP, respectively. After the intervention period, both tests were repeated. RESULTS: In AEX, the ability of insulin to suppress EGP was improved during both the low (69 ± 9 and 80 ± 6% suppression; pre-post, respectively; p < 0.05) and high (67 ± 6 and 82 ± 4% suppression, respectively; p < 0.05) insulin infusion periods. Despite markedly improved muscle insulin sensitivity, SGU was reduced in AEX after training (22.9 ± 3.3 and 9.1 ± 6.0 g pre-post in AEX, respectively; p < 0.05). CONCLUSIONS: In obese T2D subjects, exercise training improves whole-body glucose metabolism, in part, by improving insulin-mediated suppression of EGP and enhancing muscle glucose uptake, which occur despite reduced SGU during an oral glucose challenge.

Initiation of droxidopa during hospital admission for management of refractory neurogenic orthostatic hypotension in severely ill patients.

Orthostatic hypotension (OH) is a common cause of hospitalization, particularly in the elderly. Hospitalized patients with OH are often severely ill, with complex medical comorbidities and high rates of disability. Droxidopa is a norepinephrine precursor approved for the treatment of neurogenic OH (nOH) associated with autonomic failure that is commonly used in the outpatient setting, but there are currently no data regarding the safety and efficacy of droxidopa initiation in medically complex patients. We performed a retrospective review of patients started on droxidopa for refractory nOH while hospitalized at Vanderbilt University Medical Center between October 2014 and May 2017. Primary outcome measures were safety, change in physician global impression of illness severity from admission to discharge, and persistence on medication after 180-day follow-up. A total of 20 patients were identified through chart review. Patients were medically complex with high rates of cardiovascular comorbidities and a diverse array of underlying autonomic diagnoses. Rapid titration of droxidopa was safe and well tolerated in this cohort, with no cardiovascular events or new onset arrhythmias. Supine hypertension requiring treatment occurred in four patients. One death occurred during hospital admission due to organ failure associated with end-stage amyloidosis. Treating physicians noted improvements in presyncopal symptoms in 80% of patients. After 6 months, 13 patients (65%) continued on droxidopa therapy. In a retrospective cohort of hospitalized, severely ill patients with refractory nOH, supervised rapid titration of droxidopa was safe and effective. Treatment persistence was high, suggesting that symptomatic benefit extended beyond acute intervention.

A Phase I, Single Ascending Dose Study of Cimaglermin Alfa (Neuregulin 1ß3) in Patients With Systolic Dysfunction and Heart Failure.

A first-in-human, phase 1, double blind, placebo-controlled, single ascending dose study examined the safety, tolerability, and exploratory efficacy of intravenous infusion of a recombinant growth factor, cimaglermin alfa, in patients with heart failure and left ventricular systolic dysfunction (LVSD). In these patients on optimal guideline-directed medical therapy, cimaglermin treatment was generally tolerated except for transient nausea and headache and a dose-limiting toxicity was noted at the highest planned dose. There was a dose-dependent improvement in left ventricular ejection fraction lasting 90 days following infusion. Thus, cimaglermin is a potential therapy to enhance cardiac function in LVSD and warrants further investigation.

The Impact of Inpatient Versus Outpatient Initiation on Early Warfarin Dosing.

BACKGROUND AND OBJECTIVES: Dosing algorithms for warfarin incorporate clinical and genetic factors but may not account for the numerous comorbidities affecting patients who start warfarin while hospitalized. We aimed to determine whether these algorithms perform differently when warfarin is initiated for inpatients compared with outpatients. PATIENTS AND METHODS: We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial who were randomized to either pharmacogenetically or clinically guided warfarin dosing algorithms. Clinicians and participants were blinded to dose during the first 28 days. We compared groups, based on location at the time of the first warfarin dose request, in relation to the following outcomes: percentage of time in the therapeutic international normalized ratio (INR) range (PTTR) during the first 4 weeks, time to first therapeutic INR, time to maintenance dose, and the difference between predicted and observed maintenance doses. RESULTS: A total of 527 participants started warfarin as inpatients and 488 as outpatients. There was no difference in PTTR based on location: 43.2 % for inpatient versus 47.4 % for outpatient initiation [mean adjusted difference -2.2 %; 95 % confidence interval (CI) -5.9 to 1.6]. Similarly, there were no differences in time to first therapeutic INR [hazard ratio (HR) 1.06; 95 % CI 0.91-1.24] or to maintenance dose (HR 0.96; 95 % CI 0.81-1.14). There was no evidence of interaction between study intervention (pharmacogenetically vs. clinically guided therapy) and location of initiation for these main outcomes. The difference between predicted and observed maintenance doses was similar for both locations. CONCLUSION: The warfarin dosing algorithms performed similarly for subjects who initiated warfarin as inpatients and outpatients, regardless of whether dosing was pharmacogenetically or clinically guided.

Consuming a balanced high fat diet for 16 weeks improves body composition, inflammation and vascular function parameters in obese premenopausal women.

OBJECTIVE: Inflammation, insulin resistance and vascular dysfunction characterize obesity and predict development of cardiovascular disease (CVD). Although women experience CVD events at an older age, vascular dysfunction is evident 10years prior to coronary artery disease. Questions remain whether replacing SFA entirely with MUFA or PUFA is the optimal approach for cardiometabolic benefits. This study tested the hypotheses that: a) body composition, inflammation and vascular function would improve with a high fat diet (HFD) when type of fat is balanced as 1/3 SFA, 1/3 MUFA and 1/3 PUFA; and b) body composition, inflammation and vascular function would improve more when balanced HFD is supplemented with 18C fatty acids, in proportion to the degree of 18C unsaturation. METHODS: Obese premenopausal women were stabilized on balanced HFD and randomized to consume 9g/d of encapsulated stearate (18:0), oleate (18:1), linoleate (18:2) or placebo. RESULTS: Significant improvements occurred in fat oxidation rate (↑6%), body composition (%fat: ↓2.5±2.1%; %lean: ↑2.5±2.1%), inflammation (↓ IL-1α, IL-1ß, 1L-12, Il-17, IFNγ, TNFα, TNFß) and vascular function (↓BP, ↓PAI-1, ↑tPA activity). When compared to HFD+placebo, HFD+stearate had the greatest effect on reducing IFNγ (↓74%) and HFD+linoleate had the greatest effect on reducing PAI-1 (↓31%). CONCLUSIONS: Balancing the type of dietary fat consumed (SFA/MUFA/PUFA) is a feasible strategy to positively affect markers of CVD risk. Moreover, reductions in inflammatory molecules involved in vascular function might be enhanced when intake of certain 18C fatty acids is supplemented. Long term effects need to be determined for this approach.

Circadian variability of fibrinolytic markers and endothelial function in patients with obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is strongly associated with cardiovascular disease, including stroke and acute coronary syndromes. Plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue-type plasminogen activator (t-PA), has a pronounced circadian rhythm and is elevated in both OSA and cardiovascular disease and may be an important link between the two conditions. Endothelial dysfunction is one of the underlying pathophysiological mechanisms of cardiovascular disease, and may be altered in OSA. Our primary aim was to compare circadian variability of PAI-1 and t-PA in patients with OSA and normal controls by determining the amplitude (peak level) and mesor (rhythm adjusted mean) of PAI-1 and t-PA in serial blood samples over a 24-h period. The secondary aim was to measure markers of endothelial function (brachial and radial artery flow) in patients with OSA compared with normal controls. SETTING: Cross-sectional cohort study. PATIENTS OR PARTICIPANTS: Subjects age 18 y or older, with a body mass index of 25-45 kg/m(2), with or without evidence of untreated OSA. INTERVENTIONS: Plasma samples were collected every 2 h, in OSA patients and matched controls, over a 24-h period. PAI-1 and t-PA antigen and activity were measured. The presence or absence of OSA (apnea-hypopnea index of 5 or greater) was confirmed by overnight polysomnography. Endothelial function was measured via brachial artery flow mediated vasodilatation and computerized arterial pulse waveform analysis. MEASUREMENTS AND RESULTS: The rhythm-adjusted mean levels of PAI-1 antigen levels in the OSA group (21.8 ng/mL, 95% confidence level [CI], 18 to 25.7) were significantly higher as compared to the non-OSA group (16 ng/mL, 95% CI, 12.2 to 19.8; P = 0.03). The rhythm-adjusted mean levels of PAI-1 activity levels in the OSA group (23.9 IU/mL, 95% CI, 21.4 to 26.5) were also significantly higher than in the non-OSA group (17.2 IU/ mL, 95% CI, 14.6 to 19.9; P < 0.001).There were strong correlations between amplitude of PAI-1 activity and severity of OSA as measured by AHI (P = 0.02), and minimum oxygen levels during sleep (P = 0.04). Endothelial function parameters did not differ significantly between the two groups. CONCLUSION: The presence of obstructive sleep apnea adversely affects circadian fibrinolytic balance with higher mean plasminogen activator inhibitor-1 activity and antigen, and significantly lower mean tissue-type plasminogen activator activity compared with controls. This perturbation may be an important mechanism for increased cardiovascular events in patients with obstructive sleep apnea. Intermittent hypoxia and changes in circadian clock gene activity in obstructive sleep apnea may be responsible for these findings and warrant further study. Favorable changes in fibrinolytic balance may underlie the reduction in cardiovascular events observed with the treatment of obstructive sleep apnea.

A pharmacogenetic versus a clinical algorithm for warfarin dosing.

BACKGROUND: The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS: We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS: At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

The pharmacokinetics and pharmacodynamics of valsartan in the post-myocardial infarction population.

INTRODUCTION: The most common risk factors for heart failure are hypertension and myocardial infarction. Angiotensin receptor blockers (ARBs) attenuate the deleterious effects of angiotensin II. Valsartan is a once or twice daily ARB that is FDA-approved for hypertension, LV dysfunction post-myocardial infarction and congestive heart failure as both an adjunct in ACE-inhibitor tolerant, and alternative in ACE-I intolerant patients. AREAS COVERED: This article presents a comprehensive review of the literature regarding the pharmacokinetics and pharmacodynamics of valsartan, with particular attention paid to the post-myocardial infarction population. EXPERT OPINION: Valsartan is a safe, well-tolerated and readily titratable ARB. In addition to its vasodilatory effects there are pleotropic effects associated with the ARB such as modulation of a number of neurohormonal regulators, cytokines and small molecules. Given the clear evidence-based benefits above and beyond its hypertensive properties, it has the potential, if priced appropriately, to grow in its impact as a pharmacotherapeutic long after its patent expires.

Pentoxifylline lowers plasminogen activator inhibitor 1 levels in obese individuals: a pilot study.

Plasminogen activator inhibitor 1 (PAI-1), the primary inhibitor of fibrinolysis and C-reactive protein (CRP), is a predictor of myocardial infarction. Both are upregulated by tumor necrosis factor-alpha (TNF-α) within the obese population. This pilot study tested the hypothesis that TNF-α blockade with pentoxifylline lowers PAI-1 and high-sensitivity CRP (hsCRP) in obese individuals. Twenty participants were treated with pentoxifylline for 8 weeks. A proportional odds model was used to compare the change in PAI-1 and CRP in the pentoxifylline and placebo groups. Plasminogen activator inhibitor 1, but not hsCRP levels, decreased over the 8-week period of the study (P = .025 and P = NS). There was significant dropout of participants due to drug tolerability. These findings suggest that these markers of cardiovascular risk are differentially regulated in obesity and that PAI-1 levels can be reduced by pentoxifylline in this population.