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It is tempting to view different topics as completely separate, but in fact the ideas we cover in this course are often connected to one another. Using this practice set can help you do well both in this module and as you move through the course.
Click here to view the practice set for The Circulatory System. You’ll need to create a free log-in to practice these items, if you haven’t already.
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Biology Model Questions
I. Answer the following in A Word Or A Sentence each:
1. Define metabolism.
2. Name the non-chordate phylum whose few members have the ability to fly.
3. What is aestivation?
4. Why does enzyme activity decrease at higher temperature?
5. Where are 70S type of ribosomes found in eukaryotic cells?
6. Which technique is used for the separation of leaf pigments?
7. Sino Atrial Node is known as the pacemaker of the heart. Justify.
8. What is fascia?
9. Name the granular bodies found in the cell body of neurons.
10. An ovarian hormone is known to induce changes in the secondary sex organs of human females to prepare for anticipated pregnancy. Name this hormone.
II. Answer ANY FIVE of the following in 3-5 sentences each, wherever applicable:
11. Write any two commercial uses of algae.
12. Define the following terms: i) Epiphyllous stamens ii) Staminode
13. What are the twin characters of growth?
14. Give the suitable technical term to denote the following floral characters: i) Stamens united into one bunch ii) Carpels of a flower are fused
15. Write any two differences between primary and secondary metabolites.
16. Name any two synthetic auxins.
17. Distinguish between Inspiratory Reserve Volume (IRV) and Expiratory Reserve Volume (ERV).
18. What is myogenic heart? Give one example.
III. Answer ANY FIVE of the following in 40-80 words each, wherever applicable:
19. Write a note on the steps involved in sexual cycle of fungi.
20. There has been an increase in the number of chambers in heart during the evolution of vertebrates.
Give the names of the classes of vertebrates having two, three and four chambered heart, respectively.
21. Write a note on adipose tissue.
22. What are the three distinct components of a nucleotide?
23. What would be expected to happen if, i) Gibberellic acid is applied to sugarcane? ii) Ethephon is applied to Cucumber plants? iii) You forget to add cytokinin to culture medium?
24. List any three factors that influence the formation of oxyhaemoglobin.
25. Name any three disorders of the circulatory system in humans.
26. Explain the structure of a meromyosin.
IV. Answer ANY FOUR of the following in 200-250 words each, wherever applicable:
27. Enumerate any five characteristic features of Gymnosperms.
28. Write any five differences between Chondrichthyes and Osteichthyes.
29. Distinguish between skeletal muscle and cardiac muscle with suitable diagrams.
30. Name the cell organelles in which following structures are found:
31. Draw a neat labelled diagram of a typical animal cell.
32. Explain Prophase and Metaphase stages of Mitosis division
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Modelling the maximal aerobic flight performance of birds
where Q̇ is maximum cardiac output(ml min -1 ) and is found to scale as Q̇ = 213Mh 0.88± 0.04 (where Mh is in g) CaO2 is the oxygen content of the arterial blood (ml O2 100 ml -1 blood) and is calculated as haemoglobin concentration (in g) per 100 ml blood ×1.36 (to calculate saturated oxygen carrying capacity) and then by 0.94 (assuming 94% saturation during maximal activity) and CV̄O2 is the oxygen content of the mixed venous blood returning to the heart and is taken to be 0.038 (ml O2 100 ml -1 blood) under conditions of V̇O2max (for details, see Bishop, 1997).
Using Eq. 3 and the above assumptions, I have estimated the V̇O2max available to the flight muscles and hence Pmet,fm for various bird species, using relative Mh data from Magnan(1922) and Hartman(1961), available for each individual species in the study of Hedenström and Alerstam(1992), except for a couple of cases where I used a value for the same genus or family.
The goal of this study was to investigate 65 students' evidence scores of emotions while they engaged in cognitive and metacognitive self-regulated learning processes as they learned about the circulatory system with MetaTutor, a hypermedia-based intelligent tutoring system. We coded for the accuracy of detecting students’ cognitive and metacognitive processes, and examined how the computed scores related to mean evidence scores of emotions and overall learning. Results indicated that mean evidence score of surprise negatively predicted the accuracy of making a metacognitive judgment, and mean evidence score of frustration positively predicted the accuracy of taking notes, a cognitive learning strategy. These results have implications for understanding the beneficial role of negative emotions during learning with advanced learning technologies. Future directions include providing students with feedback about the benefits of both positive and negative emotions during learning and how to regulate specific emotions to ensure the most effective learning experience with advanced learning technologies.
This engaging course supports teaching of the Science framework both theoretically and practically, with full coverage of the Scientific Enquiry framework integrated throughout the series. This Coursebook for Stage 8 gives a thorough introduction to the concepts, and offers a wealth of ideas for hands-on activities to make the subject matter come to life.
- Endorsed by Cambridge International Examinations.
- Supports teaching of the Science framework both theoretically and practically.
- Full coverage of the Scientific Enquiry framework integrated throughout the series.
- Coursebook gives a thorough introduction to the concepts and offers a wealth of ideas for hands-on activites to make the subject matter come to life.
- Workbook contains exercises that develop students’ ability to apply their knowledge, as well as Scientific Enquiry skills relating to planning experiments and recording results.
- Teacher’s Resource CD-ROM provides suggestions for how to introduce concepts in the classroom and how to deal with common misconceptions, as well as worksheets and activity suggestions.
Biology: 1. Plants
2. Food and digestion
3. The circulatory system
5. Reproduction and development
Chemistry: 6. State of matter
7. Elements and compounds
9. Material changes
Physics: 10. Measuring motion
Glossary and index
21.8: Cerego- The Circulatory System - Biology
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Secondary Lymphoid Organs and their Roles in Active Immune Responses
Lymphocytes develop and mature in the primary lymphoid organs, but they mount immune responses from the secondary lymphoid organs. A naïve lymphocyte is one that has left the primary organ and entered a secondary lymphoid organ.
Naïve lymphocytes are fully functional immunologically, but have yet to encounter an antigen to respond to. In addition to circulating in the blood and lymph, lymphocytes concentrate in secondary lymphoid organs, which include the lymph nodes, spleen, and lymphoid nodules. All of these tissues have many features in common, including the following:
- The presence of lymphoid follicles, the sites of the formation of lymphocytes, with specific B cell-rich and T cell-rich areas
- An internal structure of reticular fibers with associated fixed macrophages
- Germinal centers, which are the sites of rapidly dividing and differentiating B lymphocytes
- Specialized post-capillary vessels known as high endothelial venules the cells lining these venules are thicker and more columnar than normal endothelial cells, which allow cells from the blood to directly enter these tissues
Lymph nodes function to remove debris and pathogens from the lymph, and are thus sometimes referred to as the “filters of the lymph” (Figure 21.8). Any bacteria that infect the interstitial fluid are taken up by the lymphatic capillaries and transported to a regional lymph node. Dendritic cells and macrophages within this organ internalize and kill many of the pathogens that pass through, thereby removing them from the body. The lymph node is also the site of adaptive immune responses mediated by T cells, B cells, and accessory cells of the adaptive immune system. Like the thymus, the bean- shaped lymph nodes are surrounded by a tough capsule of connective tissue and are separated into compartments by trabeculae, the extensions of the capsule. In addition to the structure provided by the capsule and trabeculae, the structural support of the lymph node is provided by a series of reticular fibers laid down by fibroblasts.
Figure 21.8 Structure and Histology of a Lymph Node Lymph nodes are masses of lymphatic tissue located along the larger lymph vessels. The micrograph of the lymph nodes shows a germinal center, which consists of rapidly dividing B cells surrounded by a layer of T cells and other accessory cells. LM × 128. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)
The major routes into the lymph node are via afferent lymphatic vessels (see Figure 21.8). Cells and lymph fluid that leave the lymph node may do so by another set of vessels known as the efferent lymphatic vessels. Lymph enters the lymph node via the subcapsular sinus, which is occupied by dendritic cells, macrophages, and reticular fibers. Within the cortex of the lymph node are lymphoid follicles, which consist of germinal centers of rapidly dividing B cells surrounded by a layer of T cells and other accessory cells. As the lymph continues to flow through the node, it enters the medulla, which consists of medullary cords of B cells and plasma cells, and the medullary sinuses where the lymph collects before leaving the node via the efferent lymphatic vessels.
Lymph nodes are distributed widely throughout the body with clusters localised in regions such as
Cervical lymph nodes: Located in the neck adjacent to the internal jugular vein. Receive lymph from the head and neck.
Axillary lymph nodes: Located in the armpit (axillary region). Drain lymph from the upper limbs and breast.
Mesenteric lymph nodes: Located in the mesentery of the small intestines. Receive lymph from the gastrointestinal tract.
Inguinal lymph nodes: Located in the groin (inguinal region). Receive lymph from the lower limbs.
In addition to the lymph nodes, the spleen is a major secondary lymphoid organ (Figure 21.9). It is about 12 cm long and is attached to the lateral border of the stomach via the gastrosplenic ligament. The spleen is a fragile organ without a strong capsule, and is dark red due to its extensive vascularization. The spleen is sometimes called the “filter of the blood” because of its extensive vascularization and the presence of macrophages and dendritic cells that remove microbes and other materials from the blood, including dying red blood cells. The spleen also functions as the location of immune responses to blood-borne pathogens.
Figure 21.9 Spleen (a) The spleen is attached to the stomach. (b) A micrograph of spleen tissue shows the germinal center. The marginal zone is the region between the red pulp and white pulp, which sequesters particulate antigens from the circulation and presents these antigens to lymphocytes in the white pulp. EM × 660. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)
The spleen is also divided by trabeculae of connective tissue, and within each splenic nodule is an area of red pulp, consisting of mostly red blood cells, and white pulp, which resembles the lymphoid follicles of the lymph nodes. Upon entering the spleen, the splenic artery splits into several arterioles (surrounded by white pulp) and eventually into sinusoids. Blood from the capillaries subsequently collects in the venous sinuses and leaves via the splenic vein. The red pulp accounts for the bulk of the splenic tissue and consists of reticular fibers with fixed macrophages attached, free macrophages, and all of the other cells typical of the blood, including some lymphocytes. Within the red pulp, aged or abnormal red blood cells are removed by macrophages. Thus, the red pulp primarily functions as a filtration system of the blood, using cells of the relatively nonspecific immune response. The white pulp surrounds a central arteriole and consists of germinal centers of dividing B cells surrounded by T cells and accessory cells, including macrophages and dendritic cells. White pulp is where adaptive T and B cell responses are mounted.
The other lymphoid tissues, the lymphoid nodules, have a simpler architecture than the spleen and lymph nodes in that they consist of a dense cluster of lymphocytes without a surrounding fibrous capsule. These nodules are located in the respiratory and digestive tracts, areas routinely exposed to environmental pathogens.
Tonsils are lymphoid nodules located along the inner surface of the pharynx and are important in developing immunity to oral pathogens (Figure 21.10). The tonsil located at the back of the throat, the pharyngeal tonsil (or nasopharyngeal tonsil), is sometimes referred to as the adenoid when swollen. Such swelling is an indication of an active immune response to infection. Histologically, tonsils do not contain a complete capsule, and the epithelial layer invaginates deeply into the interior of the tonsil to form tonsillar crypts. These structures, which accumulate all sorts of materials taken into the body through eating and breathing, actually “encourage” pathogens to penetrate deep into the tonsillar tissues where they are acted upon by numerous lymphoid follicles and eliminated. This seems to be the major function of tonsils—to help children’s bodies recognize, destroy, and develop immunity to common environmental pathogens so that they will be protected in their later lives. Tonsils are often removed in those children who have recurring throat infections, especially those involving the palatine tonsils on either side of the throat, whose swelling may interfere with their breathing and/or swallowing.
Figure 21.10 Locations and Histology of the Tonsils (a) The pharyngeal tonsil is located on the roof of the posterior superior wall of the nasopharynx. The palatine tonsils lay on each side of the pharynx. The lingual tonsil is located in the posterior region of the tongue. (b) A micrograph shows the palatine tonsil tissue. LM × 40. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)
Mucosa-associated lymphoid tissue (MALT) consists of an aggregate of lymphoid follicles directly associated with the mucous membrane epithelia. MALT makes up dome-shaped structures found underlying the mucosa of the gastrointestinal tract, breast tissue, lungs, and eyes. Peyer’s patches, a type of MALT in the small intestine, are especially important for immune responses against ingested substances (Figure 21.11). Peyer’s patches contain specialized endothelial cells called M (or microfold) cells that sample material from the intestinal lumen and transport it to nearby follicles so that adaptive immune responses to potential pathogens can be mounted.
Figure 21.11 Mucosa-associated Lymphoid Tissue (MALT) Nodule LM × 40. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)
Bronchus-associated lymphoid tissue (BALT) consists of lymphoid follicular structures with an overlying epithelial layer found along the bifurcations of the bronchi, and between bronchi and arteries. They also have the typically less-organized structure of other lymphoid nodules. These tissues, in addition to the tonsils, are effective against inhaled pathogens.
The bidirectional communication and crosstalk between the gut and brain has been well recognized, termed the “gut-brain axis” [1𠄳]. Emerging evidence implicates gut microbiota in playing a pivotal role in the bidirectional communication that occurs in the gut-brain axis , leading to the more recent concept of the “gut-brain-microbiota axis” (GBMAx). Notably, this tripartite axis is coordinated by classical neuro-immune-endocrine and metabolic pathways , however the molecular regulation of GBMAx remains undetermined.
MicroRNAs (miRNAs) are small, non-coding RNA molecules capable of modulating gene expression at post-transcriptional level . As an important intracellular component of extracellular vesicles (EVs) miRNAs can be secreted by and transferred to varied target cells . Acting as a vital mediator of intercellular communication, EV-derived miRNAs have been implicated in microbiome-host communication [7, 8]. This review will present the current advances on EV-derived miRNAs and their functional link with GBMAx bi-directional communication. We propose that EV-derived miRNAs represent a novel regulatory system for GBMAx and a potential therapeutic target to modulate GBMAx function.
Circulatory Dynamics During Pulmonary Vein Isolation Using the Second‐Generation Cryoballoon
Circulatory dynamics change during pulmonary vein (PV) isolation using cryoballoons. This study sought to investigate the circulatory dynamics during cryoballoon‐based PV isolation procedures and the contributing factors.
Methods and Results
This study retrospectively included 35 atrial fibrillation patients who underwent PV isolation with 28‐mm second‐generation cryoballoons and single 3‐minute freeze techniques. Blood pressures were continuously monitored via arterial lines. The left ventricular function was evaluated with intracardiac echocardiography throughout the procedure in 5 additional patients. Overall, 126 cryoapplications without interrupting freezing were analyzed. Systolic blood pressure ( SBP ) significantly increased during freezing (138.7±28.0 to 148.0±27.2 mm Hg, P<0.001) and sharply dropped (136.3±26.0 to 95.0±17.9 mm Hg, P<0.001) during a mean of 21.0±8.0 seconds after releasing the occlusion during thawing. In the multivariate analyses, the left PV s (P=0.008) and lower baseline SBP (P<0.001) correlated with a larger SBP rise, whereas a higher baseline SBP (P<0.001), left PV s (P=0.017), lower balloon nadir temperature (P=0.027), and female sex (P=0.045) correlated with larger SBP drops. These changes were similarly observed regardless of preprocedural atropine administration and the target PV order. PV occlusions without freezing exhibited no SBP change. PV antrum freezing without occlusions similarly increased the SBP , but the SBP drop was significantly smaller than that with occlusions (P<0.001). The SBP drop time‐course paralleled the left ventricular ejection fraction increase (66.8±8.1% to 79.3±6.7%, P<0.001) and systemic vascular resistance index decrease (2667±1024 to 1937±513 dynes‐sec/cm 2 per m 2 , P=0.002).
With second‐generation cryoballoon‐based PV isolation, SBP significantly increased during freezing owing to atrial tissue freezing and dropped sharply after releasing the occlusion, presumably because of the peripheral vascular resistance decrease mainly by circulating chilled blood.
What Is New?
This study clarified the circulatory dynamics during pulmonary vein isolation using second‐generation cryoballoons, and they were characterized by a gradual rise in the systolic blood pressure (SBP) during the freezing phase and a sharp drop in the SBP after balloon deflation.
The rise in the SBP was not observed during occlusions without freezing and was not affected by the administration of atropine sulfate or the order of the cryoballoon applications.
The drop in the SBP was less sharp after freezing without an occlusion.
The systemic vascular resistance significantly decreased along with the sharp drop in the SBP.
What Are the Clinical Implications?
Our study results suggested (1) that the freezing of the atrial tissue might be the dominant reason for the SBP elevation and (2) that the leakage of the dammed chilled blood inside the pulmonary vein might be mainly associated with a sharp drop in SBP.
This may contribute to understanding some aspects of the reaction to such stimulation and the nature of the circulatory dynamics during cryoballoon‐based pulmonary vein isolation.
Pulmonary vein isolation (PVI) is a standard therapeutic intervention for atrial fibrillation. 1 , 2 Cryoballoon technology is becoming a major alternative owing to a less complicated technique, a shorter procedure time, and higher durability of the PVI compared with conventional radiofrequency catheter ablation. 3 , 4 , 5 The recently developed second‐generation cryoballoon has exhibited a significantly higher performance than the first‐generation cryoballoon owing to the improved cooling effect. 5 , 6 Multiple investigations have reported the noninferiority of the midterm outcome after the cryoballoon‐based PVI (CBPVI) compared with radiofrequency. 5
A successful CBPVI needs to occlude the entire proximal trunk of the targeted pulmonary vein (PV), which is completely different from point‐by‐point radiofrequency ablation. Because the myocardial injury is significantly more extensive after cryoballoon ablation than radiofrequency ablation, 7 the impact of an application on the circulatory dynamics should be much enhanced after the cryoballoon ablation. To date, however, no data have become available regarding the circulatory dynamics during CBPVI. The purpose of this study was to investigate the common pattern of circulatory dynamics during the CBPVI procedure and to elucidate the factors contributing to the circulatory change.
We retrospectively enrolled atrial fibrillation patients who underwent their first PVI using second‐generation cryoballoons in our institute. From a total of 140 consecutive patients, we selected 35 in whom all 4 PVs were successfully isolated by a single 3‐minute cryoapplication so as to eliminate the impact of the occlusion quality on the study results. We excluded 104 patients who required repeated cryoapplications to the same PV and 1 patient who exhibited a pain reaction during the cryoablation. Femoral arterial access was routinely acquired for continuous arterial pressure monitoring, and the heart rate and blood pressure (BP) were monitored throughout the procedure. The CBPVI was performed with a single 3‐minute freeze technique, without a routine bonus application, using only large (28‐mm) cryoballoons. In 5 additional patients, left ventricular (LV) function was evaluated with intracardiac echocardiography throughout the procedure. atrial fibrillation was classified according to the latest guidelines. 2 All patients gave their written informed consent. The study protocol was approved by the hospital's institutional review board. The study complied with the Declaration of Helsinki.
All antiarrhythmic drugs were discontinued for at least 5 half‐lives before the procedure. The surface ECG, bipolar intracardiac electrograms, and femoral intra‐arterial BP were continuously monitored and stored on a computer‐based digital recording system. The bipolar electrograms were filtered from 30 to 500 Hz. A 7F 20‐pole 3‐site mapping catheter was inserted through the right jugular vein for pacing, recording, and internal cardioversion.
The procedure was performed under moderate sedation obtained with dexmedetomidine. Immediately following venous access, 100 IU/kg body weight of heparin was administered, and heparinized saline was also infused to maintain the activated clotting times at 250 to 350 seconds. A single transseptal puncture was performed using an radiofrequency needle and an 8‐Fr–long sheath. The transseptal sheath was exchanged over a guidewire for a 15‐Fr steerable sheath. A 20‐mm circular mapping catheter was used for mapping all PVs before and after the cryoablation to confirm electrical isolation. A spiral mapping catheter was used to advance the cryoballoon into the PV for support and mapping the PV potentials. When the left PVs (LPVs) were initially targeted (LPV‐first group), atropine sulfate was always administered before ablation to anticipate bradycardia caused by a vagal reaction. 8 Following sealing at the PV antrum, complete occlusion was confirmed by injecting contrast medium. No 23‐mm cryoballoons were used in any cases. This was followed by a freeze cycle of 180 seconds. No additional applications were performed after the isolation. To avoid bilateral phrenic nerve injury, all cryoballoon applications were applied under diaphragmatic electromyography monitoring. 9 When the balloon nadir temperatures exceeded −60°C or if phrenic nerve injury was suspected, the application was interrupted. 10 As the standard deflation technique, the intraballoon shaft was manually straightened when the intraballoon temperature reached 15°C to rewrap the balloon before deflation. The procedural end point was defined as an electrical PVI verified by the 20‐mm circular mapping catheter.
Evaluation of the Circulatory Dynamics
PV occlusion without freezing
In 15 patients, the circulatory dynamics were evaluated during a 3‐minute simple PV occlusion without freezing and after deflation (at least >2 minutes). The tests were all performed at the right superior PV (RSPV) before the start of the ablation procedure.
Order of the targeted PVs
In 7 patients, the LPVs were initially targeted, followed by the right PVs (LPV‐first group). In the remaining 28 patients, the right PVs (RPVs) were initially targeted, followed by the LPVs (RPV‐first group).
In 20 patients, including 7 patients in the LPV‐first group, 0.5 mg atropine sulfate was given preprocedurally by intramuscular injection.
Freezing at the PV antrum without complete occlusion
In 10 patients, 2‐minute cryoapplications were applied at the left superior PV (LSPV) antrum without a complete LSPV occlusion, which was confirmed by a contrast injection, after the achievement of a PVI of all 4 PVs.
Evaluation of LV Function
In 5 additional patients, an intracardiac echocardiography probe was placed in the right ventricle for monitoring the LV wall motion in the longitudinal axis view throughout the procedure. The LV ejection fraction (LVEF) was measured by the Teichholz formula at specific time points: T0 min, T3 min, T15°C, Tnadir, and Trecovery. The approximated systemic vascular resistance index (SVRI) was also calculated from the heart rate, echocardiographic calculated systolic volume (shown as SV), mean BP (shown as mBP), and body surface area (shown as BSA) using the following formula: SVRI=80×mBP/(SV×heart rate×1000×BSA).
All statistical analyses were performed using R version 3.2.2 software (R Foundation for Statistical Computing). Continuous variables are reported as mean±SD and were compared using a Student t test. The estimated mean difference (EMD), with a 95% confidence interval (CI) followed by a P value, was described for every comparison of 2 groups. Differences between proportions were compared using Fisher exact tests. Differences in the mean values between ≥3 groups were evaluated by a Welch ANOVA. The changes in the circulatory parameters were compared by a paired t test for 1 group or a repeated ANOVA between classified groups. Because few data were available to predict the circulatory dynamics during freezing of a specific organ in a living body, we performed an exploratory calculation. A multiple regression analysis was performed (backward elimination method) to search for the factors affecting the SBP rise/drop from the possible candidates (clinical characteristics including age, sex, body mass index, left atrial volume, and in‐procedural parameters including baseline SBP, in‐balloon temperature, and target PV). All P values were 2‐sided, and statistical significance was established at a P<0.05. All P values obtained from the Student t test, Welch ANOVA, and multiple regression analyses were verified by permutation tests.
The patient characteristics are shown in Table 1. In all patients, 4 PVs were successfully isolated by a single cryoballoon application. Of 140 cryoballoon applications, 15 were interrupted during 3‐minute freezing. The remaining 125 applications (33 LSPVs, 33 left inferior PVs, 28 RSPVs, and 31 right inferior PVs) in which 3‐minute freezing was applied without any interruption were further analyzed. Twenty‐eight (22.4%) of 125 freezes were applied during atrial fibrillation. The mean nadir in‐balloon temperature during the freezing phase was −51.4±7.0°C, and it significantly differed among the 4 PVs (−51.8±4.5°C in the LSPV, −47.4±4.0°C in the left inferior PV, −55.3±4.1°C in the RSPV, and −53.3±5.9°C in the right inferior PV, P<0.001). The mean interval between T3 min to T15°C was 39.9 seconds, and the interval differed significantly among the 4 PVs (Table 2).
Table 1. Clinical Characteristics of the Patients
BMI indicates body mass index BSA, body surface area LAD, left atrial diameter LAV, left atrial volume LVDd, left ventricular diastolic diameter LVEF, left ventricular ejection fraction.
Table 2. Changes in the Circulatory Dynamics in All 4 Pulmonary Veins
HR indicates heart rate LIPV, left inferior pulmonary vein LSPV, left superior pulmonary vein RIPV, right inferior pulmonary vein RSPV, right superior pulmonary vein SBP, systolic blood pressure T0 min, starting points of freezing T15°C, time points at 15°C for the in‐balloon temperature during the thawing phase T3 min, end points of freezing Tnadir, time points at the nadir of the BP after balloon deflation Trecovery, time points during recovery of blood pressure at the baseline level.
Circulatory Dynamics During the Freezing Phase
All SBP and heart rate data are plotted in Figure 1 individually for the 4 PVs. Of 125 PVs, the SBP increased from 138.7±28.0 to 148.0±27.2 mm Hg during the 3‐minute freezing phase (EMD: 9.3 [95% CI, 6.7–11.8] P<0.001). The time‐course pattern of SBP was similar among the 4 PVs (P=0.11 Figure 2A) however, the magnitude of SBP rise differed significantly among the 4 PVs (P=0.031 Table 2) and was greater in LPVs than RPVs (12.0±15.7 versus 6.3±12.4 mm Hg EMD: 5.7 [95% CI, 0.8–10.7] P=0.026). SBP reached a plateau at T1 min in the RPVs but continued to increase during the entire 3‐minute freezing phase in the LPVs. A multiple regression analysis revealed that LPVs (P=0.008) and lower SBP at T0 min (P<0.001) correlated with greater magnitude of SBP rise. The change in heart rate was analyzed in 97 applications (25 LSPVs, 26 left inferior PVs, 23 RSPVs, and 23 right inferior PVs) in which sinus rhythm was maintained throughout the application. The heart rate significantly increased from 61.9±12.2 to 67.7±11.7 beats/min during the freezing phase at the RSPV (EMD: −4.3 [95% CI, 0.5–8.1] P=0.028) but did not significantly increase at the remaining 3 PVs (Figure 2B). This increase was observed during the first 1 minute of the freezing phase. The range of the distribution of SBP rise in the 4 PVs is described in Figure 3A.
Figure 1. All data plots of the transition in SBP and HR during the freezing and thawing phases in the 4 pulmonary veins. HR indicates heart rate LIPV , left inferior pulmonary vein LSPV , left superior pulmonary vein RIPV , right inferior pulmonary vein RSPV , right superior pulmonary vein SBP , systolic blood pressure T0min, starting points of freezing T1min, 1 minute from T0min T15°C, time points at 15°C for the in‐balloon temperature during the thawing phase T2min, 2 minutes from T0min T3min, end points of freezing Tnadir, time points at the nadir of the BP after balloon deflation.
Figure 2. A transition of the systolic blood pressure (SBP) and heart rate (HR) during the freezing and thawing phases in the 4 pulmonary veins (PVs). A, The SBP rose during the freezing phase and recovered to the baseline level during the initial thawing phase, followed by a sharp drop after T15°C (time point at 15°C for the in‐balloon temperature during the thawing phase). B, HR increased during the initial freezing phase at the right superior PV but did not at the remaining 3 PV s. LI indicates left inferior LS, left superior RI, right inferior RS , right superior T0min, starting points of freezing T1min, 1 minute from T0min T2min, 2 minutes from T0min T3min, end points of freezing Tnadir, time points at the nadir of the BP after balloon deflation Trecovery, time points during recovery of blood pressure at the baseline level.
Figure 3. A, Percentage of applications with an SBP rise during the freezing phase. B, Percentage of applications with an SBP drop during the thawing phase. SBP indicates systolic blood pressure. LIPV , left inferior pulmonary vein LSPV , left superior pulmonary vein RIPV , right inferior pulmonary vein RSPV , right superior pulmonary vein T0min, starting points of freezing T1min, 1 minute from T0min T2min, 2 minutes from T0min T3min, end points of freezing.
Circulatory Dynamics During the Thawing Phase
During the thawing phase following the 3‐minute freezing, the SBP gradually decreased until the manual stretch of the cryoballoon (at T15°C) and rapidly dropped to the nadir thereafter (from 136.3±26.0 mm Hg at T15°C to 95.0±17.9 mm Hg at Tnadir EMD: 41.3 [95% CI, 38.5–44.1] P<0.001 Figure 2A). The mean interval from T15°C to Tnadir was 21.0±8.0 seconds. In the multiple regression analysis, higher SBP at T0 min (P<0.001), LPVs (P=0.017), lower nadir balloon temperature (P=0.027), and female sex (P=0.045) significantly correlated with greater magnitude of SBP drop. In contrast, heart rate did not significantly change during the thawing phase (from 68.9±10.3 beats/min at T15°C to 68.9±13.5 beats/min at Tnadir EMD: 0 [95% CI, −1.8 to 1.8] P=1.000 Figure 2B). The magnitude of the SBP drop (P=0.011) and the interval between T15°C and Tnadir significantly differed (P=0.042), but the interval between Tnadir and Trecovery was similar among the 4 PVs (P=0.614 Table 2). The range in the distribution of SBP drop in the 4 PVs is described in Figure 3B.
Impact of PV Occlusions Without Freezing
A 3‐minute PV occlusion without freezing resulted in no BP change during the 3‐minute occlusion phase (127.1±30.7 versus 126.3±29.4 mm Hg EMD: 0.9 [95% CI, −2.6 to 4.4] P=0.604) and after balloon deflation. Consequently, the magnitude of SBP change was significantly greater during occlusion (7.8±11.7 versus −0.9±6.3 mm Hg EMD: 8.6 [95% CI, 2.3–14.9] P=0.012) and after deflation using the standard cryoballoon application than during PV occlusion without freezing (Figure 4A).
Figure 4. A, A simple pulmonary vein ( PV) occlusion without freezing did not result in any systolic blood pressure ( SBP) change during 3‐minute occlusion or after deflation, which significantly differed from freezing with a PV occlusion. The right figure shows the mean value in each group. B, Nonoccluded freezing at the PV antrum resulted in a similar SBP rise during the freezing phase but a significantly smaller magnitude of the SBP drop during the thawing phase compared with freezing with a PV occlusion. The right figure shows the mean value in each group. T0min, starting points of freezing T1min, 1 minute from T0min T15°C, time points at 15°C for the in‐balloon temperature during the thawing phase T2min, 2 minutes from T0min T3min, end points of freezing Tnadir, time points at the nadir of the BP after balloon deflation.
Impact of the Order of Targeted PVs
The order of the targeted PVs did not significantly affect the magnitude of SBP rise during the freezing phase (RPV‐first versus LPV‐first: 9.2±14.4 versus 9.6±14.9 EMD: 0.4 [95% CI, −6.0 to 6.7] P=0.909 Figure 5A) or of SBP drop during the thawing phase (RPV‐first versus LPV‐first: −40.5±15.7 versus −44.1±16.0 mm Hg EMD: 3.6 [95% CI, −3.3 to 10.5] P=0.305 Figure 5B). The results were similar for all 4 individual PVs.
Figure 5. Effect of atropine and the order of the targeted pulmonary veins ( PV s) on systolic blood pressure ( SBP ) change. The order of the targeted PV s did not significantly affect the SBP rise (A) or drop (B). Administration of atropine did not significantly affect SBP rise (C) and drop (D). LPV indicates left pulmonary vein RPV, right pulmonary vein.
Impact of a Preprocedural Atropine Administration
Administration of atropine did not affect the magnitude of SBP rise during the freezing phase (with versus without atropine: 8.8±14.2 versus 9.8±14.8 mm Hg EMD: 1.0 [95% CI, −4.2 to 6.1] P=0.705 Figure 5C) or of SBP drop during the thawing phase (with versus without atropine: −43.2±15.6 versus −39.0±15.8 mm Hg EMD: 4.2 [95% CI, −1.4 to 9.8] P=0.139 Figure 5D). The results were similar among the 4 individual PVs.
Impact of Freezing at the PV Antrum Without an Occlusion
The magnitude of SBP rise during the freezing phase (7.9±5.6 versus 11.1±18.3 mm Hg EMD: 3.2 [95% CI, −8.7 to 15.1] P=0.588) and of SBP decline from T2 min (nonoccluded freezing) or T3 min (occluded freezing) to T15°C (−14.2±15.7 versus −10.0±12.9 EMD: 4.2 [95% CI, −5.7 to 14.1] P=0.392) was similar for nonoccluded and occluded freezes. However, the magnitude of the SBP drop from T15°C to Tnadir was significantly smaller in the nonoccluded freezes than in occluded freezes (−17.2±15.6 versus −48.3±13.2 mm Hg EMD: 31.1 [95% CI, 21.1–41.2] P<0.001 Figure 4B). The intervals between T15°C and Tnadir (11.8±9.3 versus 23.3±8.1 seconds EMD: 11.6 [95% CI, 5.2–17.9] P<0.001) and from Tnadir to Trecovery (18.9±8.9 versus 32.8±13.4 seconds EMD: 14.0 [95% CI, 3.8–24.2] P<0.001) were significantly shorter in the nonoccluded than the occluded freezes.
LV wall motion was evaluated during 20 freezes in 5 patients. Although there was no significant change in LVEF (T0 min versus T3 min: 63.3±9.9 versus 62.3±9.3% EMD: 0.9 [95% CI, −2.3 to 4.2] P=0.557) and SVRI (T0 min versus T3 min: 3487±1324 versus 3905±1510 dynes‐sec/cm 2 per m 2 EMD: 418 [95% CI, −181 to 1017] P=0.161) during the freezing phase, a significant increase in LVEF (T15°C versus Tnadir: 66.8±8.1% versus 79.3±6.7% EMD: 12.4 [95% CI, 8.7–16.1] P<0.001) and a decrease in SVRI (T15°C versus Tnadir: 2667±1024 versus 1937±513 dynes‐sec/cm 2 per m 2 EMD: 730 [95% CI, 316–1144] P=0.002) were observed during the thawing phase (Figure 6). These changes were observed following visualization of a hyperechoic bubble‐like shadow in the LV just after balloon deflation, and then the time‐course paralleled that of the change in the SBP.
Figure 6. A, Transition of the LVEF during and after the cryoapplication. B, Transition of the SVRI during and after the cryoapplication. LVEF indicates left ventricular ejection fraction SVRI , systemic vascular resistance index. T0min, starting points of freezing T15°C, time points at 15°C for the in‐balloon temperature during the thawing phase T3min, end points of freezing Tnadir, time points at the nadir of the BP after balloon deflation Trecovery, time points during recovery of blood pressure at the baseline level.
To the best of our knowledge, this report is the first to investigate circulatory dynamics during CBPVI. We found (1) that SBP tended to increase during the freezing phase and to recover to the baseline level during the initial thawing phase (T3 min to T15°C) and then dropped sharply following balloon deflation (T15°C to Tnadir), (2) that a PV occlusion alone did not result in any BP change, (3) that administration of atropine and the order of the targeted PVs did not affect this change, (4) that freezing at the PV antrum without a PV occlusion seemed to result in an SBP rise during the freezing phase but the magnitude of the BP drop (T15°C to Tnadir) during the thawing phase tended to be significantly smaller than that for freezing with a PV occlusion, and (5) that the time‐courses of the increase in LVEF and the decrease in SVRI appeared to parallel those of SBP drop during the thawing phase. All P values calculated by the Student t test, Welch ANOVA, and multiple regression analyses were compatible with those from the permutation tests.
Circulatory Dynamics During Cryoballoon Ablation
The present study initially showed a rise in BP during the freezing phase, recovery of BP during the initial thawing phase, and a sharp drop in BP after releasing PV occlusion. Prior studies showed that cryoablation at the LSPV could result in bradycardia due to a vagal response during the thawing phase, 11 and this reaction disappeared with a preceding RSPV ablation. 8 In the present study, the order of the targeted PVs and vagal denervation by the administration of atropine did not have an impact on BP change, suggesting that the association of ganglionated plexi and the autonomic nervous system was limited. Simple PV occlusion without freezing did not result in any BP change, suggesting that mechanical stimulation (at the PV antrum) and damming of the blood flow in the PV might not have been responsible for this response. On the contrary, a nonoccluded tissue freeze tended to result in similar BP elevation during the freezing phase and smaller BP drop after balloon deflation than for occluded freezes. This result, together with the observation of a BP rise in all 4 PVs, suggests that freezing of atrial tissue might have resulted in BP elevation. Indeed, the elevated BP recovered to the baseline level during the initial thawing phase (T3 min to T15°C) before balloon deflation. The increase in heart rate during the initial freezing phase at the RSPV could be explained by the destruction of the efferent vagal neurons from the anterior right ganglionated plexus projecting onto the sinoatrial node by RSPV ablation. 8 , 12
In contrast, a sharp BP drop was always initiated just after stretching of the balloon shaft between T15°C and balloon deflation, which was the timing of releasing the PV occlusion. That suggested that acute warming of the iced atrial tissue and leakage of the dammed chilled blood inside the PV appeared to be associated with the sharp BP drop. Because freezing without an occlusion tended to lack a deep nadir, the latter seemed to be the most likely mechanism for the sharp BP drop. Our study further clarified that the time‐course of the sharp BP drop tended to parallel that of the decrease in SVRI and the increase in LVEF the mean interval from T15°C to Tnadir was 21 seconds. Moreover, the balloon nadir temperature during freezing tended to correlate with the magnitude of the sharp BP drop, and the only predictor of the interval from T15°C to Tnadir was the magnitude of the BP drop. These data support the hypothesis that the chilled blood flow released from the occluded PV might have affected the peripheral circulation, and the magnitude of the BP drop depended on the amount of chilled blood flow. The slightly different magnitude of the BP change among the 4 PVs might be explained by the different balloon‐tissue contact areas, different nadir balloon temperatures, and different amounts of dammed chilled blood inside the occluded PV, given anatomic variations. The not‐so‐negligible SBP decline in nonoccluded freezing could suggest that rapid thawing of the myocardial tissue also might have played some role in BP decrease after balloon deflation. Another possible explanation of circulatory alteration was the shunting of blood due to vasoconstriction, change in the preload of the left atrium due to the occlusion of one of the PVs, a change in the preload via the hepatic venous system by phrenic nerve pacing, and the impact on other organs via cold stimulus or humoral factors like cytokines.
Few data are available reporting the effect of the chilled blood flow and direct cryothermal stimulation of the circulatory system in humans. This might be caused by cooling peripheral receptors or specifically stimulating organs such as the brain. Ohta et al reported that brain hypothermia established by extracorporeal circulation decreased arterial pressure in sedated dogs. 13 Further investigation is necessary to clarify the fundamental physiology. This report may contribute to understanding some aspects of the reaction to such stimulation as well as the nature of the circulatory dynamics during the CBPVI.
First, this study was a single‐center retrospective study. Second, the number of participants was limited, especially in the echocardiographic study. The heart rate analysis was exclusively performed in 78% of the applications during which sinus rhythm was maintained however, the results were consistent throughout the study population. Third, some potential contributing factors were not evaluated. Pain during the procedure might have affected circulatory change, although patients with pain were not included in the present study. We did not investigate any biomarkers such as catecholamines or cytokines. Fourth, the full cardiac hemodynamics were not evaluated and, the SVRI was calculated by an approximate formula.
In second‐generation CBPVI, BP tended to increase significantly during the freezing phase and drop sharply after release of the occlusion during the thawing phase. Our study results suggested that direct cryothermal stimulation of the atrial tissue might result in a BP rise during freezing, whereas a decrease in peripheral vascular resistance by circulating chilled blood might be the main mechanism of the sharp BP drop during the thawing phase.