Regional differences in the cerebral blood flow velocity response to hypobaric hypoxia at high altitudes.

Symptoms of acute mountain sickness (AMS) may appear above 2,500 m altitude, if the time allowed for acclimatization is insufficient. As the mechanisms underlying brain adaptation to the hypobaric hypoxic environment are not fully understood, a prospective study was performed investigating neurophysiological changes by means of near infrared spectroscopy, electroencephalograpy (EEG), and transcranial doppler sonography at 100, 3,440 and 5,050 m above sea level in the Khumbu Himal, Nepal. Fourteen of the 26 mountaineers reaching 5,050 m altitude developed symptoms of AMS between 3,440 and 5,050 m altitude (Lake-Louise Score ⩾3). Their EEG frontal beta activity and occipital alpha activity increased between 100 and 3,440 m altitude, i.e., before symptoms appeared. Cerebral blood flow velocity (CBFV) in the anterior and middle cerebral arteries (MCAs) increased in all mountaineers between 100 and 3,440 m altitude. During further ascent to 5,050 altitude, mountaineers with AMS developed a further increase in CBFV in the MCA, whereas in all mountaineers CBFV decreased continuously with increasing altitude in the posterior cerebral arteries. These results indicate that hypobaric hypoxia causes different regional changes in CBFV despite similar electrophysiological changes.

Middle cerebral artery preponderance in ischemic stroke: a coincidence or fate?

Stroke is the leading cause of disability and the third leading cause of death in the United States. More than 700,000 persons per year suffer a first-time stroke in the United States, with 20% of these individuals dying within the first year after the stroke. Ischemic stroke accounts for majority of cases of stroke and within this subgroup also, anterior circulation stroke involving the middle cerebral artery (MCA) is the commonest one. There has been no speculation so far as to why this anatomical preponderance to middle cerebral artery exists in thrombotic stroke. While the role of nitric oxide (NO) as a vasculoprotective molecule has been well established, understanding the stimulus for its release and anatomical course of middle cerebral artery can provide a good justification for the clinical finding mentioned above. This bench to bedside correlation not only explains the predilection of ischemic thrombotic stroke to MCA but also highlights the significance of NO as a vasculoprotective molecule in cerebrovascular disease which has not been emphasized earlier.

Post percutaneous coronary intervention antiplatelet therapy: current perceptions, prospects and perplexity.

Dual antiplatelet therapy (DAT) has become standard care for patients undergoing percutaneous coronary intervention (PCI). Following balloon injury and stent placement, the intima at the site is distressed, resulting in the activation of coagulation cascade and platelets. In the case of bare metal stents (BMS), it takes six to eight weeks for the stent surface to be covered with neointima. However, in the case of a drug-eluting stent (DES), the process of healing is delayed and neointima may not form for months or even years. To prevent the formation of platelet thrombi, dual antiplatelet therapy is given as a combination of aspirin and clopidogrel for three months in a case of BMS and for a minimum of one year in a case of DES. A prolonged duration of therapy is often required for a subset of patients who are highly prone to thrombus formation. During most non-cardiac surgeries, dual antiplatelet therapy should be continued if bleeding can be directly controlled and excessive bleeding will have no adverse effect on the outcome of surgery. Prasugrel, another thienopyridine, is more potent and faster acting than clopidogrel, and is therefore of great value in cases of acute coronary syndrome during PCI, particularly in diabetics. Triple drug therapy, by adding cilastozol, is reserved for some selected thrombotic lesions. Ticagrelor and cangrelor are two new antiplatelet agents undergoing various clinical trials. (Cardiol J 2011; 18, 6: 712-717).

Hypertension in the elderly: Are we all on the same wavelength?

Hypertension is of frequent occurrence in the elderly population. Isolated systolic hypertension (ISH) accounts for the majority of cases of hypertension in the elderly. ISH is associated with a 2-4-fold increase in the risk of myocardial infarction, left ventricular hypertrophy, renal dysfunction, stroke, and cardiovascular mortality. There have been many studies to determine the optimal treatment for hypertension in the elderly. Why, when and how to treat hypertension in the elderly was the scope of the majority of these trials. Despite countless efforts many aspects remain obscure. While a number of novel drugs are being developed, the issue of whether all antihypertensive drugs bestow parallel benefits or whether some agents offer a therapeutic advantage beyond blood pressure control remains of crucial importance. Furthermore, the response of the elderly to different antihypertensive agents also differs from that of younger patients and may explain some of the disparities in outcomes of trials conducted in elderly patients with hypertension.

Mild functional ischemic mitral regurgitation following acute coronary syndrome: a retrospective study.

BACKGROUND: Ischemic mitral regurgitation is a frequent complication of acute coronary syndrome. It primarily occurs in patients with a prior myocardial infarction but also may be seen with acute ischemia, a setting in which the MR typically resolves after the ischemia resolves. The vast majority of patients have "functional" ischemic MR. In these individuals, the papillary muscles, chordae, and valve leaflets are normal. However, the leaflets do not coapt and restricted leaflet motion is frequently noted on echocardiography. Ischemic mitral regurgitation indicates a poor prognosis after acute myocardial infarction. This study addresses the clinical characteristics of patients of acute coronary syndrome with mild functional ischemic mitral regurgitation and its impact on immediate in-hospital cardiovascular outcomes and death. PATIENTS AND METHODS: From March 2006 through May 2007, patients who underwent 2-dimensional (2D) color doppler echocardiographic quantification of ischemic mitral regurgitation within 10 days of admission for acute coronary syndrome (ACS) in Manipal Teaching Hospital, a tertiary hospital in the western region of Nepal were noted. The demographic details, conventional risk factors of coronary artery disease, clinical and laboratory findings, treatment course and in-hospital outcomes of all the patients with mild functional ischemic MR following ACS in that time duration were recorded in a designated Performa. A total of 94 patients enrolled in the study were divided into two groups: Group I with mild functional ischemic MR and Group II without MR on 2D echocardigraphic assessment. Patient characteristics, risk factors, ejection fraction, and cardiovascular outcome and death among the two groups were compared and analyzed using software package SPSS 17.0 version. RESULTS: Group I constituted 64.89% of the study population and Group II comprised of 35.11%. The patients in Group I was more likely to be elderly diabetic (P<0.05), and smokers with hypertension (P < 0.05). Mild functional ischemic MR was more common in patients with STEMI as compared to those with unstable angina and NSTEMI (55.7%, 36.1%, and 8.2%; P < 0.05).The mean ejection fraction in the first group was 54.84% in contrast to 58.92% observed in group II (P < 0.05).The type of wall involvement inferred from EKG analysis was homogeneously distributed in both the groups. Finally, there was no difference in immediate in-hospital (within 10 days) mortality or cardiovascular outcomes (heart failure, ventricular tachycardia/fibrillation, hypotension, and cardiogenic shock) between these two groups. CONCLUSION: Ischemic mitral regurgitation following acute coronary syndromeare more likely in elderly diabetics and hypertensive smokers. It is a more common finding in STEMI. Although mild MR following ACS does reduce ejection fraction, the immediate (within 10 days) in-hospital mortality and cardiovascular outcomes are not significantly altered.

Acute mountain sickness in children at 4380 meters in the Himalayas.

OBJECTIVE: To determine the incidence of and risk factors for acute mountain sickness (AMS) in native Nepalese children during a pilgrimage trip to Gosaikunda Lake in the Langtang National Park Region of Nepal (elevation 4380 m). METHODS: A descriptive, noninterventional, cross-sectional study was completed on a group of children during the pilgrimage to Gosaikunda. Participants were interviewed about the symptoms of AMS using the Lake Louise Scoring System. RESULTS: Thirty-six children between 3 and 15 years of age were interviewed after a rapid ascent (over 1 to 3 days) from 1950 m to 4380 m. Acute mountain sickness was diagnosed in 17 of 36 (47.2%) children. The sickness was seen in only 5 of 20 (25%) children who took 2 or more days to ascend, compared with 12 of 16 (75%) children who spent only 1 night (reaching the study site at Gosaikunda on the second day) to complete the same ascent (P < or = .01, odds ratio [OR] = 9.0, 1.61 < OR < 57.36). No significant correlation was found between the incidence of AMS and gender, previous exposure to high altitude, or concurrent illness. CONCLUSIONS: Our results indicate that the incidence of AMS in this group of Nepalese children was high and associated with rapidity of ascent. Rapid ascent to high sleeping altitude and increased physical activity were observed as possible risk factors. We suggest organizing educational programs to make children and their parents aware of altitude-related problems and advise gradual ascent to such high-altitude pilgrimage sites.

Two hypoxia sensor genes and their association with symptoms of acute mountain sickness in Sherpas.

INTRODUCTION: Hypoxia-inducible factor (HIF) and von Hippel-Lindau tumor suppressor protein (VHL) are hypoxia sensors that control cellular responses to hypoxia. Although many Sherpas live at high altitudes for their entire lives, some of them manifest symptoms of acute mountain sickness (AMS) during mountaineering at extremely high altitudes. We hypothesize that the two hypoxia sensor genes might associate with the occurrence of AMS symptoms in Sherpas at extremely high altitude. METHODS: In a village at an altitude of 3440 m, 104 Sherpas who had mountaineered at extremely high altitudes (over 5000 m) were divided into two groups: Sherpas with (N = 45) and without (N = 59) histories of AMS symptoms. The rs11549465 SNP in the HIF-1alpha gene (HIF1A) and the rs28940298, rs779805, rs779808, rs1678607, and 1149A > G SNPs in the VHL gene (VHL) were identified in the two Sherpa groups using PCR following RFLP. RESULTS: There were no significant differences in ei-ther the genotype distributions or the allele frequencies of the HIF1A and VHL genetic variants between the two Sherpa groups. CONCLUSION: These genetic variants of HIF1A and VHL are not associated with AMS symptoms that occur in Sherpas at extremely high altitudes. It seems unlikely that HIF1A and VHL are associated with hypoxic sensing sensitivity in Sherpas.

Adaptation to high altitude in Sherpas: association with the insertion/deletion polymorphism in the Angiotensin-converting enzyme gene.

OBJECTIVE: Sherpas are well-known for their physical strength at high altitudes. They adapt to high altitude so well that little acute or chronic mountain sickness has been documented in them. The possible genetic basis for this adaptation is, however, unclear. The objective of this study was to elucidate the genetic background underlying this characteristic among Sherpas with respect to the angiotension-converting enzyme (ACE) gene. METHODS: We enrolled 105 Sherpa volunteers in Namche Bazaar (3440 meters) and 111 non-Sherpa Nepalese volunteers in Kathmandu Valley (1330 meters) in Nepal. Information about high-altitude exposure and physiological phenotypes was obtained via fieldwork investigation. The genotype of the insertion/deletion (I/D) polymorphism in the ACE gene was identified by polymerase chain reaction. Serum ACE activity was also measured. RESULTS: The distribution of the I dominant genotype (II & ID) and the I allelic frequency were significantly more prevalent in Sherpas (II & ID: 94.3%, I allele: 73.3%) than in non-Sherpas (II & ID: 85.6%, P = .035; I allele: 64.0%, P = .036). Moreover, despite residing at high altitude, the circulating ACE levels of Sherpas were statistically similar to those of non-Sherpas at low altitudes (Sherpas: 14.5 +/- 0.4 IU/L/37 degrees C; non-Sherpas: 14.7 +/- 0.4 IU/L/37 degrees C; P = .755). CONCLUSIONS: These findings suggest that the overrepresented I allele of the ACE gene in Sherpas might be one of the fundamental genetic factors responsible for maintaining physiological low-altitude ACE activity at high altitude, which may have an advantageous physiological role in adapting to a high-altitude environment.

Right temporal cerebral dysfunction heralds symptoms of acute mountain sickness.

Acute mountain sickness (AMS) can occur during climbs to high altitudes and may seriously disturb the behavioral and intellectual capacities of susceptible subjects. During a Himalayan expedition 32 mountaineers were examined with electroencephalography (EEG) and transcranial doppler sonography (TCD) to assess relative changes of middle cerebral artery velocity in relation to end-expiratory CO2 (EtCO2), peripheral saturation (SaO2), and symptoms of AMS. We tested the hypothesis that O2 desaturation and EtCO2 changes precede the development of AMS and result in brain dysfunction and compensatory mechanisms which can be measured by EEG and TCD, respectively. Contrary to our hypothesis, we found that subjects who later developed symptoms of AMS between 3,440 m and 5,050 m altitude exhibited an increase of slow cerebral activity in the right temporal region already at 3,440 m. Cerebral blood flow increased in these mountaineers in the right middle cerebral artery at 5,050 m. These findings indicate that regional brain dysfunction, which can be documented by EEG, heralds the appearance of clinical symptoms of AMS.

Symptoms of acute mountain sickness in Sherpas exposed to extremely high altitude.

Droma, Yunden, Masayuki Hanaoka, Buddha Basnyat, Amit Arjyal, Pritam Neupane, Anil Pandit, Dependra Sharma, and Keishi Kubo. Symptoms of acute mountain sickness in Sherpas exposed to extremely high altitude. High Alt. Med. Biol. 7:312-314, 2006.--The aim of this field interview was to investigate the current state of affairs concerning acute mountain sickness (AMS) in high-altitude residents, specifically the Sherpas at 3440 m above sea level, when they are exposed rapidly to altitudes significantly higher than their residing altitudes. Out of 105 Sherpas (44 men and 61 women, 31.2 +/- 0.8 yr), 104 had mountain-climbing experiences to 5701.4 +/- 119.1-m altitude in average 3.5 times each year. On the other hand, only 68 out of 111 non-Sherpas (29.9 +/- 0.8 yr) had experience of 1.4 +/- 1.5 climbs to an average 2688.6 +/- 150.4-m altitude in their mountaineering histories (p < 0.0001). Among the 104 Sherpas, 45 (43.3%) complained of at least one AMS symptom (headache, gastrointestinal symptoms, weakness, dizziness, and difficulty sleeping) in their experiences of mountaineering at an average 5518.9 +/- 195.9-m altitude. And 16 out of the 68 non-Sherpas (23.5%) reported the AMS symptoms at a mean altitude of 2750.0 +/- 288.8 m. Moreover, we also noticed that the Sherpa women showed a significantly higher Sa(O(2) ) (93.9 +/- 0.2%) than did Sherpa men (92.4 +/- 0.3%, p = 0.0001) at an altitude of 3440 m. The brief field interview evidenced that Sherpas might suffer from AMS when exposed to altitudes significantly higher than their residing altitude.

Genetic contribution of the endothelial nitric oxide synthase gene to high altitude adaptation in sherpas.

The Sherpas' adaptation to high altitude has been hypothesized as being due to a genetic basis since the beginning of the last century, but this has yet to be demonstrated. We randomly enrolled 105 Sherpas in Namche Bazaar (3440 m) and 111 non-Sherpa Nepalis in Kathmandu (1330 m) in Nepal. The genotypes of Glu298Asp and eNOS4b/a polymorphisms of the endothelial nitric oxide synthase (eNOS) gene were identified. The metabolites of nitric oxide (NO( x ): nitrite and nitrate) in serum were measured. The frequencies of the Glu and eNOS4b alleles were significantly higher in Sherpas (Glu: 87.5%; eNOS4b: 96.7%) than in non-Sherpas (Glu: 77.9%, p = 0.036; eNOS4b: 90.5%, p = 0.009). In addition, the combination of the wild types of Glu298Glu and eNOS4b/b was significantly greater in Sherpas (66.7%) than non-Sherpas (47.7%, p = 0.008). However, the serum NO( x ) was significantly lower in Sherpas (53.2 +/- 4.6 micromol/L) than in non-Sherpas (107.3 +/- 9.0 micromol/L, p < 0.0001). The wild alleles of the Glu298Asp and eNOS4b/a polymorphisms of the eNOS gene may be a benefit for the Sherpas' adaptation to high altitude. The nitric oxide metabolites (NO( x )) in serum vary individually, thus it is not a reliable indicator for endogenous nitric oxide production.

Increase in 6-hydroxymelatonin excretion in humans during ascent to high altitudes.

Melatonin (MLT), the pineal gland hormone involved in the regulation of circadian rhythms, shows characteristic diurnal variation. Its physiological role in humans is not clear. Exposure to high altitudes may disrupt the circadian rhythm and lead to various endocrine changes. MLT in humans has not been studied under these conditions. Urinary 6-hydroxy-MLT sulfate (aMT6s) excretion was analyzed during the day (0700-2200 h) and night (2200-0700 h) phases. A cohort of 33 healthy volunteers, aged 19-65 yr, was studied during an ascent to a high altitude in the Himalayas on three occasions (at a lower altitude, at 3400 m, and after reaching maximal altitudes of 5600-6100 m). aMT6s excretion during the daytime remained unchanged during exposure to high altitudes. As expected, nocturnal values were higher than diurnal values at each point in time. However, there was a significant increase in nocturnal MLT excretion after the ascent to high altitudes. Ascent to high altitudes is associated with increased nocturnal excretion of aMT6s. The mechanism and physiological significance of this MLT increase are unclear.