function in a needle holder compared to a conventional needle holder in a pelvitrainer model

Tibor Andrea Zwimpfer^1,2, Bernhard Fellmann-Fischer², Robert Oehler³, Andreas Schötzau², André B. Kind²

¹Gynecological Clinic, Cantonal Hospital Olten, Olten, Switzerland; ²Gynecological Clinic, University Hospital of Basel, Basel, Switzerland;

³Medical Centre Biel, MZBCMB, Biel, Switzerland

Contributions: (I) Conception and design: TA Zwimpfer, B Fellmann-Fischer; (II) Administrative support: AB Kind, R Oehler, B Fellmann-Fischer; (III) Provision of study materials or patients: R Oehler, B Fellmann-Fischer; (IV) Collection and assembly of data: TA Zwimpfer; (V) Data analysis and interpretation: TA Zwimpfer, A Schötzau; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Background: Needle-loading is the most challenging step in laparoscopic suturing. The rotational needle holder (RNH) is a handheld laparoscopic instrument, which increases the degree of freedom relative to the needle by the rotation of the instrument’s tip. By moving the jaws of the needle holder with a clamped needle a rotational movement is achieved, which allows the needle to be adjusted. The aim of this study was to compare the RNH with the conventional needle holder (CNH) in a pelvitrainer model.

Methods: Twenty medical students with no prior laparoscopic experience performed four standardized exercises. The participants were randomly divided into two groups. Group RC performed the suture exercises using the RNH first and the CNH thereafter. Group CR performed these tasks in the reverse sequence. The number of errors, precision, and time taken were measured. After each task, the students had to answer specific questions about the methods used.

Results: The 270-degree angle task was performed with significantly fewer mistakes (P=0.003) and more rapidly using the RNH in the second period (P=0.008). The students performed the 180-degree angle task more rapidly during the second run, regardless of which technique was used (P=0.042). Neither of the other two tasks showed any significant difference. The precision was very good overall, and in all four tasks it was superior when the rotational method was used, although no significant difference was observed. The students made more mistakes when using the CNH. The questionnaire confirmed a clear advantage for the RNH, but the participants expressed concerns about its counterintuitive handling.

Conclusions: The advantages of the RNH were only partially confirmed. For some angles, the rotational function was beneficial. However, this value was decreased for participants with greater experience and superior laparoscopic skills. More intuitive control of the rotation function may potentially offer an advantage in terms of speed and may be associated with a steeper learning curve.

Keywords: Laparoscopy; rotational needle holder (RNH); degree of freedom; pelvitrainer

Received: 17 October 2019; Accepted: 07 November 2019; Published: 15 January 2020. doi: 10.21037/ls.2019.11.03

Introduction

Laparoscopic surgery is an increasingly favoured technique among surgeons. In addition to its cosmetic benefits, it is associated with reduced postoperative infection rates,

shorter hospitalization periods, and minimal loss of blood, compared to open surgery (1-3). However, laparoscopic surgery is generally longer in duration, and the operating surgeons tire more rapidly (3,4). Robotic-assisted

 

Figure 1 By triggering the rotary knob the clamped needle can be adjusted in situ.

Figure 2 An illustration of the whole (A) rotational needle holder and (B) the conventional needle holder.

laparoscopy offers the potential to mitigate these drawbacks, by improving the instruments’ range of motion and ergonomic qualities (5,6). In general, the learning curve of conventional laparoscopic surgery is relatively flat compared to open surgery or robotic-assisted laparoscopy (7-12). The main reasons for this are the commonly used two- dimensional imaging and the limited degrees of freedom available (13,14). While evidence for the benefits of three- dimensional imaging has already been presented (13,15-19), the practical benefits of laparoscopic instruments, which can perform three-dimensional movements, remain to be verified (20-24). Theoretically, the positive advantage of an added feature is clear. We may cite, for example, the flexible endoscope in single-incision multiport laparoscopic surgery, or the Kymerax^© precision-drive articulating surgical system, which is advantageous in certain contexts, such as suturing at difficult angles and cutting along complex structures (22,25). Furthermore, the minimally invasive manipulator offers a cost-effective, non-robotic alternative for endoscopy (26). The positioning of the needle is one of the main difficulties in laparoscopic suturing (27,28). While the simplification of this surgical step would be

Laparoscopic Surgery, 2020

 welcomed, the question as to whether its theoretical benefits would be substantiated in practice remains to be answered. We selected a hand-operated needle holder with an additional rotation feature from Storz. Using a rotary control on the handle, it is possible to move the jaws and, consequently, the fixed needle can be rotated and positioned as appropriate to the circumstances (tfigure 1). This study aimed to compare the rotational needle holder (RNH) from Storz with a conventional needle holder (CNH) from Storz (tfigure 2A,B). For analysis of the operating devices, a simulation was used. The pelvitrainer has been proven effective in professional training, as well as in the evaluation of laparoscopic instruments (8,22). Using four simple tasks, we aimed to determine whether the RNH has advantages in terms of time, error rate, and precision. The four exercises tested suture competence at different angles in the direction of view. Furthermore, the participants’ subjective perceptions of the were determined using a questionnaire.

Study population

Due to the explorative nature of the evaluation, no setup was required for a formal number of cases. The study represents an initial evaluation of the RNH. A total of 23 participants were selected, all of whom were medical students at the University of Basel who had no prior laparoscopic experience. No left-handed students were recruited for the study. The ethics committee of Northwest and Central Switzerland (EKNZ) confirmed that the project is not defined as a research project according to Human Research Act Art. 2; therefore, IRB approval and written consent were not required.

 

Study design

 

All participants were assigned to two different groups. Group RC performed each task using the RNH first and subsequently using the CNH, while Group CR performed the tasks in reverse order. To enable the participants to become accustomed to laparoscopic conditions, one standardized identical instructional task was performed using the RNH and CNH. Subsequently, four tasks were performed using the RNH and CNH. The time taken, the overall precision, and the number of mistakes were recorded. After they had finished each exercise, the participants completed a questionnaire.

 

Instrument setup

 

A pelvitrainer with anatomical conditions was used for all exercises. It was full-featured with a 24-inch monitor and a 300W Xenon light source. For the imaging modality, a camera control unit with a capacity for recording videos of up to 720p resolution was installed. Two access points equivalent to the lateral ancillary trocar entry points were used for the needle holders. For the left hand, a CNH from Storz was available. The right hand had alternating access to the CNH and a needle holder with a normal up-righting function from Storz. The only variable that changed during testing was the needle holder (i.e., RNH or CNH).

 

 

Instruction

 

Initially, both needle holders were introduced and their functions explained. Thereafter, before each exercise, an introduction video was shown once to guarantee the reproducibility of the instruction. No questions were allowed. The participants were instructed to find the optimum combination in terms of precision, time, and errors. Precision and minimization of error are of utmost importance; however, efficiency is also crucial. To accustom the participants to the instruments and the pelvitrainer, an adaption task was performed in which the participants completed a simple task by grasping and fixating the needle, and attempting to form stitches.

 

 

Exercises

 

Tasks 1–4 were all suture tasks with the same fundamental principle. Each task consisted of three stitches from left to right or top down with a 20-cm long Variosoft 0 thread with a GS22 needle (Medtronic, Switzerland, Münchenbuchsee). The stitches were marked by two dots separated by a distance of 10 mm on silicone pads measuring 9×9 cm². The pads had a consistency similar to that of a uterus. The individual tasks differed in one crucial aspect, namely, the angle in the direction of view. In the first exercise, the angle was 315° in the direction of view and horizontal to the ground; in the second, the angle was 270° (horizontal); in the third, the angle was 0° (horizontal); and the angle in the fourth exercise was 180° (vertically to the ground) (tfigure 3). Each task was performed once with the CNH and RNH. Three different study parameters were measured: time taken, errors, and precision. Time was measured in minutes and seconds, and the maximum time allowed per

exercise was 12 minutes. If the time limit was reached, the participant was obliged to cease work on the exercise instantly, but was not excluded. If the needle had been removed from the pad before the stitch was finished, this amounted to an error. Dropping the needle as part of the learning process did not count as a mistake. Precision was determined by measuring the deviation from the dot to the insertion and extraction points from the tip of the needle in millimetres. After each task, the participants were asked ten questions about their subjective perceptions of the exercise.

Questionnaire

 

The questionnaire comprised ten questions. The participants were asked the first five questions after each sequence of tasks:

• How would you describe the task`s difficulty level?
• Did you familiarize yourself with the instruments

while performing the task?

• Did you familiarize yourself with the rotation

function while performing the task?

• Did you perceive either of the needle holders to have

any advantages over the other?

• Did you lose concentration at any point?

The participants answered the remaining five questions

after they had used both devices to complete the exercises:

• Did the RNH simplify the tasks?
• Did the advantages (if applicable) of the RNH

decrease over time?

• Was the rotational function intuitive?
• Would a neutral position of the rotational function

improve its performance?

• Is there any other potential for improvement?

 

Statistical analysis

An explorative statistical analysis of the primary and secondary endpoints was carried out. To this end, a statistical evaluation of the 2×2 crossover was conducted using a linear mixed-effects model. The results were calculated as the average difference between the rotational and conventional techniques. Moreover, to adjust for a learning and sequence effect, a period and sequence effect was added to the design. The mean difference between time, precision, and errors between methods were evaluated with a 95% confidence interval and the corresponding P value. The questionnaire items were

Figure 3 Tasks 1–4 with the angle in direction of view.

 

 

 

compared using McNemar’s test or the chi-squared test, as appropriate. A P value <0.05 was considered to be significant. All evaluations were performed using the statistical software R version 3.1.1 (29).

 

 

Results

 

Task 1 was performed at a 315-degree horizontal angle. In terms of time, neither the methods nor comparison of the sequences and periods showed any significant difference (tfigure 4). The same was true of the parameters’ precision and the occurrence of mistakes (tfigures 5,6) (Table 1).

Task 2 was performed at a 270-degree horizontal angle: when utilizing the RNH, the participants made significantly fewer mistakes than when they used the CNH (P=0.003). This could not be confirmed in terms of difference between the sequences (P=0.961) or periods (P=0.200) (tfigure 4). No apparent improvement in precision was observed (tfigure 5). The participants finished the second period significantly

 

faster (P=0.008); however, when compared with respect to the methods and sequences, the time difference was not significant (tfigure 6) (Table 2).

Task 3 was performed at a 0-degree horizontal angle: the students could not reduce the time required for the task by using the RNH (tfigure 4). Precision and incidence of errors were not significantly improved by either method, period, or sequence (tfigures 4-6; Table 3).

Task 4 was performed at an 180-degree vertical angle: regarding the time required for task 4, no significant difference was observed between the methods (P=0.585) or sequences (P=0.336). It was clear that the students performed the task more efficiently during the second run, regardless of which technique was used (P=0.042) (tfigure 4) (Table 4). No significant differences were observed with regard to precision or the incidence of errors. Neither was any significant difference observed between the exercises overall with respect to time taken, incidence of errors, or precision for either method.

 

Figure 4 Analysis of time. C, conventional needle holder; R,

rotational needle holder; 1–4= tasks.

Figure 6 Analysis of mistakes. C, conventional needle holder; R,

rotational needle holder; 1–4= tasks.

seven out of ten (1= easiest and 10= most difficult), except for task number 3, which was the easiest with an average rating of five out of ten. More than 65% of the participants had the impression that the RNH was advantageous in the first three exercises, and 87% of the participants expressed the same opinion in relation to task 2. Nevertheless, for the fourth challenge the majority saw no benefit. Less than 50% of the participants lost concentration during the practice, and 69.6% had the impression that the RNH was of benefit to them in performing the exercises, but that this effect decreased as they progressed through the tasks. The handling of the RNH was evaluated as counterintuitive by 69.6% of the students. All but one of the participants considered that a neutral position for the rotation function would be an advantage, and the majority thought that there was room for improvement in terms of the RNH’s manipulation.

 

Figure 5 Analysis of precision. C, conventional needle holder; R,

rotational needle holder; 1–4= tasks.

 

 

Questionnaire results

 

According to the questionnaire’s results, most participants became accustomed to the equipment and to the rotational function after the first task. The students evaluated the level of difficulty of the tasks, giving average ratings of six and

seven out of ten (1= easiest and 10= most difficult), except for task number 3, which was the easiest with an average rating of five out of ten. More than 65% of the participants had the impression that the RNH was advantageous in the first three exercises, and 87% of the participants expressed the same opinion in relation to task 2. Nevertheless, for the fourth challenge the majority saw no benefit. Less than 50% of the participants lost concentration during the practice, and 69.6% had the impression that the RNH was of benefit to them in performing the exercises, but that this effect decreased as they progressed through the tasks. The handling of the RNH was evaluated as counterintuitive by 69.6% of the students. All but one of the participants considered that a neutral position for the rotation function would be an advantage, and the majority thought that there was room for improvement in terms of the RNH’s manipulation.

 

 

Discussion

 

The purported benefits of the RNH are that it offers an improved learning curve and allows surgeons to work with greater speed, more accuracy, and fewer mistakes, resulting in a shorter operation time and cost reduction. In our study, the RNH increased the degrees of freedom relative to the needle. Because the results regarding the advantages and disadvantages of instruments with three-dimensional

 

 

Parameter	Contrast	Collation	Difference	Lower CL	Upper CL	P value
Time	CR-RC	Sequence	50.31	−63.42	164	0.368
	1-2	Period	9.186	−69.36	87.73	0.8102
	C-R	Method	−28.27	−106.8	50.27	0.4625
Precision	CR-RC	Sequence	0.09091	−1.576	1.758	0.9108
	1-2	Period	−0.1288	−0.8412	0.5836	0.7107
	C-R	Method	−0.03788	−0.7503	0.6745	0.913
Mistake	CR-RC	Sequence	0.553	−0.3547	1.461	0.219
	1-2	Period	0.6439	−0.1042	1.392	0.0879
	C-R	Method	0.1894	−0.5588	0.9375	0.6041

C, conventional needle holder; R, rotational needle holder; CR-RC, the sequence, first with the conventional followed by the rotational  needle holder vs. the sequence, first with the rotational followed by the conventional needle holder.

 

 

Table 2 Results exercise 2: mean difference of time, precision and mistakes and corresponding P value. This was analysed for the sequence, period and method

Parameter	Contrast	Collation	Difference	Lower CL	Upper CL	P value
Time	CR-RC	Sequence	78.17	−33.14	189.5	0.159
	1-2	Period	98.14	27.28	169	0.008959
	C-R	Method	35.86	−35	106.7	0.3045
Precision	CR-RC	Sequence	−0.2955	−2.291	1.7	0.7612
	1-2	Period	0.2576	−0.4142	0.9293	0.4341
	C-R	Method	0.07576	−0.596	0.7475	0.8168
Mistake	CR-RC	Sequence	0.02273	−0.9512	0.9966	0.9618
	1-2	Period	0.4318	−0.2482	1.112	0.2008
	C-R	Method	1.068	0.3882	1.748	0.003685

C, conventional needle holder; R, rotational needle holder; CR-RC, the sequence, first with the conventional followed by the rotational  needle holder vs. the sequence, first with the rotational followed by the conventional needle holder.

 

 

 

movement depend on the individual tool, we performed a randomized crossover study to validate the effectiveness of the RNH.

We anticipated that beginners in particular would benefit most from this technique, so in this study we chose participants who had no prior experience in laparoscopy. In principle, two techniques may be used to ensure the needle is at the appropriate angle in contact with the tissue: either the tissue is brought into the plane of the needle or the needle’s angle is adjusted with respect to the tissue. In our exercises, the latter procedure was necessary. We anticipated

that the CNH would offer a clear advantage for this exercise. However, this could be only partially confirmed on the basis of our results. The data presented in Table 2 demonstrate that the second exercise with an angle of 270° was performed with the RNH with significantly fewer mistakes, and in the second period, significantly faster. Moreover, task 4 was performed faster during the second run, regardless of which technique was used. Neither of the other two tasks showed any significant difference (Tables 1,3), and overall comparison of all exercises revealed no significant difference between the two methods.

 

 

Parameter	Contrast	Collation	Difference	Lower CL	Upper CL	P value
Time	CR-RC	Sequence	31.66	−31.67	94.99	0.3103
	1-2	Period	−30.08	−93.41	33.25	0.3346
	C-R	Method	−2.258	−65.59	61.07	0.9416
Precision	CR-RC	Sequence	0.6705	−0.2822	1.623	0.1581
	1-2	Period	0.2992	−0.3607	0.9592	0.3564
	C-R	Method	0.1174	−0.5426	0.7774	0.7151
Mistake	CR-RC	Sequence	−0.1061	−0.7627	0.5506	0.7403
	1-2	Period	−0.2273	−0.8839	0.4293	0.4796
	C-R	Method	0.2273	−0.4293	0.8839	0.4796

C, conventional needle holder; R, rotational needle holder; CR-RC, the sequence, first with the conventional followed by the rotational needle holder vs. the sequence, first with the rotational followed by the conventional needle holder.

 

 

Table 4 Results exercise 4: mean difference of time, precision and mistakes and corresponding P value. This was analysed for the sequence, period and method

Parameter	Contrast	Collation	Difference	Lower CL	Upper CL	P value
Time	CR-RC	Sequence	65.59	−73.1	204.3	0.3365
	1-2	Period	134.6	5.114	264.1	0.04233
	C-R	Method	−34.5	−164	94.97	0.5853
Precision	CR-RC	Sequence	0.5076	−0.8627	1.878	0.4497
	1-2	Period	0.6212	−0.5602	1.803	0.2865
	C-R	Method	0.7121	−0.4693	1.894	0.2238
Mistake	CR-RC	Sequence	−0.1061	−0.9271	0.715	0.7908
	1-2	Period	0.5455	−0.2756	1.367	0.1816
	C-R	Method	−0.5455	−1.367	0.2756	0.1816

C, conventional needle holder; R, rotational needle holder; CR-RC, the sequence, first with the conventional followed by the rotational  needle holder vs. the sequence, first with the rotational followed by the conventional needle holder.

 

For all tested exercises, the participants performed the second round more efficiently. This may be attributed to  a learning effect. To eliminate this bias, we conducted a crossover analysis. Additionally, the students improved their skills in tasks that included loading the needle on the needle holder, passing the needle through tissue, and manipulating the thread during suturing. Consequently, they performed each subsequent task more efficiently than the previous exercise. For the last exercise, which was more difficult, the participants needed more time (tfigure 1). This was confirmed by the questionnaire results, wherein most of the

participants reported that they became accustomed to the equipment after the first task and to the rotational function after the second task. Task 3 was rated easiest by most participants.

This study’s findings indicate that the RNH is superior to some extent, particularly for specific angles, but that this value is reduced for users with more experience and better laparoscopic skills. The results of the questionnaire supported this assessment and emphasized the counterintuitive handling of the RNH. Participants suggested that a neutral position for the rotation function

 

 

 

would be superior. Laparoscopy continues to develop, and new methods, such as robot-assisted laparoscopy, improve the learning curve by simplifying execution and using superior equipment, including instruments that offer enhanced three-dimensional views, or laparoscopic devices with more degrees of freedom (5). However, these methods are cost intensive, and the outcomes have yet to be proven superior (30,31). Another strategy is to design mechanisms aimed at simplifying operational steps. For example, the laparoscopic stapler and the coagulation cutting instrument have gained wide appeal (32,33). The RNH is also designed to simplify an operational step, namely loading the needle. This study provides a first assessment of the rotational method. We recommend that the RNH be improved through a more intuitive execution of the needle holder. Future research should focus on whether experts profit from the rotational function, and whether it is associated with any difference in tissue loading. Incorrect placement of a curved needle leads to difficulty in driving the needle and, consequently, tissue force is drastically increased, in turn raising the risk of tissue rupture (34,35).

Procedures that are performed low in the pelvis at difficult angles for suture, such as sacrocolpopexy, could potentially benefit from a RNH with another degree of freedom. Comparison of this added degree of freedom and the superior three-dimensional view offered by robot- assisted laparoscopy is recommended as a topic for future studies.

 

 

Acknowledgments

 

None.

 

 

Footnote

 

Conflicts of Interest: The authors have no conflicts of interest

to declare.

 

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The ethics committee of Northwest and Central Switzerland (EKNZ) confirmed that the project is not defined as a research project according to Human Research Act Art. 2; therefore, IRB approval and written consent were not required.

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Andrea Ruzzenente, Laura Alaimo, Simone Conci, Fabio Bagante, Tommaso Campagnaro, Andrea Ciangherotti, Alfredo Guglielmi

General and Hepatobiliary Surgery, Department of Surgery, “G.B. Rossi” University Hospital, School of Medicine, University of Verona, Verona, Italy Contributions: (I) Conception and design: A Ruzzenente, L Alaimo; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: S Conci, F Bagante; (V) Data analysis and interpretation: T Campagnaro, A Ciangherotti; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Andrea Ruzzenente, MD. General and Hepatobiliary Surgery, Department of Surgery, School of Medicine, University of Verona, “G.B. Rossi” University Hospital, Piazzale L. Scuro, 10, 37134, Verona, Italy. Email: andrea.ruzzenente@univr.it.

Abstract: Caroli’s disease is a rare hepatobiliary disorder characterized by malformations of the intrahepatic medium and large bile ducts, resulting in non-obstructive ductal dilatation, with focal or multifocal segmental involvement of the liver. It is often associated with hepatolithiasis and acute cholangitis. The curative treatment of the localized form is surgical liver resection involving any pathologic bile duct tissue, in order to avoid the development of recurrent disease and life-threatening complications. We have reviewed the literature during the period 2005–2018 concerning the surgical treatment of Caroli’s disease (including 243 liver resections), in order to evaluate the impact of laparoscopic surgery, its technical aspects, feasibility, safety, short- and long-term outcomes. Only 6 reports describing 16 cases available in the most recent literature (years 2009–2018) reported laparoscopic liver resections (7 left lateral hepatic sectionectomies, 7 left hepatectomies, 1 segmentectomy, 1 right anterior sectionectomy). Only 1 conversion to open surgery and 1 complication (a fluid collection) treated conservatively were described. Few data have been reported about the long-term post-operative follow-up. Caroli’s disease is a rare condition with variable clinical complexity, due to the extension of the disease, the localization of pathological bile ducts and the presence of complications. Radical surgery is the treatment of choice for localized disease and in these cases minimally invasive liver resection can have an important therapeutic role, particularly for left located Caroli’s disease. Minimally invasive approach to Caroli’s disease requires high expertise in liver surgery and in complex biliary procedures. Data of the literature are still lacking in long term results and more studies are necessary to confirm the short and long-term results.

Keywords: Caroli’s disease (CD); laparoscopic liver resection; hepatolithiasis; hepatic monolobar disease; laparoscopic hepatectomy

 

Received: 28 September 2019; Accepted: 24 October 2019; Published: 15 January 2020. doi: 10.21037/ls.2019.11.01

Introduction

Caroli’s disease (CD) belongs to the group of congenital intrahepatic bile duct dilatation diseases (IHBDD). CD is a rare hepatobiliary disorder characterized by malformations of the intrahepatic medium and larger bile ducts without pancreatic biliary junction dysfunction, resulting in non-obstructive ductal dilatation, with focal or multifocal segmental involvement of the liver (1). It was

exhaustively described for the first time in 1958, by the French gastroenterologist Jacques Caroli, who attempted its classification and defined this condition as a congenital malformation of the intrahepatic bile ducts, characterized by mono- or bilobar segmental polycystic dilatation (2). This disorder induces biliary stasis, leading to unspecific related symptoms and complications, mainly represented by lithiasis, cholangitis, localized or systemic infections, secondary biliary cirrhosis and bile duct cancers.                                                                                                                    

The CD is a rare disorder, with a prevalence of approximate less than one in 1,000,000 inhabitants, more frequently affecting female with a ratio male-female of 1:1,8. The onset of the disease in 80% of cases is before 30 years of age (3). There are multiple genetic and acquired factors supposed to contribute to the pathogenetic mechanisms of CD. Even if the specific etiology of this disorder is still unknown, many studies have suggested that the more frequent mode of inheritance is autosomal recessive, in particular in association with the polycystic kidney disease. The supposed cytogenetic mechanism could be an unbalanced translocation between chromosome 3 and 8, producing in particular the loss of distal 3p and/or gain of 8q. Other embryological events could be involved in the etiopathogenesis of CD, resulting in an abnormal remodeling of bile ducts (3). The abnormal or incomplete development of embryonic biliary ductal plate can be localized or involve the entire intrahepatic biliary tree (3). Jacques Caroli reported the two forms of the disease: simple form is characterized by localized cystic dilatation of the intrahepatic bile ducts without other concomitant conditions, and the complex form termed Caroli’s syndrome is associated with coexisting congenital intrahepatic fibrosis and/or even cirrhosis, portal hypertension, renal cystic congenital disease (4).

The conditions associated to CD affecting kidneys are the autosomal polycystic kidney disease, both the dominant and recessive forms (ARPKD), medullary sponge kidney, medullary cystic disease. In those conditions, renal tubular ectasia or cystic lesions of kidney are similar to the lesions of the bile ducts. The common pathogenetic factor is the recessive mutation of PKHD1 gene (5). This gene is expressed in the fetal biliary system and contributes to the bile duct embryogenesis. In patients with ARPKD or other similar kidney diseases the presence of CD should be suspected and the application of proper imaging techniques is encouraged, allowing early detection and prevention of severe complications. In patients with ARPKD, CD can be found in 30 % of cases (6).

Clinical presentation

Even though the disease can be asymptomatic, the clinical presentation usually occurs within the first three decades of life. There is not a specific clinical scenario of presentation. The most frequent symptoms are: recurrent fever, cholestasis, jaundice, pruritus, pancreatitis, weight loss, epigastrium and right hypochondrium pain.

Recurrent acute cholangitis is the most frequent presentation of the disease that can reduce significantly the quality of life of these patients. The expected survival for patients with recurrent cholangitis is 5–10 years (5).

Complications of the disease are: liver abscesses, intra- or extra-hepatic lithiasis and cholangiocarcinoma, with a frequency of 2.5–16% of patients. Therefore, the risk of developing this malignancy is estimated to be 100-fold increase in CD (1,3). The proposed factors promoting carcinogenesis are chronic inflammation and the prolonged exposure to carcinogenetic substances contained in the bile (1). This condition could cause a chronic injury to liver function, secondary biliary cirrhosis and the clinical consequences of portal hypertension, as reported in Caroli’s syndrome. Blood tests usually show elevation of alkaline phosphatase, direct bilirubin, leukocytosis and, in more severe cases, liver function impairment (3). In patients with Caroli’s syndrome thrombocytopenia and leucopenia are frequently present due to the presence of portal hypertension (4). Associated kidney disease occurs in 60% of the cases with different degree of function impairment. Other associated pathologic findings are: portal vein cavernomatosis, pulmonary hypertension with arteriovenous fistula, pulmonary fibrosis, congenital heart disease, Joubert’s syndrome, amyloidosis, Laurence-Moon Beidl syndrome and neurofibromatosis (5,7).

Diagnosis and imaging

The diagnosis of CD can be very challenging giving clinical presentation with unspecific findings and symptoms (8). When asymptomatic the diagnosis can be incidental, based on blood tests and imaging findings (1). The differential diagnosis between CD and advanced cases of intrahepatic biliary stone disorder can be particularly difficult. Nevertheless, in case of choledocholithiasis without gallbladder stones the presence of CD should be suspected and properly investigated (3,8).

Characteristic imaging findings of CD are cystic dilatation in continuity with the biliary tree. The more frequently utilized tools are: ultrasonography (US), computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP). In addition, other diagnostic methods are: endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC), Technetium TC 99m colloid sulfur and DISIDA scintigraphy.

In particular, common finding of US and CT are liver cysts, intrahepatic lithiasis and portal radicles surrounded by

dilated intrahepatic bile ducts (9). MRCP is a non-invasive diagnostic tool that can precisely visualize the entire biliary tree and is the preferred detection method for CD. Commonly, the MRCP pathognomonic radiological finding is the enhancing fibrovascular bundles along the dilated bile ducts (“central dot sign”) (3).

ERCP and PTC allow an accurate diagnosis, but the incidence of serious complications such as sepsis, bile leakage, bleeding and death can reach 3% of procedures and for this reason are suggested only with therapeutic intent.

Liver biopsy can be useful providing information about the presence of fibrotic changes or cirrhosis, epithelial dysplasia and cancer (8).

Finally, the conclusive diagnosis is achieved through the evidence of radiologic “central dot sign”, saccular or fusiform segmental dilatations connected with normal distal and/or proximal bile ducts associated in some cases with liver fibrosis at liver biopsy (10).

The diagnosis of biliary duct cancers can be challenging because the imaging finding of CD can mask the presence of cancer and for this reason diagnosis of cancer is frequently incidental at final pathologic examination after surgical intervention for CD.

Pathological features

The definitive diagnosis of CD is confirmed by pathological examination. In surgical specimens studies, CD is characterized by non-obstructive, segmental and subsegmental cystic dilatations of the intrahepatic bile ducts, fibrosis and stenosis of bile ducts, intracystic lithiasis, intraluminal protrusions of patent fibrovascular peripheral branches (3). This finding corresponds to the radiologic description of “central dot sign”.

Biliary epithelium is usually irregular and abraded with a normal surrounding hepatic parenchyma or with fibrotic changes in case of recurrent cholangitis or associated congenital hepatic fibrosis (1). In addition, persistence of ductal plate-like structures can be detected confirming the supposed pathogenesis with defective remodeling of the ductal structures (8).

 

 

Differential diagnosis

 

Differential diagnosis for CD should consider all the biliary diseases with chronic inflammation and cholestasis. In detail, primary sclerosing cholangitis (PSC), recurrent pyogenic cholangitis, polycystic liver disease, choledochal

cysts, biliary papillomatosis and chronic obstructive biliary disease are the most frequent conditions with clinical and radiological findings similar to CD. However, PSC is frequently characterized by more isolated and fusiform dilatations and it is associated with inflammatory bowel disease in about 70% of the patients. In polycystic liver disease, the hepatic cysts are rarely in continuity with the bile ducts and the biliary tree is usually normal. Choledochal cystic disease is usually limited to the extrahepatic bile ducts without intrahepatic involvement. The differential diagnosis with recurrent pyogenic cholangitis is more difficult for the presence of sepsis with intra- and extrahepatic dilatation commonly observed also in CD (3).

Classification systems

Over the years, many classifications of congenital intrahepatic bile duct dilatations have been proposed. Guntz et al. radiological subclassification of IHBDD described three types: the type I (including CD) in case of “grape bunch-like” saccular dilatation of peripheral intrahepatic bile ducts alternating with normal ones, the type II with fusiform communicating dilatation of large intrahepatic bile ducts and the type III with saccular communicating dilatation of large intrahepatic bile ducts (10,11).

The classification of biliary tree malformations proposed by Todani et al. is the more frequently adopted, it is based on both morphologic features and location of the abnormalities and describes five different categories: type I includes spherical or fusiform dilatation of the entire extrahepatic biliary tract; type II that corresponds to the extrahepatic supraduodenal biliary diverticulum; type III is the cystic dilatation of the intramural duodenal segment of the common bile duct, termed choledochocele; type IV when there are multiple extrahepatic biliary cysts, either alone or in association with multiple large intrahepatic biliary cysts; CD corresponds to the group V (12,13).

Treatment

The choice of treatment depends on the extension of the disease, the associated conditions, the clinical course of the disorder and patient’s performance status. Monolobar disease is more frequent (80% of cases) and usually located in the left lobe, while right monolobar disease is extremely rare (5). Patients suffering from monolobar disease are potentially curable by resective surgery, that demonstrated to be effective, obtaining good long-term results with

 

complete and long-lasting relief from symptoms (1). Basic principle of resective surgery should include the complete resection of any pathologic bile duct, in order to avoid the development of recurrent disease or cancer. The risk of carcinogenesis and recurrence of cholangitis increase over time, for these reasons surgical radical treatment should be performed as soon as possible and with the purpose of removing all pathological bile ducts (14). Surgery results are significantly related to pre-operative management and the presence of infective complications before surgery. Endoscopic or percutaneous invasive procedures prior to surgery are associated with an increased risk of overall complications and high rate of post-operative infections (10,14).

However, it was reported in literature that about 20% of the patients undergoing surgery need subsequent radiologic or endoscopic procedures for biliary complications or for recurrent disease of contralateral lobe. Notably, the clinical course of localized CD is extremely different from the bilobar one, despite the similar etiopathogenetic mechanism. While localized CD may be successfully treated with radical surgical resection, the bilobar disease has a poor prognosis, since it is characterized by the onset of several severe complications with complex and demanding treatment. Specifically, recurrent cholangitis and cirrhosis are related to a mortality rate of 20–40% and morbidity of 44–80% due to the progressive deterioration of liver function and severe infective complications.

Patients affected by extensive bilobar disease are candidates for liver transplantation, which is indicated in patients developing progressive hepatic disease with liver decompensation, but also in extensive asymptomatic disease (7). CD represents less than 0.2% of all liver transplantation’s indications (10). Nevertheless, the results of transplantation are worsened in case of congenital hepatic fibrosis, recurrent cholangitis and incidental cholangiocarcinoma, because of the high recurrence rate (3). Medical therapy for patients with CD includes ursodeoxicolic acid and appropriate and tailored antibiotic therapy for cholangitis. In case of biliary obstruction, abscesses and lithiasis, biliary drainage can be required. The choice of endoscopic, radiological approach is based on the location of the disease and local medical expertise (3). However, these non-surgical procedures are associated with high risk of infectious complications and high recurrence rate, increasing morbidity and mortality with a delay in a

potential curative surgical intervention.

Laparoscopic surgery

Minimally invasive liver surgery (MILS) has been increasingly widespread in the recent years for treatment of benign and malignant diseases. From this perspective, many studies have demonstrated benefits and safety of minimally invasive approach in comparison with open surgery (15). In particular, the laparoscopic approach became the standard of care in left lateral sectionectomy, but nowadays it can be safely applied for more complex resections (16).

Up to now, the most common surgical approach to CD is open resection. Indeed, scientific literature on MILS focused on CD is considerably lacking in this topic, even though left hepatectomy and left lateral sectionectomy are the most frequent treatments for localized disease (15).

The scarce experience in MILS can be explained by the rarity of the disease and its complex presentation involving segmental or lobar bile ducts (14). The presence of severe complications as recurrent cholangitis and diffuse hepatolithiasis are often a limitation to MILS approach, moreover complex intraoperative biliary procedures such as cholangioscopy and bilio-enteric anastomosis are additional factors limiting MILS approach. Secondly, according to the etiopathogenesis of the disease, the only effective resective treatment is the complete excision of the involved segments, leading to the necessity of more complex surgery with anatomical resection.

However, MILS is considered to be feasible, reaching excellent long-term results and with a low rate of conversion, also in CD.

In addition to the well-known laparoscopic advantages, patients with impairment of liver function should benefit from MILS, with a lower risk of post-hepatectomy complications (15). Furthermore, the MILS could be suggested as primary approach in patients for whom, because of the complexity of CD, liver transplantation could be eventually required.

According to literature, MILS for CD requires standard laparoscopic equipment, but particular attention should be paid to intraoperative bile ducts examinations. Although, cholangioscopy and cholangiography can be useful to confirm the presence of residual stones and ensure the complete resection of pathological bile ducts (tfigures 1,2) (17).

Intraoperative biopsy with frozen section histological examination is suggested in case of suspected malignancy (18). In patients with incidental intraoperative diagnosis of cholangiocarcinoma, radical margin free resection and Laparoscopic Surgery, 2020

Figure 1 Left Caroli’s Disease with hepatolithiasis: (A,B) CT images showing left cystic bile ducts dilatation with “central dot sign”; (C) laparoscopic intraoperative cholangioscopy through left bile duct stump; (D) surgical field after laparoscopic left hepatectomy. CT, computed tomography.

 

Figure 2 Right segmental Caroli’s disease with hepatolithiasis of segment 6: (A,B) MR images showing segmental fusiform cystic bile ducts dilatation of segment 6 bile duct; (C) laparoscopic intraoperative images showing cyst dilatation of segment 6 bile duct with saccular dilatations; (D) surgical field after laparoscopic segmental resection with intraoperative cholangioscopy. MR, magnetic resonance.

regional lymphadenectomy are required with open or MILS approach (14).

We have reviewed the existing literature in MEDLINE database of peer review papers published during the period 2005–2018 included 243 liver resections for CD (19-22).

Among these published papers only six more recent (2009– 2018) reported MILS resections for CD (7 left lateral hepatic sectionectomies, 7 left hepatectomies, 1 segmentectomy; 1 right anterior sectionectomy) describing technical aspects, feasibility, safety, short- and long-term outcome. The

Table 1 MILS resections for CD reported in literature (2009–2018) included in the review: 7 LLLHS, 7 LLH, 1 S5; 1 LRAS. The reported conversion rate is 0–12.5% and the rate of complication is 6.2%

Authors	Patients	Operative procedures	Conversion	Complications	Follow-up
Abayie et al. (2018) (23)	1	LLLHS	0	0	–
Chen et al. (2018) (18)	1	LLH	0	0	18 months
Mabrut et al. (2013) (10)	8	LLLHS (n=5); LLH (n=2); S5 (n=1)	1 (LLLHS)	–	–
Hwang et al. (2012) (24)	1	LRAS	0	Fluid collection, conservatively treated	–
Di Giuro et al. (2010) (25)	4	LLH	0	–	–
Boni et al. (2009) (26)	1	LLLHS	0	0	–

MILS, minimally invasive liver surgery; CD, Caroli’s disease; LLLHS, laparoscopic left lateral hepatic sectionectomy; LLH, laparoscopic left hepatectomy; S5, segmentectomy V; LRAS, laparoscopic right anterior sectionectomy.

 

total number of reported cases of MILS for CD is only 16 (Table 1). In these cases, CD was limited to the left liver. The reported conversion rate was 0–12.5% and the rate of complication was 6.2%. Finally, there are few reported data about long term follow-up, in particular authors did not report the recurrence rate of CD and of hepatolithiasis.

Conclusions

CD is a rare condition with variable clinical complexity due to the extension of the disease, the localization of pathological bile ducts and the presence of complications. The radical surgery is the treatment of choice for localized disease and in these cases MILS can have an important therapeutic role, in particular for left located CD. MILS approach to CD requires high expertise in liver surgery and in complex biliary procedures.

Data of the literature are still lacking in long-term results and more studies are necessary to confirm the short and long-term results.

Acknowledgments

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest

to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

References

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3. Yonem O, Bayraktar Clinical characteristics of Caroli’s disease. World J Gastroenterol 2007;13:1930-3.
4. Wang ZX, Li YG, Wang RL, et al. Clinical classification of Caroli’s disease: an analysis of 30 HPB (Oxford) 2015;17:278-83.
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6. Kumar A, Akselrod D, Prikis Caroli Disease Revisited: A Case of a Kidney Transplant Patient With Autosomal Polycystic Kidney Disease and Recurrent Episodes of Cholangitis. Transplant Proc 2019;51:541-4.
7. Habib S, Shakil O, Couto OF, et Caroli’s disease and orthotopic liver trans-plantation. Liver Transpl 2006;12:416-21.
8. Yadav P, Adhikari S, Pandit N, et Caroli’s disease: a diagnostic challenge. Int Surg J 2018;5:3750-3.
9. Choi BI, Yeon KM, Kim SH, et Caroli disease: central dot sign in CT. Radiology 1990;174:161-3.
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therapeutic procedure. Apropos of 3 personal cases and 101 cases in the literature. J Chir (Paris) 1991;128:167-81

12. Todani T, Watanabe Y, Narusue M, et al. Congenital

bile duct cysts: Classifi-cation, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg 1977;134:263-9.

13. Banks JS, Saigal G, D’Alonzo JM. Choledochal malformations: surgical im-plications of radiologic findings. AJR Am J Roentgenol 2018;210:748-60.
14. Fahrner R, Dennler SGC, Dondorf F, et Liver resection and transplantation in Caroli disease and syndrome. J Visc Surg 2019;156:91-5.
15. Goh BK, Chan CY, Lee SY, et al. Laparoscopic liver resection for tumors in the left lateral liver JSLS 2016. doi: 10.4293/JSLS.2015.00112.
16. Buell JF, Cherqui D, Geller DA, et al. The international position on laparoscopic liver surgery. Ann Surg 2009;250:825-30.
17. Ramia JM, Palomoque A, Muffak K, et Indications and therapeutical options in hepatolithiasis. Rev Esp Enferm Dig 2006;98:597-604.
18. Chen CB, Hu WD, Zhao WW, et al. Laparoscopic hepatectomy for the treat-ment of Caroli’s disease: a case Ann Surg Treat Res 2018;94:162-5.
19. Bockhorn M, Malagò M, Lang H, et al. The role

of surgery in Caroli’s disease. J Am Coll Surg 2006;202:928-32.

20. Lendoire J, Barros Schelotto P, Alvarez Rodriguez J, et Bile duct cyst type V (Caroli’s disease): surgical strategy and results. HPB (Oxford) 2007;9:281-4.
21. Mabrut JY, Partensky C, Jaeck D, et al. Congenital intrahepatic bile duct dila-tation is a potentially curable disease: long-term results of a multi-institutional Ann Surg 2007;246:236-45.
22. Kassahun WT, Kahn T, Wittekind C, et Caroli’s disease: liver resection and liver transplantation. Experience in 33 patients. Surgery 2005;138:888-98.
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26. Boni L, Dionigi G, Rovera F, et al. Laparoscopic left liver sectoriectomy of Caroli’s disease limited to segment II and J Vis Exp 2009. doi: 10.3791/1118.

Elie Akl, MDa, Mohammed K. Rashid, MDa, Ahmad Alshatti, MDa, Sanjit S. Jolly, MD, MSca,b,*

 

INTRODUCTION

Transradial access (TRA) is associated with less bleeding and vascular complications than trans- femoral access (TFA) in patients with acute coro- nary syndromes (ACS).^1,2 A large body of evidence currently supports embracing TRA to improve outcomes in these patients. This is re- flected in a 2018 scientific statement from the American Heart Association in which a radial- first approach was strongly recommended in all patients undergoing cardiac  catheterization, with a graduated level of center and operator experience for TRA use in patients with ACS.³

Bleeding Is an Important Outcome in Patients with Acute Coronary Syndrome

Although advances in adjuvant pharmaco- therapy have reduced the risk of ischemic PCI- related complications, the use of antithrombotic agents, especially in the presence of an

 

arteriotomy site, increases the risk of bleeding complications. The incidence of bleeding in- creases with the acuity of clinical presentation and is higher in patients with ACS compared with those with stable coronary artery disease.⁴ Verheugt and colleagues⁵ examined the prog- nostic impact of 30-day bleeding in a combined dataset from the REPLACE 2, ACUITY, and HO- RIZONS AMI trials that included 17,393 patients with ACS undergoing PCI. The rate of access site bleeding was 2.1% and that of non–access site bleeding was 3.3%. One-year mortality was 2.54% in patients with no bleeding, 6.16% with access site bleeding (relative risk [RR], 2.33; 95% confidence interval [CI], 1.53–3.53), and 14.4% with non–access site bleeding (RR, 5.40; 95% CI, 4.32–6.74). After adjustment, the hazard ratio (HR) of non–access site bleeding was more than double that of access site bleeding (HR, 3.94; 95% CI, 3.07–5.15; P<.0001 vs HR, 1.82;

 

 

 

^a Department of Medicine, Division of Cardiology, McMaster University, Room C3-118, DBCVSRI Building, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada; ^b Population Health Research Institute, Hamilton, Ontario, Canada

* Corresponding author. Hamilton General Hospital, Room C3-118, DBCVSRI Building, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

E-mail address: sanjit.jolly@phri.ca

 

Intervent Cardiol Clin 9 (2020) 33–40 https://doi.org/10.1016/j.iccl.2019.08.003

2211-7458/20/ª 2019 Elsevier Inc. All rights reserved.

 

 

 

 

95% CI, 1.17–2.83; P 5 .008, respectively), but both were associated with increased mortality. These findings were subsequently corroborated in larger studies.^6,7

It is unclear whether bleeding is a marker of risk or causal for mortality. Nonetheless, several mechanisms by which bleeding may affect mor- tality have been proposed. These include pre- mature cessation of dual antiplatelet therapy, blood transfusion-related adverse affects, exag- geration of inflammatory responses, and gener- ation of a prothrombotic milieu through  activation of the coagulation cascade.⁸ Anemia itself decreases oxygen delivery, increases oxy- gen demand, and can lead to ischemic events owing to supply–demand mismatch. Regardless of the mechanisms involved, if bleeding in- creases mortality, then avoiding it should decrease mortality. Multiple strategies can be used to minimize bleeding risk in patients with ACS. Pharmacologic therapies that reduce bleeding in ACS have been associated with re- ductions in mortality (bivalirudin in HORIZONS AMI⁹ and fondaparinux in the OASIS 5 and 6 tri- als¹⁰). This finding supports the mechanism that reducing bleeding can lead to reductions in mortality.

 

RANDOMIZED CONTROLLED TRIALS OF TRANSRADIAL ACCESS VERSUS THE FEMORAL APPROACH IN PATIENTS WITH ACUTE CORONARY SYNDROME

Several large randomized trials comparing the radial versus the femoral approach in the ACS population were published over the past  decade. The RadIal vs femorAL access for coro- nary intervention (RIVAL)¹ trial randomized a to- tal of 7021 patients with ACS with or without ST- segment elevation. The primary outcome of death, myocardial infarction (MI), stroke, or non- coronary artery bypass grafting  (CABG) bleeding at 30 days occurred in 3.7%  in  the TRA group versus 4.0% in the TFA group (HR, 0.92; 95% CI, 0.72–1.17; P 5 .50). The rate of

major adverse cardiac events (MACE; composite of death, MI, and stroke) was also similar be- tween the 2 groups (3.2% vs 3.2%; HR, 0.98;

95% CI, 0.76–1.28; P 5 .90). However, many

notable findings should be underlined. First, in centers with the highest radial PCI volumes, there was a benefit with TRA over TFA for MACE, major vascular complications, and access site crossover. Second, there was a significant benefit with TRA in patients with ST-segment elevation MI (STEMI). This is detailed in a subse- quent  section.  Third,  although  major  bleeding

did not differ as per the trial-specific definition,   a post hoc analysis showed a significant reduc- tion with radial access when the ACUITY trial bleeding definition was used (P<.0001). Fourth, the rate of major vascular complications was significantly lower with the radial  approach (1.4% vs 3.7%; HR, 0.37; 95% CI, 0.27–0.52;

P<.0001). This was driven by a reduction in large

hematoma and pseudoaneurysm needing closure.

The Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of AngioX (MATRIX) was a large trial of more than 8400 patients with ACS.² The primary outcome of MACE was lower with TRA compared with TFA (8.8% vs 10.3%; RR, 0.85;

95% CI, 0.74–0.99; P 5 .0307). Similarly, the sec- ond coprimary outcome of a net adverse clinical events (NACE) was also reduced with the radial approach  (9.8% vs  11.7%;  RR,  0.83;  95% CI,

0.73–0.96; P 5 .0092). The difference was mainly driven by bleeding academic research con- sortium (BARC) major bleeding unrelated to CABG (1.6% vs 2.3%, RR, 0.67; 95% CI, 0.49–

0.92; P 5 .0128) and all-cause mortality (1.6%

vs 2.2%; RR, 0.72; 95% CI, 0.53–0.99; P 5 .045).

 

Transradial Access Versus Transfemoral Access in Patients with an ST Elevation Myocardial Infarction

In the RIVAL-STEMI subgroup of 1958 patients, MACE (HR, 0.59; 95% CI, 0.36–0.95; P 5 .031),

NACE (HR, 0.60; 95% CI, 0.38–0.94, P 5 .026),

and all-cause mortality (HR, 0.39; 95% CI, 0.20–

0.76; P 5 .006) were decreased with radial ac- cess.¹¹ ACUITY major bleeding (HR, 0.49; 95% CI, 0.28–0.84; P 5 .009) and major vascular ac- cess site complications (HR, 0.36; 95% CI, 0.19–0.70; P 5 .002) were also significantly lower in the radial group. Another subgroup analysis of the 1451 patients treated with primary PCI showed a mortality benefit with TRA (HR, 0.46; 95% CI, 0.22–0.97; P 5 .041).

TRA provided consistent benefits in patients with NSTE-ACS and STEMI at presentation in a prespecified subanalysis of the MATRIX trial.¹² Access site BARC 2 to 5 bleeding was signifi- cantly reduced in the radial  group  irrespective of ACS presentation, as well.

The Radial vs Femoral Randomized Investiga- tion in ST-Elevation Acute Coronary Syndrome (RIFLE-STEACS) trial randomized 1001 patients with STEMI undergoing primary or rescue (8%) PCI to TRA or TFA.¹³ The composite primary outcome of death, MI, stroke, target lesion revascularization,  or  non-CABG  bleeding   at 30 days was significantly lower in the TRA arm

 

 

 

 

(13.6% vs 21%; 95% CI, 2.7%–12.0%; P 5 .003).

There was also a significant reduction in cardiac mortality (5.2% vs 9.2%; 95% CI, 0.8%–7.3%;

P 5 .020). Non–CABG-related bleeding was significantly reduced with TRA (7.8% vs 12.2%, 95% CI, 2.7–12.0; P 5 .026), mainly owing to a 60% decrease in access site-related bleeding (2.6% vs 6.8%; 95% CI, 1.6%–7.0%; P 5 .002).

The ST Elevation Myocardial Infarction Treated by RADIAL or femoral approach (STEMI-RADIAL) trial included 707 patients un- dergoing primary PCI by high-volume  opera- tors experienced in both access sites.¹⁴ The composite primary end point of major bleeding and vascular access site complications at

30 days was lower with TRA (1.4% vs 7.2%;      P 5 .0001). The NACE rate was also reduced with  the  radial   approach   (4.6%   vs   11.0%; P 5 .0028). There was a nonsignificant 26% relative reduction in mortality at 30 days and 36% at 6 months with TRA.

In the most recent trial, Safety and Efficacy of Femoral Access vs Radial Access in ST-Elevation Myocardial Infarction (SAFARI-STEMI), the pri- mary outcome of death at 30 days (1.5% vs 1.3%; RR, 1.15; 95% CI, 0.58–2.30; P 5 .69),

MACE  (4% vs  3.4%; RR,  1.17; 95%  CI, 0.77–

1.79;  P  5 .45), and  major bleeding (1.1%  vs

1.3%; P 5 .74) were  all  not  different  among the 2 groups. However, the trial was stopped early, having recruited only 2292 of the original target of 4884 patients. As a result, it is likely  that SAFARI did not have sufficient power  to test the hypothesis, which makes it difficult to draw any firm conclusion. The totality of the  data shows that radial improves outcomes compared with femoral access in STEMI.

 

Meta-analysis of Randomized Trials

An updated meta-analysis of randomized trials  of TRA versus TFA in ACS with clinical outcomes available at 30 days demonstrates a trend favor- ing TRA for MACE, defined as death from any cause (or cardiac death when all-cause mortality was not available), MI or stroke (odds ratio [OR], 0.86;  95%  CI,  0.72–1.02;  P  5  .08;  I²  5 6%)

(Fig. 1).^11–17 Radial access was associated with a decreased risk of 30-day mortality (OR, 0.71; 95% CI, 0.56–0.90; P 5 .004; I² 5 0%), major

bleeding    (OR,    0.55;    95%    CI,   0.41–0.73;

P<.0001; I² 5 24%), and vascular access compli- cations (OR, 0.32; 95% CI, 0.20–0.52; P<.00001;

I² 5 0%) at 30 days. Our findings are highly consistent with prior meta-analyses.^18–22

The evidence overwhelmingly supports a radial first approach and this is reflected in guidelines from the American Heart Association,

 

the Canadian Cardiovascular Society/Canadian Association of Intervention Cardiology, and the European Society of Cardiology/European Asso- ciation for Cardio-Thoracic Surgery, which have all endorsed the radial approach as the  preferred site for PCI^3,23,24 (Table 1).

There has previously been concerns that TRA might prolong door-to-balloon times, but contemporary studies of TRA versus TFA failed to demonstrate a significant difference in these times.^1,4,13,25 Furthermore, sensitivity analysis using the mortality benefit seen in large random- ized controlled trials with TRA suggests that the small increment in door-to-balloon times is un- likely to affect clinical benefit.²⁶

Although radial adoption in  the  United  States has been not as rapid as Europe and Canada, the use of the transradial approach is growing steadily. Data from the American Col- lege of Cardiology National  Cardiovascular  data registry has documented a greater than 6-fold increase of the radial access in primary PCI between 2007 and 2011.²⁷ Although encouraging,  these   rates   remain   much lower than those reported in European coun- tries such as Sweden and the UK, which increased from 10% to 12.5% to 55% to 60% during the same period.^28,29 These numbers underline the need  for  continuing  education  for TRA.

 

TRANSRADIAL ACCESS IN RESCUE PERCUTANEOUS CORONARY INTERVENTION

Bleeding complications in with patients with STEMI who receive fibrinolysis and undergo rescue PCI are relatively common. Thus, deter- mining the optimal access approach for these patients is of particular interest.

In the RADIAL-AMI pilot randomized trial, 50 patients requiring either primary (one-third) or rescue PCI (two-thirds) were randomized to radial versus femoral access. There was a trend toward less hematoma and less hemoglobin decrease (>30 g/L) in the radial group.¹⁵ Data from the Scottish Coronary Revascularisation Register that included 4534 patients undergo- ing primary or rescue PCI between 2000 and 2009 showed a striking reduction in 30-day mortality (adjusted OR. 0.51; 95% CI, 0.04– 0.52; P<.001), greater  procedural  success, and less access site complications or bleeding with the radial approach.³⁰ The largest evalua- tion of outcomes after rescue PCI via TRA versus TFA is from the American College of Cardiology National Cardiovascular Data

Fig. 1. Forest plots of pooled estimates of (A) MACE, (B) death, (C) major bleeding, (D) stroke, and (E) vascular access complications. MACE, major adverse cardiovascular events, defined as the composite of death, MI, and stroke.

 

 

Registry.³¹ In total, 9494 patients undergoing rescue PCI between 2009 and 2013 were stud- ied. Coronary angiography was performed at a median time of 189 minutes after fibrinolytic therapy. Only 14.2% of cases were performed transradially. Rescue PCI success  rates  were high and not different between groups (96.1% radial vs  94.7%  femoral;  P  5  .06). In propensity-matched analyses, transradial rescue PCI was associated with lower bleeding rates compared with the transfemoral approach (OR, 0.67; 95% CI, 0.52–0.97; P 5 .003), but not

 

mortality (OR, 0.81; 95% CI, 0.53–1.25;

P 5 .35). The very low in-hospital mortality (1%–2%) observed in this patient group as compared with data from  all-comers  with STEMI (in-hospital mortality, 5.5%)³² could potentially explain the  inability  to  demonstrate a mortality difference with TRA.

Given the proven decrease in bleeding end points with TRA, one should expect an incre- mental benefit with radial access in patients at highest risk of bleeding, including patients with STEMI undergoing rescue PCI.

TRANSRADIAL ACCESS IN FEMALE PATIENTS WITH ACUTE CORONARY SYNDROME

Female patients with ACS are more likely than males to suffer from bleeding and vascular com- plications.^33,34 Concerns that TRA might be more challenging in females owing to smaller

radial arteries that may be more prone to spasm make sex-specific data regarding the efficacy and safety of TRA very pertinent.

Sex-based outcomes in ACS randomized to TRA versus TFA were compared in a prespeci- fied RIVAL subgroup analysis.³³ Bleeding and major vascular complications were significantly reduced with TRA in both sexes. However, the number needed to treat to prevent 1 major vascular complication was 33 in females compared with 49 for males. Crossover rates were higher with TRA compared with TFA in both women and men, but more so in women (women:  11.1%  vs  1.9%;  HR.  5.88; P<.0001;

men: 6.3% vs 1.9%; HR, 3.32; P<.0001). PCI suc-

cess rate did not differ by sex, irrespective of ac-

 

Table 1 International Society guidelines for radial access in primary PCI   Society   Year TRA in Primary PCI CCS – STEMI 2019 Strong Guidelines23 recomm- endation, moderate- quality evidence AHA – Scientific Statement3 2018 Strong recomm- endation ESC/EACTS 2018 Class I indication Guidelines on Myocardial Revascularization24

cess site (female: HR, 1.05, P 5 .471; male: HR,

Abbreviations: AHA, American Heart Association; CCS, Canadian Cardiovascular Society; EACTS, European Asso- ciation for cardio-thoracic surgery; ESC, European Society of cardiology.

• ; P 5 .888; P_int 5 .674). When asked about their access preference for a hypothetical repeat procedure, 1% of females with TRA preferred TRA, whereas only 50.1% of females with TFA preferred TFA (P<.001).

In an analysis of the MATRIX trial,³⁴ when comparing TRA versus TFA between females and males with ACS, major adverse cardiovascu- lar and cerebrovascular events, and NACE were significantly lower with TRA in females (major adverse cardiovascular and cerebrovascular events: 9.1% vs 12.2%; RR, 0.73; 95% CI, 0.56–

0.95;  P  5 .019;  NACE:  10.4%  vs  13.9%; RR,

0.73; 95% CI, 0.56–0.93; P 5 .012), but these re-

ductions  only  trended  favorably  for  radial  in

 

Table 2 TRA versus TFA in females versus males TRA vs TFA in Females TRA vs TFA in Males Vascular complications YY Y Bleeding YY Y Crossover [[ [ PCI success 5 5 MACE Y Y/5

bleeding and access site vascular complica- tions. Patients undergoing invasive treatment for ACS are at greatest risk of bleeding and have the most to gain. The benefits of TRA have been demonstrated across the ACS spec- trum and in both sexes. A radial-first strategy should be the default approach in the ACS  population and continuous efforts should be made to increase operator expertise of TRA in these patients.

 

Abbreviation: MACCE, major adverse cardiovascular and cerebrovascular event.

 

males. BARC type 3 or 5 bleeding (P_int 5 .45) and all-cause mortality (P_int 5 0.79) were lower with TRA in both sexes.

SAFE-PCI for Women is the first randomized trial of PCI strategies performed solely in women. It differs from the above-mentioned studies in that it focused on  elective referrals  for angiography and PCI, and excluded patients with STEMI.³⁵ A total of 1787 female patients were randomized to TRA versus TFA, with 691 undergoing PCI. Unfortunately, the trial was stopped prematurely owing to a lower than ex- pected event rate. There was a significant reduc- tion in bleeding and vascular complications with TRA in the overall population (0.6% vs 1.7%; OR, 0.32; 95% CI, 0.12–0.90). There was only a trend toward benefit in the PCI group, most likely owing to the small sample size. Crossover rates were significantly higher with TRA compared with TFA (6.7% vs 1.9%; OR, 3.70; 95% CI,

2.14–6.40). Compared with women assigned to TFA, more women assigned to TRA preferred the same access route for their next procedure (71.9% vs 23.5%).

TRA is effective at significantly reducing bleeding, major vascular complications and MACE in women with similar PCI success rates compared with TFA (Table 2). The radial-first approach is especially applicable to female pa- tients who are at increased baseline risk of bleeding and vascular complications. Contin- uous efforts should be made to overcome the technical challenges with TRA in females, including gaining expertise in the use of 4F or 5F catheters to minimize the risk of spasm.

 

SUMMARY

Considerable evidence supports TRA for angi- ography and  intervention  in  patients  with  ACS, with an emphasis on decreasing major

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24. Romagnoli E, Biondi-Zoccai G, Sciahbasi A, et Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome: the RIFLE-STEACS (Radial Versus Femoral Ran- domized Investigation in ST-Elevation Acute Coro- nary Syndrome) study. J Am Coll Cardiol 2012; 60(24):2481–9.
25. Bernat I, Horak D, Stasek J, et al. ST-segment elevation myocardial infarction treated  by  radial or femoral approach in a multicenter randomized clinical trial: the STEMI-RADIAL J Am Coll Car- diol 2014;63(10):964–72.
26. Cantor WJ, Puley G, Natarajan MK, et al. Radial versus femoral access for emergent percutaneous coronary intervention with adjunct glycoprotein IIb/IIIa inhibition in acute myocardial infarction– the RADIAL-AMI pilot randomized trial. Am  Heart J 2005;150(3):543–9.
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Vittorio Emanuele Bianchi, MD

Abstract: The metabolic sources of energy for myo- cardial contractility include mainly free fatty acids (FFA) for 95%, and in lesser amounts for 5% from glucose and minimal contributions from other sub- strates such lactate, ketones, and amino acids. How- ever, myocardial efficiency is influenced by metabolic condition, overload, and ischemia. During cardiac stress, cardiomyocytes increase glucose oxidation and reduce FFA oxidation. In patients with ischemic coro- nary disease and heart failure, the low oxygen avail- ability limits myocardial reliance on FFA and glucose utilization must increase. Although glucose uptake is fundamental to cardiomyocyte function, an excessive intracellular glucose level is detrimental. Insulin plays a fundamental role in maintaining myocardial effi- ciency and in reducing glycemia and inflammation; this is particularly evident in obese and type-2 diabetic patients. An excess of F availability increase fat deposi- tion within cardiomyocytes and reduces glucose oxida- tion. In patients with high body mass index, a restricted diet or starvation have positive effects on cardiac metabolism and function while, in patients with low body mass index, restrictive diets, or starva- tion have a deleterious effect. Thus, weight loss in obese patients has positive impacts on ventricular  mass and function, whereas, in underweight heart fail- ure patients, such weight reduction adds to the risk of heart damage, predisposing to cachexia. Nutrition

Conflict of interest: The author declares no conflict of interest and no funding support to this work.

plays an essential role in the evolution of cardiovascu- lar disease and should be taken into account. An energy-restricted diet improves myocardial efficiency but can represent a potential risk of heart damage, particularly in patients affected by cardiovascular dis- ease. Micronutrient integration has a marginal effect on cardiovascular efficiency. (Curr Probl Cardiol 2020;45:100391.)Curr Probl Cardiol 2020;45:100391 0146-2806/$ see front matter

Energy Metabolism and Heart Function

he  cardiomyocyte  is  a  unique muscle  cell  which  possesses  the

tions, the contractile function is sustained by the production of adenosine

triphosphate (ATP), predominantly derived from the fatty acid oxidation (60%-90%), with the balance derived from glucose (30%-40%)¹ and a lesser contributions from lactate, ketones, amino acids, and pyruvate. Pyruvate production derives mainly from glycolysis and lactate oxidation of 10%.^2-4 The primary energy source for cardiac metabolism is supplied by free fatty acids (FFA) and by chylomicrons which cross the cell mem- brane passively or transported actively by a specific protein.⁵ In the healthy heart, although lipid oxidation represents the principal energy  source, the glucose metabolism is essential to maintain physiological car- diac function.²

Glucose uptake from cardiomyocytes is regulated mainly by Glut-4,  in response to insulin stimulation and increases during  ischemia  or  work demand (overload).⁶ Glut-4 is dependent upon activation of AMP-activated protein kinase (AMPK), nutria-sensors of the cells.⁷ Glycolysis causes the formation of pyruvate, and its oxidation is the  final step of carbohydrate (CHO) oxidation.⁸ Glucose and pyruvate oxi- dation is inhibited by FFA levels, while increased by the reduction of FFA level⁹ This interaction between fatty acids availability and glycol- ysis inhibition was first described by Randle and is called “glucose-fatty acid cycle”.¹⁰ In conditions of cardiac stress and overload, the cardio- myocyte energy source shifts towards higher utilization of glucose.

In normal cardiomyocytes, the ATP production is maintained constant by mitochondrial oxidative phosphorylation, even in the condition of overload, eg, intensive exercise or hypertension.¹¹ The increased contrac- tile force is sustained by a concomitant increase in fatty acid and carbohy- drate utilization¹² and by the nutritional state¹³ as observed during

overnutrition and restricted calorie balance that significantly changes car- diomyocyte energy metabolism.

In patients with ischemic coronary artery disease (CAD), the low oxygen availability of the myocardium is supplied by optimizing glucose utilization with an improved insulin activity and cardiomyocytes glucose sensitivity. In heart failure (HF) the global cardiac efficiency is impaired due to the reduced mitochondrial energy production¹⁷ via oxidative phosphorylation¹⁸ and these conditions favor an evolution from cardiac hypertrophy to HF.¹⁹ Glucose is the most energetically efficient substrate which is preferentially utilized dur- ing conditions of myocardial stress such as overload and HF. In these circum- stances, the increased glucose oxidation protects against acute myocardial ischemic injury.²⁰ Furthermore, in HF the myocardium metabolizes ketone bodies which become an essential fuel source for oxidative ATP production.²¹ Ketone body oxidation is metabolically more efficient than FFA oxidation²² and can acutely improve left ventricular function.²³ In the failing heart, ketones bodies represent a preferential source of energy for energy produc- tion.²¹ Although ketone bodies oxidation is a more competitive energy pathway compared with other substrates in HF, there is a great limitation due to the ketogenic diet characterized by a high fat and high protein with minimal (50 g/day) or absent intake of carbohydrates,²⁴ not at all tolerated by these patients. However, the effect of the ketogenic diet in patients with cardiovascular disease (CVD) remains to be investigated. Thus, the meta- bolic flexibility of cardiomyocyte is considerable and is responsive to changes in substrate availability and nutritional status. (Fig 1).During maximal cardiac demand, the healthy heart progressively utilizes lactate for energy.¹⁴ In the condition of cardiac stress, such as in prolonged overload and the hypertrophied heart, cardiac metabolism changes—spar- ing FFA oxidation, while increasing glucose oxidation.¹⁵ During ischemic heart conditions, glucose becomes the prevalent source of energy for myo- cardial tissue both in chronically hypertrophied and normal hearts.¹⁶ In severely ischemic hypertrophied hearts, glycogen degradation is further accelerated, and the consequent reduced CHO availability accentuates the risk of ischemia and reduced contractile performance.¹⁵

Metabolism in the Heart

FFA

FFA metabolism is less efficient energetically than glucose metabo- lism although it increases the oxygen consumption.²⁵ However, an exces- sive availability of myocardial FFA exceeds the oxidative capacity of the

FIG 1. Fatty acids are prevalently oxidized by adult heart, in diabetes, and fasting. Glucose oxi- dation is prevalent in fetal heart, hypertrophy, cardiac overload, and ischemia. During fasting are oxidized ketone bodies and amino acids.

 

myocardial tissue favoring the FFA accumulation as intramyocardial lip- ids, thus causing a “lipotoxicity,” leading to insulin resistance and impairment of the cardiac function.^26-28 A high intracellular lipids accu- mulation, as observed in type-2 diabetes, inhibits the glucose oxidation via the phosphorylation of pyruvate dehydrogenase kinase.²⁹

 

Glucose Metabolism

Glucose crosses the membrane of cardiomyocytes passively or by glu- cose transporter GLUT4 which regulates the glucose level in the cells. In

 

contrast to skeletal muscle, in cardiomyocytes, there is also a significant expression of GLUT1, which contributes to cardiac glucose uptake under certain circumstances.³⁰ Various hormones and cytokines regulate glu- cose metabolism in the myocardium contributing to the development of insulin resistance.³¹

Glucose is an oxygen sparing substrate that generates more ATP per mole of oxygen compared to fatty acids, and when the availability of oxygen is decreased, it can produce energy through glycolysis. Imaging studies using the fluorodeoxyglucose-positron emission tomography FDG-PET have shown that the ischemic myocardium in the fasting state changes the energy source switching from fatty acids to glucose. Preserving myocardial viability,³² and the degree of elevation in myocardial glucose uptake is predictive of cardiac function recovery after revascularization.³²

In patients with a nonischemic CAD, whole body substrate oxida-  tion rates did not differ from that observed in the no-CAD group.³³        In ischemic CAD patients, their myocardium will adapt to the condi-  tion of limited oxygen  availability,  although  oral  glucose  loading  does not acutely increase myocardial CHO oxidation, evidences lim-  ited metabolic flexibility. These data indicate that there is a remark-   able chronic requirement and utilization of glucose in patients with ischemic CAD.³⁴ The ability of ischemic myocardium to upregulate glucose extraction by overexpressing glucose transporters is  lim-  ited^35,36 and some evidence indicates that physiological plasma  glu-  cose levels and insulin activity are essential  to  increase  glucose delivery to tissues, thereby playing a protective  role.^37-39  In  agree-  ment with this, hypoglycemia has been shown to extend the area of necrosis in the ischemic heart,⁴⁰ and recent  trials  addressing  exces-  sive glucose reduction following the  therapy  in  type-2  diabetes patients found an increased rate of cardiovascular  events and mortal-  ity, correlated with the frequency of hypoglycemic episodes.⁴¹ How- ever, the switching from FFA to glucose substrate utilization is not completely benign. In fact, the increased use of glucose changes the glutation-related and mTOR pathways favoring hypertrophy and oxi- dative stress.⁴² Activation of mTORC1, a major regulator of  cell  growth, promotes protein synthesis and responds to  stress,  and nutrients, particularly amino acids and glucose.⁴³ AMPK is low and activated by exercise overload and ischemia and regulates the glucose uptake with an insulin-independent mechanism⁴⁴ (Fig 2).

FIG 2. Caloric restriction improves insulin sensitivity that inhibits directly the Akt/NF-kB and increase the AMPK in the cell. NF-kB inhibits phosphorylation of mTOR and reverses left ventricu- lar remodeling and cardiac function The activation of both signaling act directly on mitochondria in the cardiomyocytes. AMPK and PGC1 increase mitochondrial biogenesis and autophagy. The increased efficiency of mitochondria reduces the ROS production and improvement of cell survival and apoptosis. Prolonged starvation reduces the muscle mass and strength favoring cachexia.

 

Protein and Amino Acids

In chronic heart failure (CHF) patients, a reduced circulating level of amino acids was observed, that is correlated with HF severity.⁴⁵ Amino acids have a regulatory effect on myocardium protein turnover^46,47 and raise the oxygen consumption and glucose oxidation.⁴⁸ Amino acids have the physiological function to stimulate mitochondrial energy production under anaerobic conditions⁴⁸ and activate the protein synthesis in cardio- myocytes⁴⁷ in the presence of glucose and insulin that accelerates the for- mation of peptides chains.⁴⁹ A higher amino acid levels, more specifically branched chain amino acids (BCAA), are oxidized by the heart, and a 7% of O₂  consumption  is  required  proceeding  through  the formation of CoA derivative⁴⁹ suggesting a role as metabolic fuels and a primary anabolic effect on the human heart.⁴⁶ Amino acids avail- ability is crucial for heart and depends solely on serum amino acids lev- els.⁵⁰ Myocardial tissue uses amino acids for protein synthesis which is regulated by the availability of the circulating amino acids, by the avail- ability of oxidative substrates, by the oxygen delivery, and the availability of anabolic hormones.⁴⁷

However, recent reports found that an abnormal amino acids metabo- lism (included BCAA) were correlated with pathologic remodeling after myocardial infarction⁵¹ and a higher concentration of serum level of BCAAs was correlated with increased risk of CVD, especially stroke, in a population with high cardiovascular risk.⁵² A high level of BCAAs was correlated with cardiac diseases⁵³ and that a defect in the catabolism of BCAA is implicated in the pathogenesis of HF⁵⁴ associated with elevated oxidative stress, and profound metabolic changes in the heart. BCAA catabolism in the myocardium is an underconsidered part of metabolic dysfunction and could explain therapeutic target for the disease.

3.6 g/kg/day and lipids 1.2 g/kg/day, the level of essential and BCAAs were found extremely reduced compared to healthy (Fig 3). Nutritional intake was not responsible for the low amino acids level. However, these data show that a diet with normal caloric and protein intake in HF patients needs along much time to restore the normal circulating level of amino acids probably due to malabsorption and that protein ingestion should  beIn patients with CHF, Aquilani et al⁴⁵ found a reduced arterial amino acids levels that were correlated with the severity of left ventricular dys- function. In the study NYHA class II, III, and IV have been evaluated, and all class-patients received an adequate nutritional intake. In patients in NYHA class IV group  which  received  the  nutritional  intake  of  kcal 2132     482/day (29.2 kcal/kg/day), protein 1.3 g/kg/day and CHO

FIG 3. Serum level of total amino acids (AA), essential amino acids (essential AA) and branched chain amino acids in healthy (orange) and FH patients (blue) (from Aquilani et al⁴⁵ modified, with permission). (Color version of figure is available online.)

 

supplemented with essential amino acids. Unfortunately, in this study, the plasma level of anabolic hormones such as insulin, testosterone, estradiol, and IGF1 was not detected and this could have explained in part this aspect.

The effect of protein intake on the progression of CVD and HF remains to be fully elucidated. Epidemiologic studies have found that a high intake of protein with the diet had no deleterious effect on CVD and HF^55,56 while the greater incidence of CVD was observed in middle age women.⁵⁷ In rats with HF induced by pressure overload, a high protein intake with the diet did not affect cardiac mass, left ventricular volumes or ejection fraction, or myocardial mitochondrial oxidative capacity, but the survival was significantly reduced.⁵⁸

 

Insulin Effects on the Ischemic Heart

Insulin activity, reducing plasma glucose level, plays an important anti-inflammatory effect on the heart counteracting left ventricular and mitochondrial dysfunction in ischemic myocardial tissue, although, the complexity of insulin signaling within the myocardium is not fully eluci- dated.⁵⁹ Higher plasma glucose levels have a deleterious effect on cardiac function,⁶⁰ impairing cardiomyocytes function at the nuclear level⁶¹ and reducing diastolic and systolic function.⁶² The acute overingestion of glu- cose activates an inflammatory process and the reactive oxygen species generation⁶³ through the NF-kB (nuclear factor kB), the most sensitive transcription factor to redox signaling.⁶⁴ Glycemic control is beneficial to reduce the risk of mortality in type-2⁶⁵ and type-1 diabetes.⁶⁶ Hyperglyce- mia in the acute care setting in HF patients was associated with increased mortality. Improving glucose control and insulin sensitivity in type-1 dia- betes patients significantly reduces the risk of microvascular complications and CVD.⁶⁷ The amount of carbohydrates ingestion is extremely important in the development of the inflammatory process, which is regulated by insulin activity.⁶⁸ Insulin activity, reducing plasma glucose level, plays an important anti-inflammatory effect on the heart counteracting left ventricu- lar and mitochondrial dysfunction in ischemic myocardial tissue, although, the complexity of insulin signaling within the myocardium is not fully elu- cidated.⁵⁹ Insulin has a vasodilator effect, by increasing arterial blood flow at the microcirculatory level and stimulating nitric oxide formation,⁶⁹ which has an anti-inflammatory, antithrombotic, and antioxidant effect,⁷⁰ by modifying directly the inflammatory molecules involved in this pro- cess.⁷¹ Insulin infusion had an inhibitory effect on Reactive Oxygen Spe- cies production and NF-kB expression in obese, insulin-resistant

 

subjects.⁷² Insulin possesses anti-inflammatory effects, as documented in intensive care unit patients,⁷³ in patients who undergo to coronary artery bypass grafting,^74,75 in acute myocardial infarction^76,77 and burned patients.⁷⁸ In patients with type-2 diabetes after myocardial infarction, long-term insulin administration improved survival and reduced the inci- dence of reinfarction,⁷⁷ confirming that excessive serum glucose levels are a strong predictor of mortality. Liepinsh et al⁷⁹ demonstrated that a chronic postprandial metabolic state, characterized by insulin elevation and conse- quent increased glucose and lactate utilization, has a protective effect against myocardial infarction.

However, insulin resistance has a detrimental effect on metabolic regu- lation, is a determining factor in the development of metabolic syndrome,⁸⁰ and is correlated with left ventricular diastolic dysfunction and structural alterations.⁸¹ Insulin resistance promotes the development of HF,⁸² inde- pendently from ischemic cardiac disease.^83,84 In cardiac hypertrophy induced by pressure-overload as aortic stenosis, insulin resistance, and reduced mitochondrial oxidative capacity are the early metabolic alteration favoring the progression toward HF.⁸⁵ Experimental clinical models in humans and animals have revealed an interdependence between insulin resistance and HF.⁸⁶ Insulin resistance in HF is associated with increased serum concentrations of proinflammatory cytokines, catecholamines, cata- bolic steroids,⁸⁷ and even with reduced testosterone and adiponectin levels in males.⁸⁸ The mechanism of action of insulin is complex and well sum- marized by Riehle et al.⁵⁹ Improvement in the biologic activity of insulin, after moderate weight loss and an appropriate diet in overweight and obese patients with ischemic cardiac disease, could be part of an overall therapeu- tic strategy to improve cardiovascular function and reduce HF events.

 

Effect of Weight Loss on Heart Function

Weight loss following a restricted calorie diet in obese patients is asso- ciated with metabolic and neurohumoral adaptations that may contribute to lifespan extension.⁸⁹ Calorie restriction improves mitochondrial func- tion, DNA repair, and autophagy,⁹⁰ and stimulates stem cell regeneration. In obese subjects, many clinical studies have shown that weight reduc- tion significantly improves cardiac function (see Table). Weight loss improved both left ventricular mass and cardiac function.^91-95 In obese patients with HF, intentional weight loss increased the cardiac efficiency and the quality of life.⁹⁶ Hypocaloric diets, with carbohydrate or fat restriction, associated with modest weight loss, reduce the triglycerides depot in the cardiomyocytes by approximately 25%.⁹⁷ However, Zamora

 

 

TABLE. Effect of weight loss on cardiac functions

Authors	Patients	Age	BMI	Intervention	Duration	Effects
Utz, 2013 (106)	38	45	29	Hypocaloric diet	6 months	Weight loss reduced myocardial

triglyceride      content Guglin, 2013 (103)                         433                  56.3                 27.9                 Spontaneous           3 months                   Both RV and LV systolic function

improves              Kardassis 2012 (101)                         44                    41.5                 42.5                 Bariatric surgery       10 years                     Left ventricular volume, stroke

volume and cardiac output primarily associated with lean body mass,

Haufe, 2012 (104)	170	44	32.9	Hypocaloric diet (low	6 months	Low CHO and Low fat diet
				CHO and low fat)		improved left ventricular mass
de la Fuentes, 2009 (102)	60	47	37	Diet women: 1200-	2 years	Moderate weight loss in obese
				1500 kcal/d;		subjects is associated with
				men:1500-1800		beneficial changes in
						cardiovascular structure and
						function.
Corrao, 2000 (105)	32	45	32	Hypocaloric diet	4 months	Improvements in LV structure and

 

 

LV, left ventricular; RV, right ventricular.

function.

 

 

 

et al⁹⁸ found that the spontaneous weight loss of about 5% in patients with HF is associated with long-term mortality. These discrepancies could be explained by the different effect of nutritional intake between a balanced calorie-restricted diet and spontaneous weight loss in HF patients. In obese patients with atrial fibrillation, a long-term sustained weight has been shown to substantially reduce arrhythmia burden and maintain sinus rhythm compared to controls.⁹⁹ De Lucia et al¹⁰⁰ have recently demon- strated that a long-term calorie restricted diet in HF patients improved the cardiac sympathetic innervation and inotropic reserve. In obese (??) chronic HF patients, a weight-reducing nutritional intervention was asso- ciated with improvement in NYHA classification and decreased HF- related rehospitalization.¹⁰¹ In patients with coronary artery disease, with- out HF, Ellsworth et al¹⁰² found that a weight loss of 7%-10% determined a down-regulation of the genes which modulated the vascular endothe- lium and decreased the cardiovascular risk. After 1 year, insulin level, C- reactive protein, and leptin levels were significantly reduced, and these changes were not observed in the control group.

In patients with metabolic syndrome, the restriction of calories and car- bohydrate intake have been found to improve insulin sensitivity, post- prandial hyperglycemia, and reduce cardiovascular risk, independently of the weight loss.¹⁰³ In other studies, body fat reduction following bariatric surgery improved ventricular and overall cardiac function in type-2 dia- betes patients, also resulting in improved glycemic control.^104,105

 

Effect of Calorie Restricted Diet on Heart Function

A caloric restricted diet has a beneficial effect on metabolism reducing the development of atherosclerosis,¹⁰⁶ preventing hypertension and car- diac hypertrophy,¹⁰⁷ reducing the pathogenesis of cardiac hypertrophy pressure overload-induced.¹⁰⁸ Furthermore, caloric restriction improves myocardial function by reducing the senescent process of myocardium suppressing mTOR and increasing autophagy.¹⁰⁹ De Lucia et¹⁰⁰ demon- strated that caloric restriction in male rats with HF improved cardiac function and inotropic reserve favoring sympathetic cardiac innervation and b-adrenergic receptor levels in the myocardium. However, the antiag- ing effect of caloric restriction on the myocardium has an opposite effect in old age compared to young age subjects.¹¹⁰

Caloric restriction acts mechanistically accelerating cardiac autophagy and reducing ATP content but modulated by AMPK,¹¹¹ and short-term calorie restriction improved AMPK myocardial expression in both young and old hearts.¹¹² AMPK plays an important role in protecting cardiac

 

function and homeostasis and myocardial adaptation to starvation.¹¹¹ The AMPK signaling becomes less responsive with advancing age, and after prolonged caloric restriction leads to cellular stress and dysfunction in cardiac contractility.¹¹³

Of high relevance is the autophagic process induced by prolonged star- vation in cardiac myocytes. In cultured cardiomyocyte cells, glucose dep- rivation activates the autophagic  flux  increasing  Sirt1,  required  for  the deacetylation of FOXO1 which is essential for maintaining left ventricular function during severe caloric restriction.¹¹⁴ Metabolic remodeling at the myocardial level precedes structural alterations activating the target of rapamycin complex 1 (mTORC1), a major regulator of cell growth, resulting in increased protein synthesis and hypertrophy.¹¹⁵ Autophagy is an essential biologic mechanism to maintain cellular and tissue  renovation  and  health.¹¹⁶  The  regulation of autophagy is not only a response to the starvation but in some tis-    sue occurs actively without starvation.¹¹⁷ Metabolic alteration includ-  ing glucose and amino acids oxidation may be responsible for mitochondrial dysfunction and antecedent to HF.¹¹⁸ Excessive activa- tion of autophagic flux can favor the transition to HF.¹¹⁹

Very-low-calorie diets can also be dangerous for cardiovascular metabolism and function.¹²⁰ Van der Meer et al¹²¹ showed that in 14 healthy men a very-low-calorie diets (471 kcal/day, 50.2 g carbohydrates, protein, and 6.9 g fat) for a period of 3 days resulted in an increase in myocardial deposition of triglycerides and decreases in left ventricular diastolic function, without changes in ejection fraction. Similar results were reported by Reinolds¹²² after a 2-day fast. The increased deposition of triglycerides in cardiomyocytes is a consequence of the excessive plasma NEFA levels, as observed in type-2 diabetes and obesity.¹²⁰

 

Severely Restricted Diet and Mortality Risk

Even though weight loss has beneficial effects on cardiac function in obese patients, severely restricted diets can cause a detrimental effect on cardiac function and increase mortality risk in patients who have low body mass index (BMI)^123,124 as well as healthy adults.¹²⁴ Significant weight loss (ie, intentional or unintentional) can profoundly affect cardiac metabolism, particularly in persons with known CAD.¹²⁵ Low BMI can be associated with immobility, poor nutrition,¹²⁶ and frailty in the elderly, but is often not considered in a typical clinical evaluation.¹²⁷ Notably, some HF patients have a reduced hunger sensation, nausea, and spontane- ously restrict food intake.¹²⁸ Despite its high incidence in geriatric

 

patients, malnutrition is rarely recognized and treated¹²⁹ and is often missed as a clinical sign in patients with chronic HF.¹³⁰ Spontaneous weight loss should be treated aggressively because it represents a higher risk of muscle wasting and cachexia.¹³¹ Among healthy obese subjects, weight loss generally does not reduce mortality risk.¹³²

 

Effect of Starvation on Cardiac Function

Starvation, as observed in patients affected by anorexia nervosa, is associated with tissue alteration and many  medical  complications¹³⁶  and induces a significant  deleterious  effect  on  cardiac  function.¹³⁷  The most concerning are those related to the cardiovascular  system, such as serious arrhythmias or  structural  cardiac  alterations  which  lead to increased mortality.¹³⁸ During starvation protein and fat catab- olism are increased, which lead to loss of cellular volume and atro-     phy of various tissues, including brain, liver, intestine, kidney, and muscle, in addition to the heart muscle. Morphologic studies by ultra- sound have shown decreased cardiac mass, reduced cardiac chamber volumes, and mitral valve prolapse.^139,140  Congestive  HF  has  also  been described as a cause of  death in anorexia nervosa.¹⁴¹  Siegel et  al¹⁴² described a grossly normal heart that weighed 250 g with focal inflammation of the conduction system in association with massive weight loss due to dieting. Isner et al¹⁴³ described a reduced cardiac weight of 120-140 g, with  a grossly normal aspect. Histologically,  it  has been reported that widespread interstitial fibrosis in the papillary muscles and myxoid material deposition occurs, which can be respon- sible for rhythm disturbances in patients with anorexia nervosa.¹⁴⁴ In some anorexic patients, the cause of death was associated withProlonged calorie restriction has a deleterious effect on cardiac physi- ology and function. Cordero-Reyes et al¹³³ showed that energy starvation in HF patients caused metabolic alteration through reduced mitochondrial number but not a reduction in mitochondrial electron transport capacity. Deficient carbohydrate diets ( 800 kcal/daily) may negatively impact vascular endothelial function while maintaining recommended carbohy- drate intake generates a more favorable vascular profile.¹³⁴ In mice, a restricted caloric diet (by 40%) for 30 weeks showed a decreased ventric- ular mass and cardiomyocyte contractility, elevated phosphorylation of AMPK, and depressed phosphorylation of mTOR and ULK1.¹³⁵ These data suggest an indispensable role of AMPK in the maintenance of car- diac metabolism under prolonged caloric restriction through autophagy regulation.¹³⁵

fibrosis and myxoid material deposition which are a direct conse-  quence of starvation.¹⁴⁴  In  patients  following  severe  restrictive  diets, a mild QTc prolongation has been observed,¹⁴⁵ but  the QTc  interval  was not correlated with the disease severity¹⁴⁶ but was negatively associated with serum potassium concentrations.¹⁴⁷

Nutrition in Chronic HF Patients

In patients with chronic HF, food intake is extremely important to improve the quality of life and survival rate. Overweight and mildly obese patients with CVD, compared with underweight patients, have a better prognosis as expressed by the obesity paradox concept.¹⁴⁸ BMI has been shown to be inversely correlated with all-cause mortality,¹⁴⁹ and overall cardiovascular mortality is reduced with higher BMI.^150,151 An increase in BMI of 5 units decreases the risk of mortality by 10%.¹⁵² Notably, the mortality rate is increased at the high end of the extreme of the BMI distribution resulting in a U-shaped pattern, with increased mor- tality at both the lowest and highest BMI.^153,154

Moreover, after adjustment for confounding factors,¹⁵⁵ the group with the lowest BMI (<18) exhibited the highest mortality. The obesity para- dox could be partially explained by a significantly lower sympathetic acti- vation in obese CHF patients¹⁵⁶ (impact of visceral obesity upon the metabolic syndrome). Importantly, however, only BMI has been used as the criterion for obesity in these studies, while fat-free mass and muscle mass are arguably more important given that they are stronger predictors of LV mass than fat mass.

Macronutrient ingestion influence blood substrates which has a signifi- cant effect on the insulin-sensitive tissue.¹⁵⁷ A reduction in calorie intake exerts a profound effect on weight loss representing the principal factor of reducing all metabolic syndrome components, independent from diet composition.¹⁵⁸ Daily caloric intake of about 125 kJ/kg (=29 kcal/kg) and a daily protein intake of 1.2-1.4 g/kg body weight is recommended for elderly patients at normal weights.¹⁵⁹ In overweight and obese patients less energy intake is required (20-24 kcal/kg/day). A reduction in dietary fat intake to about 25% of total caloric intake (0.6-0.8 g/kg/day) is ade- quate because high-fat diets associated with low-carbohydrate predispose to insulin resistance.¹⁶⁰ In overweight patients, restricted calorie diets cause an improvement in insulin resistance independent of macronutrient composition. Ketogenic diets improve insulin resistance,¹⁶¹ and  low  carbohydrate  and high protein diets enhance metabolic equilibrium and reduce cardiovascular risk.¹⁶² The reduction in calorie intake is effective to

 

reduce body fat independent of diet composition, but a diet with high-CHO and low-fat composition is more effective in reducing the markers of MetS.¹⁶³ A relatively high-carbohydrate diet is suggested during submaximal exercise because it increases the rate  of  whole- body fat oxidation and reduces the rate of muscle glycogenolysis.¹⁶⁴

Weight loss induced by a very low CHO and high-saturated-fat diet is detrimental to cardiac function and has a detrimental effect on CVD risk factors.¹⁶⁵ Nilsson et al¹⁶⁶ found that a low CHO-high fat diet in mice for 2 weeks caused an increase in body fat and a reduction in lean mass; after

4 weeks cardiac function also deteriorated. Low CHO-high fat diets impair cardiomyocytes function was reduce the myocardial response to ischemia. The increased fatty acid oxidation in the presence of reduced CHO availability compromises the recovery of left ventricular function.¹⁶⁷ Also, low CHO-high fat diets have been shown to be a limiting factor in endurance athletes in whom the adaptation to training and performance benefits are negated.¹⁶⁸ Low CHO-high fat diets may have some clinical applications, but this does not appear to be the case in patients with CVD or those with dyslipidemia or insulin resistance.¹⁶⁹ In the myocardium, oxi- dation of fatty acids is inhibited proportionate to the increased availability of fatty acids causing contractile dysfunction.¹⁷⁰ This metabolic change, if protracted for an extended time (weeks or months), can cause measurable damage to the cardiac tissue causing a dramatic lipid deposition within cardiomyocytes upon fasting.

Increasing FFA oxidation results in a reduction in glucose oxidation but causes a decrease in cardiac function and efficiency.¹⁷¹ CHO metabo- lism reduces FA oxidation and cardiac alteration under stress conditions of cardiac overloads, such as exercise, hypertension, and hypertrophy.¹⁷² Improving glucose utilization by myocardial tissue is an effective strategy to prevent the progression of cardiac dysfunction such as that associated with pathologic hypertrophy.¹⁷³ A high polyunsaturated and saturated fatty acid intake was significantly associated with 1-year mortality in patients with chronic HF.¹⁷⁴ In patients without HF, higher plasma FFA were associated with a 12% higher risk of HF.¹⁷⁵

Nutritional Intake in CHF Patients

The major nutritional dysfunction in HF patients is represented by mal- nutrition. Various clinical studies have found that patients with CHF are in a prevalent malnutrition state varying from 54%¹⁷⁶ to 60%-69%,¹⁷⁷ and the prognostic value of malnutrition, assessed by the Controlling Nutritional Status, demonstrated that represent the best predictor of

 

death.^178,179 After 1-year follows up, the mortality rate was 65% between patients malnourished and frail while only 1% between those who were neither frail nor malnourished.¹⁸⁰ However, an excess of nutritional intake leads to cardiac dysfunction and HF¹⁸¹ It appears evident that an adequate nutritional intake in HF patients is recommended.

Micronutrients

Micronutrients have been proposed to have a benefit in improving clin- ical management of HF patients.¹⁸² A sodium-restricted diet (2000-4000 mg/day) with a reduction in total fluid ingestion to 1.5 l/day has been sug- gested to result in clinical improvements in HF functional class.¹⁸³ Len- nie et al¹⁸⁴ showed that higher sodium intake (more than 3 g daily) increased the risk of rehospitalization more than 2 times compared to patients with lower sodium diets. Further analysis showed no advantages related to further sodium reduction in patients with stable HF.¹⁸⁵

Omega-6 and omega-3 are essential fatty acids that mediate cellular inflammatory responses¹⁸⁶ and decrease the risk of serious arrhythmias and sudden death.¹⁸⁷ The American Heart Association has recently expanded the list of Class recommendation for Omega 3 prescription in CVD patients for their medical benefits.¹⁸⁸ Although many supplements have been suggested for HF patients including coenzyme Q10, carnitine, and vitamin D, the potential benefits to cardiac function remain to be proven.¹⁸⁹ The administration of multiple micronutrient supplementa- tions in chronic stable HF patients taken for 12 months provided no evi- dence of any benefit.¹⁸⁵

Antioxidant vitamins (vitamin C, E, and b-carotene) did not show posi- tive evidence for a protective effect on CVD and mortality.¹⁹⁰ However, the serum level of vitamin E was negatively associated with endothelin function.¹⁹¹

Coenzyme Q10 is a component of cellular membranes and is involved in the production of ATP in the mitochondria improving the electron transport chain and reducing the redox reaction. In patients with chronic HF, the administration of CoQ10 (100 mg x 3 times daily) was safe and reduced some cardiovascular complications.¹⁹² However, the beneficial effects remain uncertain, and larger randomized clinical trials on CoQ10 supplementation in patients with CVD are needed.¹⁹³ Daily intake of res- veratrol at the dose of 150 mg/daily of for 4 weeks did not improve meta- bolic markers related to cardiovascular health.¹⁹⁴ Sciatti et al¹⁹⁵ in a review evaluating the effect of micronutrients in patients with HF

concluded that a beneficial role remains to be demonstrated and large  clinical trials with a single supplement method are required.

Future Perspectives

Clinical trials in patients with HF with specific calorie-restricted diet prescription with high CHO and protein and low fats contents are neces- sary to evaluate the myocardial efficiency. A low-calorie diet of 1200-kcal/daily in obese patients was safe for a long period up to 16 weeks,¹⁹⁶ and no different effect in improving insulin resistance between high vs the low glycemic index of CHO was found.¹⁹⁷ Calorie restriction with different modalities such as intermittent fasting (60% energy restric- tion on 2 days per week) or periodic fasting (a 5-day diet providing 750- 1100 kcal) and time-restricted feeding improved insulin resistance and the risk factors for CVD¹⁹⁸ have been evaluated in healthy and over- weight human subjects with positive effects. However, further investiga- tion on the effect of a restricted calorie diet and with balanced macronutrients in patients with CVD and HF is necessary. Furthermore, in association with nutrition, the anabolic hormone level should be con- sidered at the same time.

Conclusion

Nutrition has an essential impact upon the recovery of heart func-   tion in patients with CVD and HF for improving energy metabolism   and energy transfer, and for reducing HF mortality. Macronutrients regulate cardiomyocyte activity which can be improved by the opti- mization of glucose uptake, improved insulin activity, and by reduced  fat intake. Weight loss, through excess  fat  loss,  is  useful  for  obese and type-2 diabetes patients, while some  evidence  points  to  weight loss being detrimental to underweight  patients  for  whom  mortality  risk may be increased. Thus, from a clinical perspective, dietary interventions should be personalized, based on consideration of anthropometrics data representing states of excess adiposity, under- weight, or low lean body mass.

Overweight and obese individuals should adopt a gradual restriction of calories from unhealthy fats and refined carbohydrates while main- taining lean body mass through ingestion of healthful fats, complex car- bohydrates, and appropriate protein intake consistent with body mass requirements.

Overweight and obese subjects need a calorie-restricted diet, targeted to a 40% reduction in caloric ingestion and based on basal energy

 

expenditure with high protein, low-fat composition improving insulin activity and glucose utilization by cardiomyocytes. In lean or under- weight subjects, the diet should be nutritionally balanced, and isocaloric to maintain and preserve lean body mass calorie ingestion should counter- act the risk of malnutrition to prevent cardiac cachexia and increased risk of cardiac mortality.

 

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The importance of nutrition in the recovery of heart function in patients with CVD and HF have several potential benefits.

Several perspectives can be drawn from Dr Bianchi’s review.

Macronutrients regulate cardiomyocyte activity. Heart function can be can be improved by optimizing glucose uptake, insulin activity, and by reduced fat intake.

Weight loss, through excess fat loss, is useful for obese and type-2 diabetes patients. However, in patients that are underweight weight loss could be detrimental.

Dietary interventions should be personalized, based on consideration of anthropometrics representing states of excess adiposity, underweight, and low lean body mass.

Overweight and obese individuals should adopt a gradual restriction of calories from unhealthy fats and refined carbohydrates while maintain lean body mass through ingestion of healthful fats, complex carbohydrates, and appropriate protein intake.

Diets in underweight and lean patients, should be nutritionally balanced and isocaloric to maintain and preserve lean body mass in order to prevent cardiac cachexia.

I want to thank Dr Bianchi for an interesting review of nutrition, a very important subject in the management of cardiovascular diseases.