Regional Lactic Acid-Fermented Specialties in the Philippines
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He graduated and obtained his Ph.D. in Applied Life Sciences from Tokyo University of Agriculture and Technology (Japan) in 2011. He was awarded Japanese government scholarship and he visited University of California at Davis (UCD) as an exchange student in 2010. After his graduation, he became a research fellow at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg (Germany). Dr. Ying acts as a reviewer of many scientific journals and has authored or co-authored over 25 scientific publications. 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Filipino cuisine is no exception as distinct regional flavors stem from the unique food preparation techniques and culinary traditions of each region. Although Philippine indigenous foods are reminiscent of various foreign influences, local processes are adapted to indigenous ingredients and in accordance with local tastes. Pervasive throughout the numerous islands of the Philippines is the use of fermentation to enhance the organoleptic qualities as well as extend the shelf-life of food.
Traditional or indigenous fermented foods are part and parcel of Filipino culture since these are intimately entwined with the life of local people. The three main island-groups of the Philippines, namely – Luzon, Visayas, and Mindanao, each have their own fermented food products that cater to the local palate. Fermentation processes employed in the production of these indigenous fermented foods often rely entirely on natural microflora of the raw material and the surrounding environment; and procedures are handed down from one generation to the next as a village-art process. Because traditional food fermentation industries are commonly home-based and highly reliant on indigenous materials without the benefit of using commercial starter cultures, microbial assemblages are unique and highly variable per product and per region. Hence the possibility of discovering novel organisms, products, and interactions are likely.
Various microorganisms are involved in common food fermentation processes. In particular, lactic acid bacteria (LAB) in food is a type of biopreservation system. They not only contribute to the flavor of the food but LAB are also able to control pathogenic and spoilage microorganisms through various ways that include, but are not limited to, production of peroxidases, organic acids, and bacteriocins. Traditionally, identification of LAB in foods is largely dependent on culture-based methods; and properties of each isolate are evaluated under controlled conditions. However, with the advent of molecular techniques, the enumeration of microorganisms missed by culture-dependent methods is now possible. Also, as more LAB metabolites, such as bacteriocins, are being reported, a wider database for identification and comparison with potential novel products are now available.
As the production and consumption of traditional fermented food products become increasingly relevant in the face of rapidly increasing population and food insecurity, more research and development to ensure the safety and nutritional quality of these fermented products is warranted. For a more extensive discussion of the principles and technology of Philippine fermented foods, the readers are directed to Sanchez (2008). This book is a detailed reference based on decades of research. Some data from the book will be presented again here in addition to other data from more recent studies. It is not the intention of this present paper to repeat what has been presented in the book, especially regarding fermentation processes, but only to present, as complete as possible, the data that are available regarding LAB present in indigenous/traditional fermented foods.
This paper aims to briefly review the various lactic acid-fermented indigenous fermented specialties in the different regions of the Philippines. Majority of the discussion will focus on recent data gathered from bacteriocin research and metagenomics studies of Philippine fermented specialties. Lastly, the health applications of the different fermented food products and their development as functional foods will be evaluated.
There are various lactic acid-fermented indigenous food products in the Philippines. Table 1 gives a summary of these different fermented specialties found in the different regions. Although a particular product type can be seen throughout the whole country, the texture, taste, and appearance would vary depending on the local taste, materials used, and process employed. For example, bagoong is a common fermented fish paste found all over the Philippines but the characteristic of the product found in Luzon is different from that found in the Visayas and Mindanao regions. Bagoong also takes on different names; there is bagoong na isda, bagoong alamang, bagoong na sisi, and guinamos (Sanchez, 2008). A product that is processed in a similar manner is dayok; it is made of brined fish entrails. Research indicates that this is also a lactic acid-fermented food but the LAB involved have not been identified yet (Besas and Dizon, 2012). Longanisa is sausage made of beef, pork, or chicken. It also takes on many forms depending on where it is made. The more famous ones are Vigan Longanisa in Northern Luzon, Pampanga Longanisa in Central Luzon, Lucban Longanisa in Southern Luzon, and Cebu Longanisa in the Visayas. The tastes vary from spicy, garlicky, sour, to sweet.
In lactic acid-fermented foods, LAB are important in preventing the growth of spoilage organisms, and altering flavor, aroma, and texture of the product. Although LAB are initially present in low numbers in the raw materials used, they soon proliferate as other organisms are inhibited by the initial addition of salt and as the continuous growth of LAB decreases the pH of the food making it less conducive for growth of other organisms. Recent studies, however, have shown that there are a lot more benefits that can be derived from LAB in traditional fermented foods.
CATEGORY | PRODUCT NAME | REGION | MAJOR INGREDIENTS | LACTIC ACID BACTERIA INVOLVED (as determined from culture-based methods) | APPEARANCE AND/OR USAGE |
Fermented vegetables, fruits | Burong mustasa | Luzon | Mustard leaves, cooked rice and/or rice washings | Leuconostoc mesenteroides, Enterococcus faecalis, Lactobacillus plantarum | Side dish |
Burong pipino | Whole Phil | cucumber | Leu. mesenteroides, L. brevis, Pediococcus cerevisiae, L. plantarum | Side dish | |
Burong mangga | Whole Phil | Immature mango | Leu. mesenteroides, L. brevis, P. cerevisiae, L. plantarum | Side dish | |
Atchara | Whole Phil | Immature papaya or chayote, or turnip (singkamas) | Unknown | Side dish | |
Cheese | Kesong puti | Luzon, Visayas | Cow or carabao milk | Lactococcus lactis | White soft cheese |
Fermented fish and fishery products | Balao-balao | Luzon | Cooked rice, shrimp, salt | Leu. mesenteroides, P. cerevisiae, L. plantarum | Side dish, condiment |
Burong-isda | Luzon | Freshwater fish, rice, salt | Leu. mesenteroides, E. faecalis, P. cerevisiae, L. plantarum, P. acidilactici, Leu. paramesenteroides | Side dish, condiment | |
Tinabal | Visayas | Parrot fish (for tinabal molmol) and frigate fish (for tinabal mangko), salt | P. pentosaceus, S. equinus, Leuconostoc sp., Lactobacillus sp. | Side dish, viand | |
Burong talangka | Luzon | Small shore crabs (Varuna litterata) | Leu. mesenteroides, E. faecalis, P. cerevisiae, L. plantarum | Side dish, viand | |
Patis | Whole Phil | Small fish, salt | P. halophilus (in mixed fermentation) | Fish sauce (patis), fish paste (bagoong), used as condiment, sauce, flavoring agent, viand | |
Bagoong isda | Whole Phil | Small fish, salt | |||
Bagoong alamang | Whole Phil | Small shrimps, salt | |||
Bagoong na sisi | Visayas | Shell fish, salt | |||
Guinamos | Bagoong isda in Visayas, Mindanao | Salt water small fish (dilis/belabid – Stolephorus sp.), salt | Condiment, viand, side dish | ||
Dayok | Visayas, Mindanao | Fish entrails, salt | Unidentified LAB | Condiment, viand, side dish | |
Fermented meat, sausages | Longanisa | Whole Phil | Ground pork, beef, or chicken meat, spices and preservatives | P. acidilactici, Lactococcus lactis (together with Micrococcus aurantiacus) | Viand |
Agos-os | Visayas | Sweet potato and ground pig’s head | E. faecalis | Viand | |
Burong kalabi | Luzon | Cooked rice, ground carabao meat | L. plantarum | Side dish, viand | |
Burong babi | Luzon | Cooked rice, ground pork | L. plantarum | Side dish, viand | |
Fermented rice, cassava, sugar cane, coconut, soya | Puto | Whole Phil | Rice, sugar | L. mesenteroides, E. faecalis, P. cerevisiae (in mixed fermentation with Saccharomyces cerevisiae) | Steamed rice cake |
Bibingka | Whole Phil | Rice, sugar | Baked rice cake | ||
Tapuy | Luzon | Rice, glutinous rice | Leuconostoc, L. plantarum (in mixed fermentation with molds and yeasts) | Wine; beer | |
Pangasi | Mindanao | Rice | Unknown | Wine | |
Landang | Visayas, Mindanao | Cassava, or buli palm flour | Unknown | Dried jelly pellets pellets, rice substitute | |
Puto balanghoy | Mindanao | Cassava | Unknown | Steamed cake | |
Basi | Luzon | Sugar cane | Unknown | Wine | |
Suka | Whole Phil | Sugar cane juice (for sukang Iloco), palm inflorescence sap (for sukang tuba) | Leuconostoc, Lactobacillus, Streptococcus in the initial fermentation phase only | Vinegar, condiment, flavoring | |
Sinamak | Luzon | Sugar cane juice, spices (chilies, onions, garlic) | Unknown | Spiced vinegar, condiment, flavoring | |
Pinakurat | Visayas, Mindanao | Coconut sap, chilies, salt, various spices | Unknown | Spiced vinegar, condiment, flavoring | |
Tuba | Whole Phil | Coconut sap | Unknown | Wine | |
Lambanog | Whole Phil | Coconut sap | Unknown | Wine | |
Toyo | Whole Phil | Soybeans | P. halophilus, E. faecalis, L. delbrueckii (in mixed fermentation with Aspergillus sojae and Saccharomyces rouxii) | Condiment, flavoring agent, seasoning |
Regional Lactic Acid-Fermented Specialties in the Philippines
Bacteriocins are antimicrobial proteins or peptides produced by certain bacterial strains. Unlike the peptide antibiotics they usually have a narrow spectrum of antimicrobial activity, usually inhibiting growth of closely related bacterial species or strains and lacking lethality to the producer strain (Riley and Wertz, 2002).
The bacteriocins of LAB are small, cationic, hydrophobic, or amphiphilic peptides or small proteins, composed of 20 to 60 amino acid residues (Chen & Hoover, 2003). The bactericidal mode of action and biochemical properties depend on the protein moiety that could be specific to a particular LAB strain, i.e. the N-terminal amino acids as determinant of receptors in the cell wall of the susceptible strains/species and C-terminal amino acids for the biochemical properties. LAB bacteriocin must have the following desirable properties: “(1) not active and nontoxic to eukaryotic cells, (2) become inactivated by digestive proteases, having little influence on the gut microbiota, (3) low pH and heat-tolerant, (4) have a relatively broad antimicrobial spectrum, against many food-borne pathogenic and spoilage bacteria, (5) show a bactericidal mode of action, usually acting on the bacterial cytoplasmic membrane: no cross resistance with antibiotics, and (6) have genetic determinants that are usually plasmid-encoded, facilitating genetic manipulation” (Apaga, 2012 as cited from Abriouel et al., 2007).
LAB bacteriocins have attracted attention in recent years because of their generally regarded as safe (GRAS) status and good value as natural biopreservatives which can find applications in the food and cosmetic industries (Cleveland et al., 2001; Daeschel, 1993; Riley and Wertz, 2002). Nisin, produced by strains of Lactococcus lactis, has been used in over 50 countries as anti-listerial and anti-clostridium substance. LAB bacteriocins with selective inhibition on food pathogens such as Listeria monocytogenes, but no inhibition on important lactic acid bacterial inocula such as the noted probiotic Lactobacillus paracasei or Lactobacillus rhamnosus; and yogurt-producing Lactobacillus delbrueckii subsp. bulgaricus and Lactococcus thermophilus, may provide advantage over those that have a wider spectrum of antimicrobial activity and would kill these beneficial organisms, including nisin (De Vos, 1993; Jack and Ray, 1995; Nielsen et al., 1990). Hence, efforts on the search for LAB bacteriocins and elucidation of their properties are actively being pursued by several research laboratories. The future holds a wide array of LAB bacteriocins available for various specific applications.
Some efforts on the isolation of bacteriocin-producing LAB had been started for more than a decade now in two major research institutions in the country namely: University of the Philippines Los Banos (specifically, the National Institutes of Molecular Biology and Biotechnology or BIOTECH-UPLB and the Institute of Biological Sciences or IBS-UPLB) and the Philippine Root Crop Research and Training Center, Visayas State University (VSU). These two institutions branched out knowledge on bacteriocin research through affiliate tutorship, as thesis advisers and as trainors to students and staff from a few other academic institutions which also did bacteriocin researches like University of Santo Tomas (UST), University of the Philippines Manila (UPM), De La Salle University (DLSU) and Ateneo de Manila University (ADMU). BIOTECH-UPLB and IBS-UPLB jointly worked on bacteriocins of Lactobacillus plantarum or plantaricins and those of Pediococcus acidilactici or pediocins. On the other hand, VSU devoted some efforts on the enterocins of Enterococcus spp. (Tan et al., 2001). DLSU also tried isolation of bacteriocin-producing LAB for food applications. UST was able to isolate bacteriocin-like inhibitory substances against medically important pathogens like K. pneumoniae (Dedeles et al., 2011). UPM and ADMU worked on human and animal health applications of bacteriocins.
Various fermented food products with proteinaceous components were the major sources of isolated LAB for bacteriocin screening. Such fermented food products are home-grown or produced by small enterprises and are still commercially available from public markets in Luzon, Philippines and some parts of the Visayas like Leyte island. Examples of Philippine indigenous fermented foods that were good sources of bacteriocin-producing LAB are fermented rice and shrimp (balao-balao), fermented rice and fish mixture (burong\n\t\t\t\t\tkanin at isda), fermented pork (burong babi) in Central Luzon (Elegado et al., 2003; Gervasio and Lim, 2007) and fermented pork and sweet potato (agos-os) in Eastern Visayan region (Samar and Leyte). On the other hand, pickled vegetables like mustard leaf (burong mustasa) and green papaya (achara), fermenting fruits like pickled green mango, bignay or mango wine (Samnang 2010), fermented salted fish (bagoong), spicy sausages (longganisa) may contain some LAB but often times they are not bacteriocinogenic (Gervasio and Lim, 2007). The obvious reasons are the presence of inhibitory substances like salt, spices, alcohol or acid and of course the dearth of proteinaceous materials in the food material.
In one of the first isolation studies for bacteriocinogenic LAB, various proteinaceous fermented foods native to Central and Southern, Philippines were screened for bacteriocin-producing bacterial isolates. Seventy one out of several hundreds of colony-forming unit isolated by agar plate streaking were found antagonistic to the indicator microorganism, Lactobacillus plantarum ATCC 14917, through direct assay. By “spot-on-lawn” assay by pH-neutralized culture supernatant, nine (9) isolates were confirmed to be bacteriocin producers (Elegado et al., 2003). Banaay et al. in 2004 also reported on the isolation of 1,100 putative LAB from indigenous fermented foods in Luzon, Philippines. A strain of Lactobacillus plantarum was selected as the best bacteriocin producer. In another study, out of the 160 putative LAB obtained from 19 fermented food products from public markets in Central Luzon, 32 LAB isolates were found to be bacteriocinogenic (Gervasio and Lim, 2007). Santiago et al. (2008) were also able to find two LAB isolates, Lactobacillus fermentum LBA-19 and Lactobacillus casei LTI-21, screened from among several LAB isolates from various fermented food products from different regions in the Philippines.
Being pleomorphic, identification of LAB is quite challenging. A combination of various microbiological and molecular biology tools would help in finding the real identity. Banaay et al. (2004) did a thorough identification of the bacteriocinogenic LAB isolate using conventional morphological, biochemical and physiological methods, chemotaxonomic methods, as well as molecular methods. This is especially relevant to the identification of Lactobacillus plantarum which is a known pleomorphic bacteria. Most other Philippine LAB researchers often times directly apply 16S rRNA gene sequencing and homology search for LAB purified through repeated agar streaking and putatively identified as LAB just after determining its acid–forming, Gram positive and catalase negative properties. (Elegado et al., 2003; Gervasio and Lim, 2007; Santiago et al., 2008). Aside from 16S rRNA genes, other conserved genes were used for identification such as phenylalanyl-tRNA synthase (pheS) gene (Dedeles et al., 2011). Detection of bacteriocin genes through PCR may also be helpful in confirming the identity of the bacteriocinogenic LAB as well as the probability of producing the bacteriocin (Table 2).
ISOLATE/ STRAIN No. | IDENTIFICATION | (primer) HOMOLOGY to P. acidilactici type strain | REFERENCE | Bacteriocin gene by PCR; fingerprinting; HOMOLOGY |
AA-5a | partial 16S rRNA gene ID: P. acidilactici | (1492R)98% P. acidilactici UL5; 99% P. acidilactici DSM20284 (27F) 99% P. acidilactici LAB 001; 99% P. acidilactici DSM20284 | Elegado et al. 2003 | ped + ; REP and RAPD |
4E2 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 98% P. acidilactici UL5; 99% P. acidilactici DSM20284 (27F) 99% P. acidilactici LAB 001; 99% P. acidilactici DSM20284 | Apaga (2012) | ped+ |
4E4 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 97% P. acidilactici UL5; 99% P. acidilactici DSM20284 (27F) 98% P. acidilactici 8D2CCH01MX; 99% P. acidilactici DSM20284 | Apaga (2012) | ped+ |
4E5 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 99% P. acidilactici DSM20284 (27F) 99% P. acidilactici DSM20284 | Laxamana et al. (2011) | ped+ ; REP |
4E6 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 98% P. acidilactici UL5; 99% P. acidilactici DSM20284; (27F) 99% P. acidilactici 8D2CCH01MX ; 99% P. acidilactici DSM20284 | Apaga (2012) | ped+;[ 99% P. acidilactici bacteriocin genes ; pSMB74 ] |
4E10 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 96% P. acidilactici UL5; 99% P. lolii to NGRI0510Q (27F) 99% P. acidilactici LAB 001 ; 99% P. lolii NGRI 0510Q | Apaga (2012) | ped- |
4BL7 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 98% P. acidilactici UL5; 99% P. acidilactici DSM20284 (27F) 99% P. acidilactici 8D2CCH01MX; 99% P. acidilactici DSM20284 | Apaga (2012) | ped+ |
3G3 | API CHL50 ID: Lactobacillus pentosus(doubtful) partial 16S rRNA gene ID: P. acidilactici | (1492R) 99% P. acidilactici IMAU20090 (27F) 98% P. acidilactici DSM20284 | Elegado and Perez (2012) | ped+ ; REP; ped+ |
3G8 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 99% P. acidilactici UL5 (27F) 98% P. acidilactici DSM20284 | Elegado and Perez (2012) | ped+ |
3F3 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 95% P. acidilactici UL5 (27F) 98% P. acidilactici UL5; 99% P. acidilactici DSM20284 | Apaga (2012) | ped+ |
3F8 | partial 16S rRNA gene ID: P.acidilactici | (1492R) 98% P. acidilactici UL5; 99% P. acidilactici DSM20284 (27F) 99% P. acidilactici LAB 001; 99% P. acidilactici DSM20284 | Apaga (2012) | ped+ |
3F10 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 97% P. acidilactici UL5; 99% P. acidilactici DSM20284 (27F) 97% P. acidilactici LAB 001; 99% P. acidilactici DSM20284 | Apaga (2012) | ped+ [99% P. acidilactici genomic scaffold]; |
IG7 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 97% P.acidilactici UL5 99% P. acidilactici 8D2CCH01MX; (27F) 98% P. acidilactici DSM20284 | Apaga (2012) | ped+ [100% pediocin operon;PSMB74]; |
K2A2-3 | API: Pediococcus pentosaceus (good) partial 16S rRNA gene ID: P. acidilactici | (1492R) 97% P. acidilactici UL5; 99% P. acidilactici DSM20284 (27F) 99% P. acidilactici LAB 001; 99% P. acidilactici DSM20284 | Villarante (2011); Elegado and Perez (2012) | ped+ ; plan+ ped+ ; REP |
K2A2-1 | API: P. acidilactici (doubtful) | - | Abuel (2007) | ped+ ; plan+ ped+ |
K2A2-5 | API: P. acidilactici (doubtful); partial 16S rRNA gene ID: P. acidilactici | (1492R) 97% P. acidilactici UL5; 99% P. acidilactici DSM20284 (27F) 99% P. acidilactici LAB 001; 99% P. acidilactici DSM20284 | Apaga (2012) | ped+ [99% P. acidilactici genomic scaffold]; plan+ |
K2A1-1 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 99% P. acidilactici L94; 99% P. acidilactici DSM20284 (27F) 98% P.acidilactici JS-9-4; 99% P. acidilactici DSM20284 | Apaga (2012) | ped+ |
K3A2-2 | API: Lactococcus lactis (good) partial 16S rRNA gene ID: P. pentosaceus | - | ped+ ; plan+; ped+ | |
K3A2-3 | partial 16S rRNA gene ID: P. acidilactici | 100% P. acidilactici UL5 | Elegado and Perez (2012) | ped+ |
S3 | partial 16S rRNA gene ID: P. acidilactici | (1492R) 98% P. acidilactici UL5; 99% P. acidilactici DSM20284 (27F) 97% P. acidilactici LAB 001; 99% P. acidilactici DSM20284 | Apaga (2012) | ped+ [99% pediocin operon; pSMB72]; |
Identification and bacteriocin gene determination of putative Pediococcus acidilactici through 16S rRNA and pediocin gene PCR amplification and sequencing.
Purification of bacteriocin peptides or small proteins into homogeneity is necessary in order to fully characterize them, particularly the determination of molecular mass, the primary structure or amino acid sequence and secondary structure. For pediocin, it was found that a simple and rapid method is effective for its purification. This method involves adsorption of pediocin onto the cell wall of the producer cell at pH 6 and 0.05 M NaCl and then subsequent desorption at pH 2.0 and 1 M NaCl (Elegado et al., 1997; Yang et al., 1992). This method seemed more applicable to pediocin but not with the lactococcin, nisin or plantaricin. The reason is not clear but it could be related to variation in cell wall properties. The pH-adsorption/desorption method was able to provide materials for pH and temperature tolerance assays, estimation of molecular mass through SDS-PAGE, residual activity determination after protease, amylase and other enzyme actions (Laxamana et al., 2011). Enough amount of semi-purified bacteriocin from pediococci using this method was obtained for further purification through preparative reverse phase HPLC for various characterization studies, including the determination of secondary structures by circular dichroism and confirmation of double bonds through trypsin digestion and electrospray mass spectrometry (Elegado and Kwon, 1998). Other preparative purification methods prior to reverse phase HPLC and spectrometry included ion exchange chromatography and gel filtration chromatography (Elegado et al., 2003), and hydrophobic interaction chromatography (Villarante et al., 2011). This method could also be applied with bacteriocins of pediococci and lactobacilli. The properties obtained from well characterized bacteriocinogenic LAB are shown in Table 3.
Isolate | Identity | Bacteriocin | Purification mode | Properties |
AA5a | Pediococcus acidilactici | pediocin | pH adsorption/desorption Reversed-phase HPLC | Tolerant to pH 2-9 and 121 °C |
BS25 | Lactobacillus plantarum | plantaricin | Gel filtration chromatography Reversed-phase HPLC | MW = 3,830 Da |
K2a2-3 | Pediococcus acidilactici | pediocin | Hydrophobic interaction and ion-exchange chromatographies Reversed-phase HPLC | MW = 4,626 Da |
K2a2-1 | Pediococcus acidilactici | pediocin | pH adsorption/desorption | Optimum pH = 5-7 Resistant to boiling but not to autoclaving |
4E5 | Pediococcus acidilactici | pediocin | pH adsorption/desorption | Tolerant to pH 2-9; slight loss of activity at 100 °C; loss of activity at 121 °C; tolerates high salt; est. MW = 6,500 Da by SDS-PAGE |
List of purified and characterized bacteriocins from LAB isolated from Philippine indigenous fermented foods.
Bacteriocin production is largely dependent on the nutrients and nitrogen content of the fermentation medium. For instance, increased yeast extract concentration and polypeptone amount increases bacteriocin production. Molasses, raw sugar and sago hydrolyzates of amylase digestion were found to be good carbon sources. Other possible substrate base and supplements are cheese whey, coconut water and rice bran extract. Initial sugar concentration of usually 2 to 3% and inoculation rate of 3% by volume of at least 108 cells/mL provides good bacteriocin production (Elegado et al., 2001).
Bacteriocin production is highly dependent on cell or biomass growth. LAB are microaerophilic and most are either mesophilic or slightly thermophilic. The following conditions are applicable to their production: pH= 5.5 to 6.0; temperature = 35 – 40 °C; agitation = 50 rpm; without aeration. Usually, bacteriocin is optimally produced or secreted in the culture broth during the early stationary phase of growth. For Pediococcus acidilactici, culturing at 40 °C promotes earlier optimum bacteriocin production of around 10-12 hours. At 37 °C, bacteriocin production is from 14-16 hours (Sagpao et al., 2007).
Pediocins and plantaricins are the commonly found bacteriocins in Philippine fermented foods so far studied. Their antimicrobial properties have been investigated in several studies (Banaay et al., 2004; Elegado et al., 2003, 2004, 2007; Marilao et al., 2007). Although pediocins and plantaricins show promise, their applications are limited at present because it is a well-known fact that other bacteriocins aside from nisin are not yet approved for food use. For pediocins and plantaricins, the most practical use for now would be dermatological and animal health care use. But since the bacteriocin-producing LAB are of GRAS status, those with probiotic properties such as tolerance to acidic pH (2.0 -3.0) and bile (0.3%) and adhesion properties to intestinal mucosa would be an advantage when used as adjunct inocula in fermented food products (Gervasio and Lim, 2007).
Perhaps another importance of bacteriocin-producing LAB is their effectiveness in biomedical applications. In one study, for example, partially-purified pediocin K2a2-3, through pH-mediated bacteriocin extraction method, was found cytotoxic against human colon adenocarcinoma (HT29) and human cervical carcinoma (HeLa) cells in vitro as determined by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay (Villarante et al., 2011). Other potential biomedical applications will be discussed in the succeeding section.
An offshoot of the initial research on bacteriocins of LAB isolated from indigenous fermented foods is the emergence of probiotic research towards developing functional foods for biomedical applications. Probiotics refer to microorganisms that, when administered in adequate amounts, confers health benefits to the host. Although there are many microorganisms that can be considered as probiotics, LAB are the most common types because they produce antimicrobial compounds that inhibit other harmful microorganisms, they are able to tolerate acids and bile present in the digestive system, and they are able to adhere and establish themselves in the gut surfaces.
Many benefits have been ascribed to probiotics. For example, Lactobacillus casei (Shirota strain in Yakult®) have been shown effective in preventing diarrhea due to enterotoxigenic Escherichia coli (ETEC) and choleragenic vibrios (V. cholerae biotype E1 Tor and classical V. cholerae) using rats (Jacalne et al., 1990). This may be accounted for by its ability to kill the pathogens and inhibit further growth (Consignado et al., 1994). Because the probiotic used in the two studies mentioned is a commercial strain, current research on probiotics progressed to the search for indigenous LAB for use in the development of locally-produced functional food and investigation of their utility for biomedical applications. Metagenomic approaches to investigating LAB present in fermented foods have shown the diversity of potentially beneficial species present other than those that are readily detected by conventional culture-based methods. The development of functional food products shows potential in disease management. Research using metagenomic analysis in searching for microbial markers for use in functional foods to address certain lifestyle diseases as well as malnutrition is on the way.
Traditional culture-based methods have been used for isolating LAB from fermented foods. These studies form the basis for the starter cultures used in food fermentation technologies employed for commercial production. Sanchez (2008) gives detailed information on the different technologies and cultures used for the production of some traditional as well as developed technologies that have arisen from the culture-based studies conducted in earlier years.
In recent years culture-based approaches in LAB isolation have become more targeted for detection of bacteriocin-producers and those that have potential as probiotics. In one initiative, LAB isolates from fermented foods were screened for bacteriocin production and a PCR-based assay was used to detect specific bacteriocin-encoding genes. Acid and bile tolerance were also determined. Among all the isolates tested, Lactobacillus fermentum 4B1 and Lactobacillus pentosus 3G3 (later identified as Pediococcus acidilactici) have been identified as most promising for the development of new probiotic food products, hence they were chosen for subsequent biomedical application assays (Lim and Gervacio, 2007). In another study, LAB from traditionally fermented wine and vinegar from Visayas and Mindanao were isolated, identified, and tested for inhibitory activity against Enterococcus faecium, Listeria innocua, and Staphylococcus aureus. Five Lactobacillus paracasei and one Lactobacillus brevis showed antimicrobial properties against the tester strains (Licaros and Bautista, 2009).
With the advent of molecular techniques, the existence of non-culturable microorganisms has been acknowledged especially since the occurrence of culture-bias is already well-accepted. Culture-independent approaches, therefore, have been gaining popularity in microbial diversity studies and this includes researches on microorganisms found in fermented foods. The microbial populations in selected Philippine fermented foods were assessed through Polymerase Chain Reaction followed by Denaturing Gradient Gel Electrophoresis (PCR-DGGE) in two recent studies (Dalmacio et al., 2011; Larcia, 2010). Food samples tested include burong mustasa (fermented mustard), alamang (fermented shrimp paste), burong isda (fermented rice-fish mixture), balao-balao/burong hipon (fermented rice-shrimp mixture), tuba (sugar cane wine), and sinamak (spiced vinegar). Analysis of the 16S rRNA gene sequences revealed the presence of several LAB that have not been reported in these food products before. Weissella cibaria, Lactobacillus plantarum, Lactobacillus pontis, Lactobacillus panis, and Lactobacilus fermentum were detected in burong mustasa (Larcia, 2010). L. panis and L. fermentum were present in alamang; L. pontis and L. plantarum in burong isda; L. panis, L. pontis, and L. fermentum in burong hipon; and W. cibaria, L. pontis, L. panis, L. fermentum and L. plantarum in burong mustasa (Dalmacio et al., 2011).
The results of the two studies using molecular approaches in defining diversity of LAB in Philippine fermented foods show that culture-independent approaches are efficient tools for the analysis of microbial populations in fermented foods. Majority of the identified bacteria (LAB and other bacterial groups) have not been reported in culture-dependent studies. As such, the isolated bacterial 16S rRNA genes were cloned to have an initial partial 16S rRNA gene library for Philippine fermented foods (Dalmacio et al., 2011).
Anti-Obesity
Obesity is defined as an abnormal or excessive fat accumulation that presents risks to health. Probiotics can help in fighting obesity by reducing lipid absorption through its action on bile acid metabolism, and by assimilation of cholesterol thus eliminating it from the host’s system. Several studies were conducted to examine anti-obesity properties of different probiotic strains.
In one study, oral administration of Lactobacillus paracasei K3-4C, isolated from a locally fermented food had significant effect on lowering blood glucose levels (by 46%) and body weight (by 13%) in female BALB/c mice induced to be diabetic and obese through a 28-day high-fat diet (Parungao et al., 2006). In another study, orally administered L. fermentum 4B1 reduced adipose cell size, and decreased adipose tissue weight and overall body weight of mice fed with a high-fat diet for 49 days (Bautista et al., 2008). Likewise, oral administration of P. acidilactici 3G3 reduced body weight in diet-induced obese female Swiss mice (Parungao et al., 2009). In the last two studies described, the effects of the probiotics were determined to be comparable with the effects of the commercial anti-obesity drug Orlistat based on the parameters measured.
Recently, it has been postulated that the development of obesity may be caused by a shift in the composition of the gut microbiota towards the Firmicutes population (Ley et al., 2005). Firmicutes characterize obese versus lean/non-obese individuals together with a drop or no change in Bacteroidetes (Delzenne and Cani, 2010). Interestingly, Ley et al. (2006) found that a low fat diet had an effect to reverse the shift of Firmicutes/Bacteroidetes proportion. Because of this, dietary manipulation has been seen as a potential means of changing bacterial populations in the colonic microbiota and perhaps treating or at least preventing diseases like obesity. Although the root cause of obesity is excessive caloric intake coupled with a sedentary lifestyle (Blaut and Bischoff, 2010), Ley et al. (2005) proposed in their findings that alteration in the populations of mice gut microflora may have caused or may have been an effect of obesity. Because of this, current researches aim in using probiotics in the treatment of diseases such as obesity.
In two related studies (Arroyo and Fabiculana, 2011; Parungao et al., 2012), the effect of a functional food containing P. acidilactici 3G3 on microbial community changes in the gut of obese and non-obese mice was determined through PCR-DGGE. Results of these two preliminary studies showed that obese and non-obese mice had different baseline colonic microbiota. There were also indications that treatment with probiotics shifts the microbiota of obese mice towards the normal non-obese type. As these are preliminary studies, more research is warranted to elucidate the nature of the changes in gut microbiota and how it is related to obesity and the anti-obesity effects of probiotics.
Immuno-enhancement
A preliminary in vitro study to examine the immune-enhancing properties of viable and heat-killed preparations of two LAB previously isolated from traditional fermented foods (L. fermentum 4B1 and P. acidilactici 3G3) on murine peritoneal macrophage cells and spleenic T-cells showed that isolate 4B1 was able to induce NO production in murine macrophages but, like 3G3, was unable to stimulate murine T-cell proliferation (Tan et al., 2008). Furthermore, this study showed that preparations of L. fermentum 4B1 have the ability to induce NO production in murine macrophage cells and its effects were more potent when it was alive. The study also showed that isolate 4B1 exhibited better immune-enhancing effect than the probiotic species found in a commercial probiotic drink. T-cell proliferation, however, was not observed in any of the treatments in this study and was attributed to the delayed stimulation in cells responding to a first-time exposure to the different probiotic strain preparations used.
Reduction of blood glucose levels
A study by Ngo et al. (2008) showed that oral administration of kefir, a common fermented food consumed by the elderly, significantly decreased blood glucose levels and body weight of diabetic obese male Sprague Dawley rats. The results of the study showed lower blood glucose levels (from 198.5 to 105.6 mg/dL) and clinically lower body weights (from 342.9 to 311.5 g) of the treated diabetic-obese rats than the untreated diabetic-obese control group.
Prevention of hypercholesterolemia
The effect of P. acidilactici 3G3 administration on hypercholesterolemic Swiss Albino mice was determined (Parungao et al., 2009). This strain was able to assimilate cholesterol in the in vitro plate assay and decrease HDL, LDL, and total cholesterol in the in vivo assay using mice. Strain 3G3 was also shown to adhere well to the duodenum and middle colon. Results suggest the potential of P. acidilactici 3G3 in preventing hypercholesterolemia.
The development of functional foods containing known probiotic strains stems from earlier researches on bacteriocins and isolation of potential probiotics from traditional fermented foods. The beneficial effects of probiotic-supplemented chocolate bars (Arroyo et al., 2010; Arroyo and Fabiculana, 2011), fermented mustard leaves (Calapardo et al., 2006), and coffee wine (Parungao, 2007) have been investigated. Initial studies on mango-milk and carrot juice drinks supplemented with probiotic strains have also been conducted (Bugarin et al., 2010; Elegado et al., 2005). These potential functional foods contain probiotic strains, previously isolated from traditional fermented foods such as P. acidilactici AA5a (Elegado et al., 2003), L. plantarum BS25 (Banaay et al., 2004), and P. acidilactici 3G3 (Lim and Gervacio, 2007). Research on functional foods is still in its infancy but this food category shows promise in disease management as well as in contributing to food security in the country. Commercial interest in probiotic food products is increasing due to the growing understanding of its health benefits. This growing industry can derive benefits from the researches conducted on this emerging food category.
Aside from the research works presented earlier in this paper as well as on-going follow-up studies related to them, future goals may include research on a variety of other possible biomedical applications of LAB with potential probiotic properties. The effect of probiotics on Helicobacter pylori infections (that may cause peptic ulcers) may be determined. Their ability to modulate inflammatory and hypersensitivity responses as well as their effect on irritable bowel syndrome and colitis may be investigated. Further research on possible anti-cancer properties of probiotics is warranted as follow-up studies on the work done by Villarante et al. (2011). These studies are very important as these have the potential to address some of the more serious health concerns of our society.
Much is still to be learned about the existing probiotic strains. The molecular biology and genomics of these isolates may be pursued in order to further elucidate their properties and mechanisms of action.
Determination of factors affecting probiotic viability in foods is also important as these will determine if their survival in the food, and therefore their delivery into the host, is maintained. This will constitute a quality control for functional foods.
The potential physiological effects of multiple prebiotic strains, as opposed to a single strain, are also interesting areas of research. The delivery of multiple probiotic strains may help ensure its effectiveness in an environment that contains high diversity of resident microflora. The potential benefits of synbiotics, (combination of probiotic and prebiotic) which have synergistic interaction, may also be investigated. A good combination will greatly enhance the health benefits to humans.
Following the initial description of the physiologically corrective operation for tricuspid atresia by Fontan and Baudet [1] and Kreutzer and his associates [2] almost simultaneously, such surgery was widely adapted by most pediatric cardiologists and pediatric cardiac surgeons. This concept of bypassing the right ventricle (RV) was further extended to manage other cardiac defects with a functionally single ventricle.
The original surgery as described by Fontan and Baudet [1] consisted of (1) end-to-end anastomosis of superior vena cava (SVC) with the right pulmonary artery (PA) (classical Glenn procedure [3]), (2) connection of the separated right PA to the right atrium (RA) either directly or through an aortic homograft, (3) closure of the defect in the atrial septum, (4) insertion of a pulmonary valve homograft into the orifice of the inferior vena cava (IVC), and (5) ligation of the main PA, to entirely bypass the RV. On the basis of the procedures performed, one must infer that Fontan’s concept was to use the right atrium as a pumping chamber; therefore, he inserted a prosthetic valve into the IVC and right atrial-pulmonary artery junction.
On the contrary, Kreutzer et al. [2] anastomosed the right atrial appendage to the PA directly or by a pulmonary homograft and closed the ASD. Neither a Glenn procedure was performed nor a prosthetic valve was inserted in the IVC. Kreutzer’s view appears to be that the RA does not function as a pump and that the left ventricle functions as a suction pump in the system.
The surgical procedure as generally performed appears to shadow Kreutzer’s principle, and consequently, I have used the term “Fontan-Kreutzer operation” to describe this procedure [4, 5, 6, 7, 8]. However, because of priority of publication and more common usage in the literature, I will use the term “Fontan operation” in this chapter.
In this review, I will discuss the evolution of the Fontan concepts, the indications for Fontan operation, the Fontan procedure as used currently, and the results of old and current types of Fontan.
A number of modifications of the aforementioned surgery were made by these [1, 2] and other groups of investigators [9, 10] in the field. In this section, these concepts/procedures will be reviewed.
During the first 20 years after Fontan’s [1] and Kruetzer’s [2] description of the procedure, a number of modifications of the surgery were undertaken by several surgeons, as extensively reviewed and referenced elsewhere [9, 10]. In general, there was a consensus that there is no need for a classic Glenn anastomosis and that a prosthetic valve is not necessary in the IVC. Detailed review of these papers revealed that four major types of Fontan operations were being performed for physiologic correction of tricuspid atresia. These include (1) RA-PA anastomosis, direct or through a non-valved conduit; (2) RA-PA anastomosis through a valved conduit; (3) RA-RV anastomosis, direct or non-valved anastomosis; and (4) RA-RV anastomosis through a valved conduit.
In order to understand the advantages of one operation over the other, 17 papers published as of December 1990 that have documented adequate information to evaluate mortality and reoperation rates for each of the four types of Fontan surgery were reviewed. Pooled data from these 17 articles and statistical comparisons were presented in Tables I–IV for the interested reader [9]. This analysis revealed that atriopulmonary (RA-PA) connection appears to be better than atrioventricular (RA-RV) anastomosis and direct connection is better than valved or non-valved conduit anastomosis. Nevertheless, atrioventricular valved (homograft) conduit anastomosis appears to have advantages of (1) restoring a four-valved, four-chambered, biventricular heart and (2) lower right atrial pressure than with atriopulmonary connection. Based on these data [9, 10], the following conclusions were drawn: (1) direct atriopulmonary connection for children with tricuspid atresia with normally related great arteries and a small (<30% of normal) right ventricle without trabecular right ventricular component and for patients who had tricuspid atresia with transposition of the great arteries and (2) atrioventricular valved (homograft) conduit anastomosis for patients with tricuspid atresia and normally related great arteries but with a right ventricular size greater than 30% of normal and a trabecular right ventricular component [9, 10].
Bidirectional cavopulmonary anastomosis is a modified version of classic Glenn procedure in which the upper end of the divided SVC is anastomosed end to side to the right PA without disconnecting the latter from the main PA. Thus, the SVC blood is diverted into both the right and left PAs, justifying the term, “bidirectional.”
Experimental bidirectional cavopulmonary anastomosis was first studied by Haller et al. [11] in animal models, and its first clinical use was described by Azzolina et al. [12] in 1972. Other investigators [13, 14, 15, 16, 17] later applied this technique to palliate complex heart defects with decreased pulmonary blood flow. Hemodynamic advantages of the bidirectional Glenn procedure are improvement of effective pulmonary blood flow, decrease in total pulmonary blood flow, and reduction of left ventricular volume overloading. In addition, preservation of continuity of the pulmonary artery is an added advantage and may help facilitate a low-risk Fontan procedure. When both right and left SVCs are present, bilateral bidirectional Glenn shunts should be performed, especially if the bridging innominate vein is absent or small. Based on our own experience and that published in the literature [13, 14, 15, 16, 17], the author recommended serious consideration in employing bidirectional cavopulmonary anastomosis as an interim palliative procedure for patients who are at an increased risk for the Fontan procedure [9, 10].
Puga et al. [18] positioned a patch inside the right atrium to divert the IVC blood into the PAs; they had good results in the 12 patients that they used this technique. This was later called lateral tunnel and was widely used until extra-cardiac conduits came into vogue.
To better understand the valve-less atriopulmonary anastomosis type of Fontan, de Leval et al. [19] performed hydrodynamic studies and found that (1) the right atrium is not an efficient pump in non-valved atriopulmonary connections, (2) pulsations in a non-valved circulation truly generate turbulence with consequent decrease in net flow, and (3) energy losses occur in the non-pulsatile chambers, corners, and obstructions. In an attempt to address these deficiencies, they developed a procedure which they named “total cavopulmonary connection.” In this procedure, they connected the divided SVC, end to side, to the undivided right pulmonary artery (bidirectional Glenn), and the IVC blood is diverted through a composite intra-atrial tunnel (with the use of posterior wall of the right atrium as posterior wall of the tunnel) into the cardiac end of the divided superior vena cava, which in turn was connected to the PA. They felt that technical simplicity, maintenance of low right atrial and coronary sinus pressure, and reduction of risk of atrial thrombus formation are advantages of this type of operation. They performed this procedure on 20 patients and observed two early deaths and one late death. Postoperative hemodynamic studies were performed in 10 of the survivors which indicated good results. They recommended this type of operation for patients with a non-hypertrophied right atrium. While the total cavopulmonary connection was initially devised for patients with complex atrial anatomy and/or systemic venous anomalies, it has since been used extensively for all types of cardiac anatomy with one functioning ventricle and irrespective of venous anomalies.
Subsequent experimental studies by Sharma and his associates [20] indicated that complete or minimal offset between the orifices of the SVC and IVC into the right pulmonary artery decreases energy losses.
Marcelletti et al. [21, 22] used an interposition extra-cardiac conduit from the IVC to the PA in place of lateral tunnel used in total cavopulmonary connection in 1990. Subsequently, most surgeons adopted this modification of total cavopulmonary connection, and currently extra-cardiac conduits are used in most Fontan operations.
Since the vast majority of patients requiring Fontan operation present as neonates or in the early infancy, palliative procedures are performed at the time of presentation, and subsequently (at 12–18 months of age) the Fontan operation is undertaken. A considerable mortality (~16%) was seen with primary Fontan surgery, largely related to the impact of rapid changes in ventricular geometry and development of ventricular diastolic dysfunction. The concept of further staging the procedure by performing bidirectional Glenn procedure around 6 months of age followed by final Fontan between 12 and 18 months of age was introduced in early 1990s [23, 24]. Performing the Fontan procedure in stages appears to decrease overall mortality, most likely related to improving the ventricular function by correction of the afterload mismatch that is associated with one-stage Fontan procedure. At the current time, most centers prefer staged Fontan with bidirectional Glenn initially, followed later by extra-cardiac conduit diversion of the inferior vena caval blood into the PA.
In 1978, Choussat et al. proposed several criteria for performing Fontan operation [25]. Many cardiologists and surgeons have modified these criteria. Patients not meeting these criteria were deemed to be at a higher risk for a poor prognosis following a Fontan operation than patients who are within the limits of the set criteria. For the high-risk group, several investigators have proposed the concept of leaving a small atrial septal defect (ASD) open to facilitate decompression of the right atrium [26, 27, 28]. Laks et al. advocated closure of the atrial defect by constricting the preplaced suture in the postoperative period [28], while Bridges et al. [27] used a transcatheter closure method at a later date.
Higher cardiac output and significant decreases in the postoperative pleural effusions and systemic venous congestion were noted after a fenestrated Fontan procedure. In addition, the duration of hospitalization appears to have decreased. Nonetheless, these beneficial effects are at the expense of mild arterial hypoxemia and potential for paradoxical embolism.
While the fenestrated Fontan procedure was initially designed for patients at high risk for Fontan surgery, it has since been used in patients with modest or even low risk. Although rare, reports of cerebrovascular or other systemic arterial embolic events occurring after a fenestrated Fontan operation tend to contraindicate the use of fenestrations in patients with low or usual risk. In following years, fenestrated Fontan have been routinely used at most institutions. Some data indicate that routine fenestration is not necessary [29].
Patients who have undergone a fenestrated Fontan operation or patients who have a residual atrial defect, despite correction, may have clinically significant right-to-left shunt causing varying degrees of hypoxemia. These residual defects should be closed not only to address arterial desaturation but also for prevention of paradoxical embolism [30, 31]. Although two types of fenestration closure, namely, constriction of the preplaced suture in the postoperative period [26, 28] and device closure later [27] were described, device closure is opted at most institutions. Closure of such defects can be performed by using transcatheter techniques [32, 33, 34, 35]. The procedure is usually performed 6–12 months following fenestrated Fontan procedure. Although a number of devices have been used in the past [32, 33, 34, 35], at the present time, Amplatzer septal occluders are the most commonly used devices to accomplish such closures.
The indications for opting for a Fontan operation are patients who have one functioning ventricle. At first, patients with tricuspid atresia were selected for this procedure [1, 2]. Shortly thereafter, patients with double-inlet left (single) ventricle were added to the indications for Fontan [36]. Following description of surgical palliation of hypoplastic left heart syndrome (HLHS) by Norwood et al. [37, 38] in the early 1980s, HLHS became the major lesion requiring Fontan operation. Subsequently, mitral atresia (with normal aortic root), unbalanced atrioventricular septal defects (AVSDs), pulmonary atresia with intact ventricular septum with markedly hypoplastic right ventricle, and other complex heart defects with one functioning ventricle were selected for Fontan surgery.
Attempts to insert prosthetic ventricular septum for single ventricle patients met with problems, leading to abandoning such procedures. Thereafter, Fontan became a preferred treatment method. With reasonably good results of Fontan, the pendulum swung so that any patient who could not undergo complete repair became a candidate for Fontan.
A middle of the road method, the so-called one-and-one-half ventricle repair was developed for patients with pulmonary atresia with intact ventricular septum with modest-sized right ventricle. In this procedure, a bidirectional Glenn procedure to divert the SVC flow into the PA is performed and allows the small right ventricle to pump the IVC blood into the pulmonary circuit, and the patent foramen ovale is closed. It is generally considered to be a better option than Fontan, although, to my knowledge, there are no comparative studies to assess this issue.
Because of relatively high mortality rates (17.0–31.7%) [39, 40] and low actuarial survival rates (66.5% at 5 years and 64.4% at 15 years) [41] for unbalanced AVSD patients following Fontan, a number of institutions attempted single stage or staged biventricular repair or conversion from single ventricle (Fontan) to biventricular repair [39, 42, 43, 44, 45, 46, 47]. Detailed analysis by Nathan et al. [39] suggested that the biventricular repair and conversion from single ventricle (Fontan) to biventricular repair groups had reasonably similar mortality rates and a similar need for cardiac transplantation, but these parameters were lower than those seen in the Fontan palliation cohort.
Cardiac transplantation is a surgical alternative in the management of HLHS [48] and other single ventricle lesions. While heart transplantation was used at several institutions initially for HLHS, because of non-availability of donor hearts, most institutions have reverted to the Norwood/Fontan route. In addition, following successful cardiac transplantation, multiple medications for the prevention of graft rejection, frequent outpatient visits and periodic endomyocardial biopsy, to recognize rejection very early, are necessary in the management of these children. At the present time, cardiac transplantation is used for patients failing Fontan operation at a limited number of institutions.
As reviewed above, since the original description in the early 1970s, the Fontan procedure has undergone numerous modifications, and, at the present time it is best described as staged total cavopulmonary connection (TCPC) with an extra-cardiac conduit and fenestration. It is performed in three stages.
The majority, if not all, of patients who require Fontan operation (see Section 3. Indications for Fontan Operation) present during the neonatal and early infancy period, and the Fontan cannot be performed at that time because of naturally high PA pressure and high pulmonary vascular resistance (PVR). Therefore, Fontan, by necessity, becomes a multistage procedure. These babies should receive palliative intervention to allow them to reach the age and size to undergo successful Fontan surgery. The type of palliation is largely dependent upon the hemodynamic disturbance produced by multiple defects associated with a given congenital heart defect (CHD).
In neonates with decreased pulmonary blood flow, the ductus arteriosus should be kept open by administration of prostaglandin E1 (PGE1) intravenously at a dose of 0.05–0.1 mcg/kg/min. Once the O2 saturation improves, the dosage of PGE1 is gradually reduced to 0.02–0.025 mcg/kg/min to minimize the side effects of the prostaglandins. Following stabilization and diagnostic studies, as necessary to confirm the diagnosis, a more permanent way of providing pulmonary blood flow should be instituted. A number of methods to augment pulmonary blood flow have been used over the years [49, 50]. These include subclavian artery to ipsilateral PA anastomosis (classic Blalock-Taussig shunt), descending aorta to the left PA anastomosis (Potts shunt), ascending aorta to the right PA anastomosis (Waterston-Cooley shunt), SVC to right PA anastomosis, end-to-end (classic Glenn shunt), enlargement of the ventricular septal defect (VSD), formalin infiltration of the wall of the ductus arteriosus, central aortopulmonary fenestration or expanded polytetrafluoroethylene (Gore-Tex; W. L. Gore and Associates, Inc., Newark, Delaware) shunt, Gore-Tex interposition graft between the subclavian artery and the ipsilateral PA (modified Blalock-Taussig shunt), balloon pulmonary valvuloplasty, and stent implantation into the ductus arteriosus. Currently modified Blalock-Taussig (BT) shunt [51] by insertion of a Gore-Tex graft between the subclavian artery to the ipsilateral PA (Figure 1a) is performed by most surgeons to address pulmonary oligemia. More recently connecting the RV outflow tract with the PA via non-valve Gore-Tex graft is being used at several institutions to palliate pulmonary oligemia. Placement of a stent in the ductus arteriosus [52, 53, 54] and balloon pulmonary valvuloplasty (if the predominant obstruction is at the pulmonary valve level) [55, 56, 57] are other available options to augment the pulmonary blood flow.
Stage I Fontan. Selected frames form cineangiograms in two different babies; the first with pulmonary oligemia who received Blalock-Taussig (BT) shunt (a) and the second with pulmonary plethora who had pulmonary artery banding (PB) (b). C, catheter; LPA, left pulmonary artery; RPA, right pulmonary artery (Reproduced from [30]).
In babies with increased pulmonary blood flow, optimal anti-congestive measures should be started immediately. Once the congestive heart failure (CHF) is adequately addressed, PA banding (Figure 1b) is performed [58] irrespective of control of CHF.
Infants with near normal pulmonary blood flow with O2 saturations in the low 80s do not need intervention and are clinically followed until Stage II.
Neonates with hypoplastic left heart syndrome usually have Norwood palliation (Figure 2) [37, 59] in the neonatal period; in this operation, the following procedures are performed: (1) the main pulmonary artery and the aorta are anastomosed together; additional prosthetic material is used as needed; (2) the pulmonary circulation receives blood supply by connecting the aorta to the PA via a modified BT shunt [51] (Figure 2b); (3) atrial septum is excised to allow unhindered blood flow from the left to the atrium; and (4) ductal tissue is removed, and coarctation of the aorta, if present is repaired. Some surgeons use alternative Sano shunt [60], connecting the RV outflow tract to the PA (Figure 2c) instead of BT shunt.
Stage I Fontan for hypoplastic left heart syndrome. Selected frames from cineangiograms demonstrating Norwood operation in which the neoaorta (NAo) and hypoplastic aorta (HAo) perfuse the coronary arteries (CAs) as shown in (a), Blalock-Taussig (BT) shunt as illustrated in (b) and Sano shunt as depicted in (c). (b) and (c) are from two different babies. LPA, left pulmonary artery; RPA, right pulmonary artery (Reproduced from [30]).
In patients with inter-atrial obstruction, it should be relieved either by transcatheter methodology or by surgery as deemed appropriate for a given clinical scenario. If there is associated coarctation of the aorta, it should also be relieved. Some patients with double-inlet left ventricle may have significant obstruction at the level of bulboventricular foramen [61]. Similarly some babies with tricuspid atresia with transposition of the great arteries may have obstruction at the VSD level, causing obstruction to systemic blood flow [61, 62]. Such babies require Damus-Kaye-Stansel (connection of the aorta to the PA) [63] along with a BT shunt. Inter-atrial obstruction may be present frequently in babies with mitral atresia and single ventricle [64]. In such babies, predictable fall in PVR occurs following balloon or surgical relief of inter-atrial obstruction [64]; consequently, PA banding should be undertaken without hesitation at the time of relieving the atrial septal obstruction, so as to reduce the probability for CHF, lower the PVR and PA pressure, prevent pulmonary vascular obstructive disease (PVOD), and pave the way for Fontan approach [64].
Irrespective of the type of palliative surgery in the neonatal period, bidirectional Glenn procedure [12, 13, 14, 17, 23], namely, anastomosis of the SVC to the right PA, end-to-side (Figure 3) is performed around the age of 6 months. The previously performed BT or Sano shunt is ligated at the same time. Although performing the procedure at 6 months is generally adopted, it can be performed as early as 3 months provided normalcy of PA pressure and anatomy can be documented.
Stage II of Fontan. Selected frames from cineangiograms in two different children illustrating bidirectional Glenn operation in which the superior vena cava is anastomosed to the right pulmonary artery (RPA). Unobstructed flow from the SVC to the right (RPA) and left (LPA) pulmonary arteries is clearly seen. (Reproduced from [30]).
In patients with persistent left SVC, bilateral bidirectional Glenn (Figure 4) is undertaken especially in patients with a small or absent left innominate vein. A bidirectional Glenn procedure may also be performed for patients with infrahepatic interruption of the IVC with azygos or hemiazygos continuation, and such a procedure is called a Kawashima procedure by some authorities.
Stage II Fontan. Selected frames from cineangiograms in a different child than shown in Figure 3, illustrating bilateral bidirectional Glenn operation. (a) Superior vena caval angiogram demonstrates immediate visualization of the right pulmonary artery (RPA). Un-opacified blood flow from persistent left SVC (PLSVC) is indicated by the arrow in (a). (b) PLSVC angiogram illustrates rapid opacification of the left pulmonary artery (LPA). Un-opacified blood from the right SVC is shown by the arrow in (b). Flow from the respective SVCs into the pulmonary arteries is clearly seen (Reproduced from [30]).
Prior to the bidirectional Glenn procedure, normal PA pressures and adequate size of the branch PAs should be ensured by cardiac catheterization and cineangiography. Echo-Doppler or other imaging studies (magnetic resonance imaging [MRI] or computed tomography [CT]) is advocated at some institutions.
If PA stenosis is present, it may be addressed with balloon angioplasty or stent implantation, as deemed appropriate, or it may be addressed during the bidirectional Glenn procedure. Atrioventricular valve regurgitation, aortic coarctation, subaortic obstruction, and other abnormalities should also be repaired/addressed at the time of this operation.
During the final Stage III, the IVC flow is diverted into the PA along with creation of a fenestration. We arbitrarily divided [30] these procedures into Stage IIIA (diversion of IVC into the PA) and Stage IIIB (closure of the fenestration).
In the final Stage III, the total cavopulmonary connection is achieved by diverting the IVC flow into the PA either by a lateral tunnel [18, 65] or by an extra-cardiac, non-valved conduit (Figures 5 and 6) [21, 22]; the procedure is usually performed between the ages of 1 and 2 years, usually 1 year following the bidirectional Glenn procedure. Most surgeons seem to prefer extra-cardiac conduit to accomplish this final stage of Fontan. The majority of surgeons construct a fenestration, 4–6 mm in size, between the conduit and the atria (Figures 5 and 6) [27]. While the creation of fenestration during the Fontan operation was initially proposed for high-risk patients [27, 28], most surgeons now seem to prefer fenestration, since fenestration during the Fontan improves mortality rate and reduces morbidity during the immediate postoperative period [30].
Selected cine frames in posteroanterior (a) and lateral (b) views, demonstrating Stage IIIA Fontan procedure diverting the inferior vena caval flow into the pulmonary arteries via a non-valve conduit (Cond). Flow across the fenestration (fen) is shown by arrows in (a) and (b). HV, hepatic veins; LPA, left pulmonary artery; PG, pigtail catheter in the descending aorta; RPA, right pulmonary artery.
Selected cine frames in posteroanterior (a) and lateral (b) views in a different patient to the one shown in Figure 5, demonstrating Stage IIIA Fontan procedure diverting the inferior vena caval (IVC) flow into the pulmonary arteries via a non-valve conduit (Cond). Flow across the fenestration (fen) is shown by arrows in (a) and (b). Abbreviations are the same as those in Figure 5.
Cardiac catheterization and selective cineangiography are usually performed shortly prior to Fontan conversion in order to assess the PA anatomy and pressures, trans-pulmonary gradient, PVR, and ventricular end-diastolic pressure and to assure that they are normal prior to proceeding with Fontan completion. At some institutions, MRI is used for this assessment instead of catheterization and angiography; however, the author’s preference is catheterization. During this catheterization, any significant collateral vessels that are present are also transcatheter-occluded by most cardiologists.
In the final stage, Stage IIIB, the fenestration is closed (Figures 7b, 8b, and 9B and C) by transcatheter methodology [27, 30, 31, 32, 33, 34, 35], usually 6–12 months after Fontan Stage, IIIA. In the past, most devices used to occlude ASDs [32, 33, 34, 35] were employed for this purpose, but at the present time, Amplatzer septal occluders are the most commonly used devices to accomplish such closures. If there are any other residual shunts, they should also be occluded (Figure 10) by device closure.
Stage IIIB. (a) Selected frames from cineangiograms in anteroposterior projection illustrating Stage IIIA of the Fontan operation in which the inferior vena caval (IVC) flow is diverted into the pulmonary arteries by a non-valve conduit (Cond). The fenestration (fen) is shown by the arrow in (a). (b) Closure of the fenestration with an Amplatzer septal occluder device (D) is shown with an arrow in (b). HV, hepatic veins; LPA, left pulmonary artery; RPA, right pulmonary artery (Reproduced from [30]).
Stage IIIB. (a) Selected frames from cineangiograms in lateral view of the same patient illustrated in Figure 5 showing Stage IIIA of the Fontan operation in which the inferior vena caval (IVC) flow is diverted into the pulmonary arteries by a non-valve conduit (Cond). The fenestration (fen) is shown by the arrow in (a). (b) Closure of the fenestration with an Amplatzer septal occluder device (D) is shown with an arrow in (b). (Stage IIIB). Reproduced from [30].
(A) Selected cine frame from a Fontan conduit cineangiogram in anteroposterior view, demonstrating tubular fenestration (Tu fen) with opacification of the left atrium (LA). (B) The Tu fen is closed with an Amplatzer vascular plug (AVP). (C) A follow-up conduit cineangiogram after AVP implantation, showing complete occlusion of the Tu fen. TEE, transesophageal probe.
(A) A selected cineangiographic frame showing the Fontan conduit in lateral view, demonstrating a residual shunt (RS) at the superior aspect of the conduit (Cond). (B) The RS was occluded with an Amplatzer septal occluder device (AD); the residual shunt is no longer seen. TEE, transesophageal echo probe.
In children who have one functioning ventricle requiring Fontan correction, the systemic and pulmonary circulations work in-parallel in place of the usual in-series circulation. A fragile equilibrium between the two circulations must be preserved so that adequate systemic and pulmonary perfusions are maintained. There is substantial interstage mortality ranging from 5 to 15% [66, 67, 68] which may be due to restrictive atrial communication, obstruction of the aortic arch, blockage of the shunt, distortion of the PAs, atrioventricular valve insufficiency, or a combination thereof [66]. Intercurrent illnesses such as dehydration, respiratory tract illness, or fever disturb this balance and make the patients to become critically ill and have been blamed for interstage mortality [66, 68]. The surgically created BT and Sano shunts may also get thrombosed producing severe hypoxemia [69]. Indeed, these abnormalities produce significant interstage mortality [67]; these appear to occur more frequently between Stages I and II than between Stages II and III. Consequently, extreme vigilance in managing these patients should be maintained by the caregiver [68, 70]; even trivial illnesses must be aggressively monitored and addressed as appropriate.
Immediate and follow-up results of both older and current types of Fontan will be reviewed in this section.
The results of original Fontan [1, 2] and its earlier modifications, namely, RA-to-PA or RA-to-RV anastomosis either directly or via valved or non-valved conduits, revealed high initial mortality rates. The initial mortality rates ranged from 10 to 26% [9, 10, 71, 72]. Furthermore, the postoperative stay in the intensive care setting was prolonged.
The initial mortality following staged, total cavopulmonary connection has decreased remarkably [73, 74, 75, 76, 77, 78]. Patients who had total cavopulmonary connection without fenestration had initial mortality rates ranging from 8 to 10.5% [73, 74, 75], while subjects who had total cavopulmonary connection with fenestration had slightly lower (4.5–7.5%) initial mortality rates [76, 77, 78].
In one large single institutional study examining the results of 500 consecutive Fontan surgery patients [77], early failure was associated with high (≥19 mm Hg) mean PA pressure, young age at surgery, heterotaxy syndrome, a right-sided tricuspid valve as systemic atrioventricular valve, distorted pulmonary arteries, an atriopulmonary connection, no Fontan fenestration, and longer cardiopulmonary bypass time.
These investigators also observed that a significant improvement in morbidity and mortality from early (first quartile—early failures: 27.1%) to the more recent time (last quartile—early failures: 7.5%) occurred [77]. This progress appears to be related to increasing surgical and intensive care experience as well as to more recently introduced Fontan modifications.
Long-term follow-up results were also poor with older types of Fontan [9, 10]. The late mortality rates varied from 1 to 11%, and when early and late mortality rates were combined, they varied between 11 and 25%. The need for reoperations was present in 1–11% of patients. Factors adversely influencing late mortality and reoperation rates are earlier calendar year of operation, age of patient at the time of surgery, type of prior palliative procedures, hypoplasia, distortion or obstruction of PAs, subaortic obstruction, significant mitral valve insufficiency, elevated PA pressure or resistance, decreased left ventricular function, increased left ventricular muscle mass, asplenia syndrome, and others [9, 10].
Following the introduction of staged cavopulmonary anastomosis (both lateral tunnel and extra-cardiac conduit diversion of IVC blood to the PA), the long-term outcomes have improved. In one study in which results of follow-up for 10.2 ± 0.6 years of 196 patients were examined, the estimated Kaplan-Meier survival was 93 and 91% at 5 and 10 years, respectively [79]. An equally impressive finding was freedom from supraventricular arrhythmias in 96 and 91% of patients at 5 and 10 years following surgery. In a different study, the actuarial survival 15 years following surgery was 85% [80]. But, late re-interventions were necessary in 12.7% of patients. When lateral tunnel and extra-cardiac conduit types of Fontan were compared, the outcomes were found to be similar for both groups [81, 82].
Using fenestration during Fontan appears to improve early mortality and morbidity, particularly demonstrated in high-risk patents [83]. A more recent analysis in a smaller group of patients did not demonstrate significant advantage of fenestrated Fontan over the non-fenestrated [84]. However, the general consensus is that using fenestration during Fontan decreases mortality and morbidity during the postoperative period [30, 76, 77, 78].
Periodic follow-up following Fontan is generally recommended. These patients are evaluated at 1, 6, and 12 months after Stage IIIB (device closure of fenestration) and yearly thereafter. During the follow-up, platelet-inhibiting doses of aspirin 2–5 mg/kg/day in children or clopidogrel 75 mg/day in adults to prevent thrombus formation and angiotensin-converting enzyme inhibitors for afterload reduction are generally prescribed. Electrocardiograms and echocardiograms are generally performed during evaluation of these patients with additional imaging studies, as indicated. Any abnormalities, as and when detected, are addressed.
During follow-up, a number of complications were reported, and these include arrhythmias, obstructed Fontan pathways, cyanosis, paradoxical emboli, thrombi, development of collateral vessels, and protein loosing enteropathy [30, 31, 85]. These complications appear to be more frequent with older types of Fontan than with the currently used staged, total cavopulmonary connection with extra-cardiac conduit and fenestration. When such complications develop, they should be promptly investigated and treated. In the ensuing paragraphs, a brief review of some of these complications will be presented.
Arrhythmias were more frequently seen in patients with old Fontan (atriopulmonary connection) than with staged TCPC. The observed arrhythmias were typically atrial arrhythmias, namely, atrial flutter/fibrillation and supraventricular tachycardia. Initially, anti-arrhythmic medications are used to control the rhythm disturbance. This should be followed by hemodynamic and angiographic assessment to identify obstructive lesions in the Fontan pathways. The obstructive lesions should be treated with balloon angioplasty, stent, or surgery, as applicable. Continued rhythm abnormality calls for radiofrequency ablation. Although the success rate of radiofrequency ablation is high in 80% range [86], rates of recurrence range from 30 to 40%. In subjects who have resistant arrhythmias, reducing the atrial mass, switch to TCPC with concomitant Maize procedure is advisable [87]. A few patients develop atrioventricular block or sick sinus syndrome which may require pacemaker implantation. Fortunately, ventricular arrhythmias are less frequent.
Obstructions in Fontan circulation may occur. Obstructive lesions in the SVC or IVC may arise but are less frequently seen. However, branch pulmonary artery stenoses may be seen more often. Obstructions within the lateral tunnel or extra-cardiac conduit are also uncommon, but may occur due to thrombus formation and will be addressed in the section on “Thrombus formation.” In the presence of signs and symptoms indicative of obstruction in the Fontan pathway, prompt investigation to confirm such obstruction should be made. While echo studies are useful in young children, poor echo windows in adolescents and adults may require MRI and CT, and/or angiographic studies to confirm or exclude such obstructive lesions. If the obstructive lesions are detected, they should be promptly relieved by balloon angioplasty or stent implantation (Figure 11) [88]. Surgery may be needed in rare occasions.
Selected frames from cineangiograms of the pulmonary artery in posteroanterior view illustrating normal right pulmonary artery (RPA) and narrowed (arrow) left pulmonary artery (LPA) prior to (a) and after (b) stent (arrow) placement in an adolescent who had Fontan surgery several years earlier (Reproduced from [88]).
Sometimes connections between lateral tunnel and extra-cardiac conduit on the one hand and the atrium on the other persist. These residual defects and intentionally created Fontan fenestrations result in right-to-left shunt because the pressure in the Fontan conduit is higher than that of the atrial pressures. These residual defects will result in arterial desaturation and may become the site of paradoxical embolism with consequential transient ischemic attacks (TIAs), cerebrovascular accidents (CVAs), and systemic emboli. These residual defects as well as Fontan fenestrations should be occluded by transcatheter techniques to return O2 saturations to normal and decrease the likelihood for paradoxical embolism [30, 32, 33, 83, 88, 89]. Amplatzer septal occluder (St. Jude Medical, Inc., St Paul, MN) is currently most common device used to accomplish this (Figures 7,8, and 10). Tubular fenestrations may be closed with Amplatzer vascular plug devices (St. Jude Medical, Inc.) (Figure 9). Test occlusion of the residual defect or fenestration is suggested to ensure that adequate cardiac output is maintained following defect occlusion [89, 90], especially if the procedure is performed shortly after fenestrated Fontan. Late follow-up results of fenestration closure are good [33].
There is a tendency for thrombus formation in the Fontan pathway; the reported prevalence was 15–30% [91, 92]. Regrettably the usual transthoracic echo-Doppler evaluation may not discover these thrombi. However, transesophageal echocardiography, MRI, or CT studies may be necessary to detect these thrombi. In an attempt to prevent thrombus formation in the Fontan circuit, thromboprophylaxis is commonly recommended; both warfarin and aspirin have been utilized in the past for this purpose. A multicenter, randomized trial was conducted to compare the efficacy of these two drugs; results showed less than optimal results with both drugs and no significant difference between the two regimens [93]. In the author’s experience, most children are prescribed with aspirin for thromboprophylaxis which may be switched to clopidogrel (Plavix) as the children approach adulthood.
Despite seemingly adequate thromboprophylaxis, some patients develop thrombosis of the Fontan conduits (Figure 12A). We initially employ thrombus dissolving drug therapy (tPA, heparin, etc.). If the thrombi do not resolve, we have employed stenting of the conduit to compress the thrombi against the conduit wall [94]. An example from our experience is shown in Figure 12.
(A) Selected frame from a cineangiogram of a Fontan conduit in lateral view, illustrating a thrombus (arrow in (A)). (B) and (C) position of a stent (St) before (B) and after (C) its complete expansion. (D) Cineangiographic frame demonstrating the widely patent stent after stent deployment. Also, note the residual shunt (RS) at the superior aspect of the conduit (seen in (A) and (D)). The RS was occluded with an Amplatzer septal occluder device (AD) shortly after the cine shown in (D). (F) A follow-up cineangiogram 1 year later shows the continued patency of the conduit with no RS. TEE, transesophageal echo probe (Reproduced from [94]).
Systemic venous to pulmonary venous and systemic arterial to pulmonary arterial collateral vessels may develop in some patients after the Fontan procedure [88, 95]. These may develop both shortly after the procedure and during late follow-up. Systemic venous to pulmonary venous collateral vessels produce arterial hypoxemia. In addition, they may also become potential sites for paradoxical embolism. Systemic arterial to pulmonary arterial (or venous) collateral vessels produce left ventricular volume overload. These abnormal vessels should be transcatheter-occluded with coils, vascular plugs, and ductal occluding devices depending upon the size and accessibility. Examples from the author’s experience of occluding these vessels are shown in Figures 13–16 [88, 95, 96].
(a) Selected frame from a left innominate vein (L inn) cineangiogram in posteroanterior view demonstrating an anomalous vein (AV) opacifying the atrial mass (not marked). (b) Following occlusion with Gianturco coil (arrow), the AV is completely occluded and the systemic arterial saturation improved (Reproduced from [88]).
(A) Selected frame from a cineangiogram in lateral view with the catheter positioned at the superior vena cava/azygos junction illustrating a fistula which results in opacification of the left atrium (LA). (B) The fistula was occluded with an Amplatzer vascular plug (arrow—AVP) with some residual flow. (C) Follow-up SVC injection shows complete occlusion by the AVP (Reproduced from [96]).
(A) Selected cine frame from an internal mammary artery (IMA) cineangiogram in the lateral view, demonstrating multiple small collateral vessels arising from the pericardiophrenic (PCP) branch, which resulted in a significant levophase (not shown). (B) Following occlusion with a Gianturco coil (C), there is complete occlusion of this vessel (Reproduced from [95]).
(A) Selected cine frame from a right subclavian artery (RSA) cineangiogram showing branches (white arrows) of the thyrocervical (TC) trunk which supplied a number of small vessels, giving a good degree of levophase. (B) Complete occlusion occurred following the implantation of a Gianturco coil (C) (Reproduced from [95]).
Protein losing enteropathy (PLE) is a grave long-term complication of Fontan with a prevalence of 11.1% in older types of Fontan [85, 97]. However, the incidence appears to have come down to 1.2% with staged TCPC [85, 98]. The reason for development of PLE is not understood. Intestinal protein loss secondary to lymphatic distension which in turn may be due to elevated pressure in systemic veins is considered to be a pathogenic mechanism. But, PLE has been seen even in patients with “normal” Fontan circuit pressures. Therefore, the true cause of PLE remains a mystery. The symptoms and signs of PLE are diarrhea, edema, ascites, and/or pleural effusions. Laboratory abnormalities include reduced serum albumin and elevated fecal alpha-1 antitrypsin levels. The PLE diagnosis may be confirmed with technetium 99m-labeled human serum albumin scintigraphy [99].
Because of high mortality rate seen with PLE, speedy diagnosis and implementing aggressive management strategies are important [85]. At first, supportive therapy such as medium-chain triglycerides diet, infusion of intravenous albumin, and replacement of immunoglobulins should be undertaken. Obstructive lesions in the Fontan pathway should be scrutinized, and aortopulmonary connections should be screened for. If identified, they should be treated with appropriate transcatheter measures. Surgical therapy is indicated if they cannot be adequately addressed with transcatheter intervention. A variety of other treatment regimens, including prednisone, elementary diet, calcium replacement, regular high-molecular-weight heparin, low-molecular-weight heparin, somatostatin, high-dose spironolactone, sildenafil, and resection of localized intestinal lymphangiectasia, have been utilized in the past with varying degrees of success [85].
Following a short trial of any of the above treatment modes, largely on the basis of the cardiologist’s preference, a more definitive treatment methods such as lessening the conduit pressure by creating a fenestration between the conduit and the atrium [99, 100, 101], converting atriopulmonary type of Fontan to TCPC [87, 102, 103], instituting sequential atrioventricular pacing [104, 105], and performing cardiac transplantation [106, 107, 108] should all be considered. Again, it is essential to emphasize that timely treatment should be instituted as soon as PLE is identified [85]. Fortunately, the need for use of these methods has progressively diminished since the wide use of staged TCPC.
Since the initial description of the Fontan operation in the early 1970s by Fontan, Kruetzer, and their associates, several modifications have been introduced. These include avoiding classic Glenn anastomosis; not using a prosthetic valve in the IVC; RA-PA anastomosis, direct or through a non-valved conduit; RA-PA anastomosis through a valved conduit; RA-RV anastomosis, direct or non-valved anastomosis; RA-RV anastomosis through a valved conduit; bidirectional Glenn procedure (cavopulmonary anastomosis); lateral tunnel; total cavopulmonary connection; extra-cardiac conduit, staged Fontan; fenestrated Fontan; and closure of Fontan fenestration. Currently staged, total cavopulmonary connection with extra-cardiac conduit and fenestration has become the most commonly used multistage surgery in accomplishing the Fontan.
The indications for Fontan are patients who have one functioning ventricle, and these include tricuspid atresia, double-inlet left ventricle, HLHS, mitral atresia with normal aortic root, unbalanced AVSDs, pulmonary atresia with intact ventricular septum with markedly hypoplastic right ventricle, and other complex heart defects with one functioning ventricle. Recently there has been a trend for biventricular repair, particularly for patients with unbalanced AVSDs.
Stage I consists of performing palliative procedures on the basis of pathophysiology of the defect complex at presentation, usually in the neonatal period. Stage II involves performing a bidirectional Glenn procedure (diversion of the superior vena caval blood flow into both lungs) usually at about the age of 6 months. During stage IIIA diversion of the IVC blood flow into the lungs, usually by an extra-cardiac conduit plus a fenestration, usually at about the age of 2 years. Stage IIIB consists of transcatheter closure of the fenestration 6–12 months after Stage IIIA.
Both the immediate and follow-up results have remarkably improved, both in terms of mortality and morbidity, following the introduction of staged total cavopulmonary connection with extra-cardiac conduit and fenestration with subsequent catheter closure of Fontan fenestration. Complications do occur during follow-up, and they should be addressed as and when they are detected.
The author declares no conflict of interest.
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