Is fluid retention a cardiovascular risk factor?

Endothelial dysfunction, the earliest manifestation of atherosclerosis, can be initiated by both biochemicals and biomechanical forces. Atherosclerosis occurs predominantly at arterial branch points, arterial bifurcations and the curved segments of great arteries. These are the regions that blood flows turbulently. Turbulence promotes endothelial dysfunction by reducing shear stress upon endothelial cells. The endothelial glycocalyx mediates the effect of shear stress upon the endothelium. A mathematical analysis of cardiovascular hemodynamics demonstrates that fluid retention increases turbulence of blood flow. While there is no empirical data confirming this relationship, fluid retention is associated with adverse cardiovascular events. Every medical condition that causes fluid retention is associated with increased risk of both atherosclerotic cardiovascular disease and venous thromboembolic disease. In addition, most medications that cause fluid retention are associated with increased adverse cardiovascular effects. Calcium channel blockers (CCBs) and pioglitazone are exceptions to this generalization. Even though data regarding CCBs and pioglitazone contradict the hypothesis that fluid retention is a cardiovascular risk factor, these medications have favorable cardiovascular properties which may outweigh the negative effect of fluid retention. Determining whether or not fluid retention is a cardiovascular risk factor would require empirical data demonstrating a relationship between fluid retention and turbulence of blood flow. While this issue should be relevant to cardiovascular researchers, clinicians and patients, it is especially pertinent to the pharmaceutical industry. Four-dimensional magnetic resonance imaging and vector flow Doppler ultrasound have the capability to quantify turbulence of blood flow. These technologies could be utilized to settle the matter.

Association of adverse cardiovascular events with gabapentin and pregabalin among patients with fibromyalgia.

OBJECTIVE: Fibromyalgia, a chronic pain disorder, impacts approximately 2% of adults in the US. Gabapentin and pregabalin are common treatments to manage fibromyalgia-related pain. Our recent study showed the risk of adverse cardiovascular events increased in diabetic neuropathy patients who were prescribed gabapentin or pregabalin. Here, we investigated whether the prescription of gabapentin or pregabalin has similar cardiovascular risk in patients with fibromyalgia. METHODS: This retrospective cohort study leveraged electronic health records from 64 US healthcare organizations with 112 million patients. The study population included 105,602 patients first diagnosed with fibromyalgia and followed by a prescription of gabapentin, pregabalin, or other FDA-approved drugs for treating fibromyalgia from 2010 to 2019. Outcomes were deep venous thrombosis (DVT), myocardial infarcts (MI), peripheral vascular disease (PVD), strokes, heart failure, and pulmonary embolism (PE). In propensity-score-matched cohorts, 1-year and 5-year hazard ratios (HRs) were computed with their respective 95% confidence intervals (CIs). Additionally, we conducted sensitivity analyses on the subpopulations without other possible indications. RESULTS: For 5-year follow-up, gabapentin increased the risk of PVD (HR = 1.46, 95% CI = 1.17-1.80), MI (HR = 1.31, 95% CI = 1.03-1.66), heart failure (HR = 1.27, 95% CI = 1.10-1.48), DVT (HR = 1.80, 95% CI = 1.33-2.44), and PE (HR = 2.23, 95% CI = 1.62-3.07). Pregabalin increased the risk of DVT (HR = 1.49, 95% CI = 1.01-2.20), and PE (HR = 2.24, 95% CI = 1.43-3.50). For 1-year follow-up, gabapentin increased the risk of PVD (HR = 1.32, 95% CI = 1.11-1.57), DVT (HR = 1.35, 95% CI = 1.09-1.68), and PE (HR = 1.36, 95% CI = 1.17-1.57). Pregabalin increased the risk of PVD (HR = 1.32, 95% CI = 1.06-1.63) and PE (HR = 1.25, 95% CI = 1.03-1.52). Sensitivity analyses showed similar trends. CONCLUSION: In fibromyalgia patients, the prescription of gabapentin and pregabalin moderately increased the risk of several adverse cardiovascular events. This risk, together with benefits and other adverse reactions, should be considered when prescribing these medications for fibromyalgia patients.

Cardiovascular risk of gabapentin and pregabalin in patients with diabetic neuropathy.

BACKGROUND: Gabapentin and pregabalin are commonly prescribed medications to treat pain in patients with diabetic neuropathy. Gabapentin and pregabalin can cause fluid retention, which is hypothesized to be associated with cardiovascular diseases. However, whether long-term use of gabapentin and pregabalin is associated with adverse cardiovascular diseases remains unknown. This study aims to examine the association between gabapentin use, pregabalin use and several adverse cardiovascular events. METHODS: This retrospective cohort study used propensity score matching within patient electronic health records (EHRs) from a multicenter database with 106 million patients from 69 health care organizations in the US. The study population comprised 210,064 patients who had a diagnosis of diabetic neuropathy and were prescribed diabetic neuropathy medications in their EHRs. The exposure cohort comprised patients who were prescribed gabapentin or pregabalin to treat diabetic neuropathy. The comparison cohort comprised patients who were not prescribed either gabapentin or pregabalin but were prescribed other drugs to treat diabetic neuropathy. The outcomes of interest were myocardial infarcts, strokes, heart failure, peripheral vascular disease, and venous thromboembolic events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for 3-month and 5-year risk for adverse cardiovascular events between the propensity score-matched cohorts. RESULTS: Both gabapentin and pregabalin were associated with increased risk of 5-year adverse cardiovascular events compared with the comparison group. In patients prescribed gabapentin, the highest risk was observed for deep venous thrombosis (HR: 1.58, 95% CI 1.37-1.82), followed by pulmonary embolism (HR: 1.5, 95% CI 1.27-1.76), peripheral vascular disease (HR: 1.37, 95% CI 1.27-1.47), stroke (HR: 1.31, 95% CI 1.2-1.43), myocardial infarction (HR: 1.25, 95% CI 1.14-1.38) and heart failure (HR: 1.14, 95% CI 1.07-1.21). In patients prescribed pregabalin, the highest risk was observed for deep venous thrombosis (HR: 1.57, 95% CI 1.31-1.88), followed by peripheral vascular disease (HR: 1.35, 95% CI 1.22-1.49), myocardial infarction (HR: 1.29, 95% CI 1.13-1.47), pulmonary embolism (HR: 1.28, 95% CI 1.04-1.59), stroke (HR: 1.26, 95% CI 1.12-1.42), and heart failure (HR: 1.2, 95% CI 1.11-1.3). There were significant associations between short-term (3 month) gabapentin use and heart failure, myocardial infarction, peripheral vascular disease, deep venous thrombosis, and pulmonary embolism. Short-term (3 month) pregabalin use was associated with deep venous thrombosis, peripheral vascular disease. CONCLUSION: In patients with diabetic neuropathy who were prescribed gabapentin and pregabalin, there is an increased risk for heart failure, myocardial infarction, peripheral vascular disease, stroke, deep venous thrombosis, and pulmonary embolism with long-term use. Our findings suggest that increased risk for adverse cardiovascular events, along with other side effects, the efficacy of pain control and the degree of tolerance of the patient, should be considered when prescribing gabapentin and pregabalin long-term in patients with diabetic neuropathy.

Food and drug administration regulation of drugs that raise blood pressure.

Although it is recognized that a systolic blood pressure (SBP) increase ≥ 2 mm Hg or a diastolic blood pressure (DBP) increase ≥ 1 mm Hg increases the risk of heart attacks and strokes in middle-aged adults, the Food and Drug Administration (FDA) lacks an adequate policy for regulating medications that increase blood pressure (BP). Some FDA reviewers consider a clinically significant increase in BP to occur only if a drug raises SBP ≥ 20 mm Hg or if a drug raises DBP ≥ 10 to 15 mm Hg. In recent years, numerous drugs have been regulated or taken off the market due to cardiovascular safety concerns. The list includes rofecoxib (Vioxx), valdecoxib (Bextra), nonselective nonsteroidal anti-inflammatory drugs, sibutramine (Meridia), and phenylpropanolamine. It is probable that the hypertensive effect of these drugs explains why they increase the risk of adverse cardiovascular events. Other drugs, notably serotonin-norepinephrine reuptake inhibitors and drugs used to treat attention deficit hyperactivity disorder, were approved without cardiovascular safety data despite the fact that they raise BP comparable to valdecoxib and sibutramine. It is the responsibility of the FDA to ensure that drugs are properly labeled regarding risk. Even if a drug raises BP only modestly, FDA guidelines for new drug approvals should include a requirement for cardiovascular safety data. However, such guidelines will not address the problem of how to obtain cardiovascular safety data for the many already approved drugs that increase BP. The FDA should play a role in obtaining cardiovascular safety data for such drugs.

Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis.

BACKGROUND: There is little conclusive data regarding the effect of continuous positive airway pressure (CPAP) on glycated hemoglobin (HbA(1c)). An earlier meta-analysis included two randomized controlled trials (RCTs) and found no significant effect of CPAP on HbA(1c). The meta-analysis presented here was conducted to include all relevant observational studies and RCTs on the effect of CPAP on HbA(1c). METHODS: We searched the PubMed database for all studies published prior to March 2012 for trials of the effect of CPAP on HbA(1c). Data from observational studies and RCTs that met the inclusion criteria were extracted for pre- and post-treatment HbA(1c). RESULTS: A total of nine studies that included 151 subjects met the inclusion criteria. The duration of the studies ranged from 41 days to 6 months. The mean net change in the HbA(1c) was -0.06 % [95 % CI: -0.24, 0.12] (p = 0.5). Five of the nine studies, with a total of 112 subjects, comprised patients with diabetes mellitus (DM) type 2. The mean net change in HbA(1c) for the subjects with DM type 2 was 0.08 % [95 % CI: -0.26, 0.42] (p = 0.65). The mean net change in HbA(1c) for subjects with DM type 2 in studies that were at least 3 months in duration was 0.16 % [95 % CI: -0.26, 0.58] (p = 0.45). CONCLUSIONS: This meta-analysis found that CPAP does not reduce HbA(1c) levels when used in the short term.

Effect of acute salt ingestion upon core temperature in healthy men.

Salt intake may cause conflict for the cardiovascular system as it attempts to simultaneously maintain blood pressure (BP) and temperature homeostasis. Our objective was to determine the effect of a salt and water load vs. a water load upon rectal temperature (Tre) in healthy volunteers. Twenty-two healthy, non-hypertensive Caucasian men enrolled in two trials in which they ingested either salt and body temperature water (SALT), or body temperature water (WATER). BP, Tre, cardiac index, peripheral resistance and urine output were monitored one, 2 and 3 h post-baseline. Changes in the dependent variables were compared between those subjects who were salt sensitive (SS) and those who were salt resistant (SR) at the same time intervals. The percentage change reduction in Tre was greater following SALT compared with WATER at +120 min (-1.1±0.7 vs. -0.6±0.5%, P=0.009) and at +180 min (-1.3±0.8 vs. -0.7±0.6%, P=0.003). The percentage change reduction in Tre was greater in the SR group compared with the SS group at +180 min (-1.6±0.9 vs. -0.9±0.5%, P=0.043). SALT decreased Tre more than WATER. SS individuals maintained temperature homeostasis more effectively than SR individuals following SALT. These results may explain why some individuals are SS while others are SR. If these results are generalizable, it would be possible to account for the role of sodium chloride in the development of SS hypertension.

Calculated effect of fluid retention upon velocity of blood flow and turbulence: implications for atherosclerosis.

Fluid retention increases intravascular volume and pressure. The calculations in this paper demonstrate that fluid retention increases the likelihood that blood will flow in a turbulent manner, in part due to an increase in stroke volume, regardless of whether or not blood pressure is increased. Increased turbulence will promote endothelial dysfunction, thereby contributing to the development of atherosclerotic cardiovascular disease. Accordingly, fluid retention is predictably detrimental to the cardiovascular system. The reason that some medications, such as cyclo-oxygenase-2 inhibitors, nonselective nonsteroidal anti-inflammatory drugs, estrogens, progestins, and rosiglitazone, are associated with an increased risk of myocardial infarcts and strokes may be that they cause fluid retention. Increased stroke volume and/or edema formation may indicate that a medication increases the risk of adverse cardiovascular events. For drugs that increase the risk of adverse cardiovascular events, it may be possible to reduce or neutralize the increased risk by simultaneously administering a diuretic.

The influence of interval versus continuous exercise on thermoregulation, torso hemodynamics, and finger dexterity in the cold.

The purpose of this study was to evaluate how interval (INT) and continuous (CONT) exercise alter body temperatures and manual dexterity in the cold (5 degrees C). Fourteen young men underwent two trials consisting of a 90-min period of acute cold exposure (ACE), 30 min of exercise (INT or CONT), and a 60-min recovery period (REC). Participants donned approximately 1 clo but the hands remained bare for the entire protocol so that a steep decline in dexterity performance occurred prior to the initiation of exercise. INT and CONT were isoenergetic, reflecting 50 +/- 1% of each individual's VO(2) peak. Rectal (Tre) and skin temperatures were monitored continuously and dexterity testing was conducted at ten time points throughout each 3-h trial. In addition, oxygen consumption (VO(2)) and torso hemodynamics were assessed via indirect calorimetry and impedance cardiography (ICG), respectively. As expected, finger temperature and dexterity declined during ACE, relative to baseline. Both modes of exercise increased finger temperature and dexterity, relative to ACE. However, CONT was more effective than INT at increasing finger temperature on the dominant hand, which was associated with better dexterity scores during REC. Tre was not different between trials but a significant increase in stroke volume was found following CONT. Perhaps elevated stroke volume during post-exercise REC plays a role in finger rewarming and dexterity performance. Further mechanistic studies are needed to confirm the role of cardiovascular function in the enhancement of manual performance in the cold.

Reliability of the measurement of stroke volume using impedance cardiography during acute cold exposure.

INTRODUCTION: It is well documented that cardiovascular alterations occur during acute cold exposure (ACE). Interindividual variability is present, due mainly to body size differences, gender, and age. However, no study has evaluated stroke volume in the same individual twice in the same ambient conditions (i.e., test-retest reliability). Impedance cardiography (ICG) has become a popular method to acquire hemodynamic data in both clinical and applied physiology settings. Further, ICG does not interfere with other dependent variables such as oxygen consumption. Therefore, based on the uniqueness of the methodology, we sought to test reliability in this technology at 5 degrees C for 65 min on two separate occasions. METHODS: Nine young men underwent two 65-min trials of resting ACE, separated by at least 72 h. Volunteers were clothed in approximately one layer of clothing. Core and skin temperatures, oxygen consumption, and central hemodynamics were measured. RESULTS: As expected, core and skin temperature decreased while oxygen consumption showed a modest increase over time. In both trials, stroke volume significantly increased over time as heart rate decreased. There was similarity within subjects and between trials for all variables, as assessed via bivariate correlations. CONCLUSION: Cold increased stroke volume and decreased heart rate when subjects were pooled together, but each subject retained his individuality (minimal interindividual differences). Results suggest that impedance cardiography may be a reliable technique to use during acute cold exposure.

Temperature and blood pressure following amlodipine overdose.

The cardiovascular system participates in both blood pressure (BP) and temperature regulation. As a result, salt ingestion creates conflict between BP and temperature homeostasis, as vasodilatation that would promptly lower the BP would simultaneously increase cutaneous blood flow, thereby accelerating heat loss. If temperature homeostasis has precedence over blood pressure homeostasis, as postulated by the thermoregulatory-vascular remodeling (TVR) hypothesis, then in order to minimize heat loss, BP remains elevated following salt ingestion until the kidneys excrete the excess salt. A case of amlodipine overdose offered an opportunity to test a corollary of the TVR hypothesis: vasodilators should cause a drop in body temperature and/or an increase in the metabolic rate. Following the ingestion of 1000 mg of amlodipine, the temperature and BP of a single patient were monitored during the initial 36 hours and during the 13th day of hospitalization. The BP dropped markedly between the fifth and seventh hours postingestion, but then rose steadily and normalized by 28 hours postingestion. The temperature was normal at 7 hours postingestion, declined gradually between the seventh and 26th hours postingestion, stabilized between the 26th and 31st hours postingestion, then began to rise. During this case of amlodipine overdose, a modest temperature decline lagged behind a marked BP decline. As the BP rose, the temperature also rose, but lagged behind the BP increases. These findings suggest that there is a relationship between BP and temperature and are consistent with the TVR hypothesis.